Effects of atorvastatin versus probucol on low-density lipoprotein subtype distribution and renal function in hyperlipidemic patients with nondiabetic nephropathy

Objectives: Small dense low-density lipoprotein (LDL) plays an important role in glomerular injury through conversion to an oxidatively modified form of LDL. However, few studies have evaluated the effects of antilipidemic agents on the LDL particle size and renal function in hyperlipidemic patients with nondiabetic nephropathy. Methods: This study was a randomized crossover trial comparing the effects of atorvastatin (10 mg/day) and probucol (500 mg/day) administered for 24 weeks in 31 patients (urinary albumin excretion 0.3–2.0 g/day and creatinine clearance >30 mL/min/1.73 m). Lipid parameters, mean LDL particle diameter, creatinine clearance, and urinary albumin to creatinine excretion ratio were measured before and during treatment periods. Main findings: Atorvastatin and probucol significantly reduced the serum total cholesterol and LDL cholesterol concentrations. When stratified by mean baseline LDL particle size at 25.5 nm, atorvastatin increased (p < 0.05) LDL particle size from 24.6 ± 0.5 to 25.2 ± 0.9 nm only in the <25.5 nm (pattern B) group, whereas probucol decreased (p < 0.05) LDL size from 24.8 ± 0.9 to 24.2 ± 0.9 nm in the pattern B group and from 25.9 ± 0.5 to 24.6 ± 0.8 nm in the ≥25.5 nm (pattern A) group. No significant differences in urinary albumin/creatinine excretion ratio and creatinine clearance were observed in both groups during treatment. Conclusions: Only atorvastatin improved the LDL-subtype distribution in hyperlipidemic patients with nondiabetic nephropathy, although both agents exhibited no renoprotective action, suggesting that the effects on LDL-subtype distribution do not directly lead to renoprotection.     

The Effects of Spironolactone on Nephron Function in Patients with Diabetic Nephropathy

Increasing evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular diseases. We sought to evaluate the effects of a three-month treatment with 25 mg spironolactone, an aldosterone receptor antagonist, on nephron function in 20 type II diabetic patients with persistent microalbuminuria, despite at least six months' use of an ACEi or ARB (combination group), and in eleven type II diabetic patients with persistent microalbuminuria who have never used an ACEi or an ARB (spironolactone group). In the combination group, urinary protein excretion (UPE, p = 0.015), urinary albumin excretion (UAE, p = 0.010), and the urinary albumin to creatinine ratio (ACR, p = 0.007) decreased, and serum potassium (sK⁺, p = 0.004) was significantly elevated. ACR (p = 0.016) decreased significantly in the spironolactone group. In 31 patients given spironolactone (all patients group), UPE (p = 0.019), UAE (p = 0.002), and ACR (p = 0.011) decreased, and serum creatinine (sCr, p = 0.025) and sK⁺ (p = 0.002) were significantly elevated. Changes in albuminuria showed a positive correlation with changes in GFR (p = 0.002) and a negative correlation with changes in sCr (p = 0.007), and changes in ACR showed a negative correlation with changes in sCr (p = 0.004) in all patient groups. In our study, we observed that spironolactone, both alone and in combination with ACEi/ARB treatment, was well tolerated, and that it slowed down the progression of diabetic nephropathy with a marked antialbuminuric effect. Our results showed that the antialbuminuric effect developed by the decrease of intraglomerular pressure, particularly in patients with persistent microalbuminuria despite long-term ACEi/ARB treatment; adding aldosterone blockers to treatment was beneficial.     

Microalbuminuria in children with primary and white-coat hypertension

Microalbuminuria serves as an early marker of hypertension-related renal damage in adults. However, data on the prevalence of microalbuminuria in paediatric hypertensive patients in general and in children with white-coat hypertension (WCH) specifically are lacking. The aim of our study was to investigate the prevalence of microalbuminuria in children with primary hypertension (PH) and WCH, respectively. This was a retrospective case review of children with PH and WCH treated at three paediatric nephrology centres. Untreated children with either form of hypertension for whom measurements of urinary albumin excretion (UAE) had been performed were enrolled in the study. The study cohort comprised 52 children (39 boys) with hypertension (26 children with PH, 26 with WCH). Microalbuminuria (>3.2 mg/mmol creatinine) was present in 20% of children with PH and none of the children with WCH (p < 0.01). Children with PH had a higher median UAE than those with WCH (1.27 ± 1.92 vs. 0.66 ± 0.46 mg/mmol creatinine, p < 0.05). Based on these results, we suggest that children with PH have an increased prevalence of microalbuminuria, while children with WCH show no signs of hypertension-related renal damage.     

Effects of Aerobic Exercise on Microalbuminuria and Enzymuria in Type 2 Diabetic Patients

Increased urinary albumin excretion is a strong predictor for the development of overt diabetic nephropathy and overall cardiovascular morbidity and mortality in patients with type 2 diabetes. In a previous study, regular aerobic physical activity in overweight/obese patients with type 2 diabetes mellitus was found to have significant beneficial effects on glycemic control, insulin resistance, cardiovascular risk factors, and oxidative stress. The aim of the present study was to investigate the effects of aerobic exercise in the same cohort of type 2 diabetic patients on urinary albumin excretion, serum levels and urinary excretion of enzymes, tubular damage, and metabolic control markers in type 2 diabetic patients. Changes from baseline to 3 and 6 months of aerobic exercise were assessed for urinary albumin excretion, serum activities, and urinary excretion of N-acetyl-β-D-glucosaminidase (NAGA), plasma cell glycoprotein 1 (PC-1) and aminopeptidase N (APN), as well as their association with insulin resistance, cardiovascular risk factors, and oxidative stress parameters in 30 male type 2 diabetic patients (aged 54.8 ± 7.3 years, with a mean BMI of 30.8 ± 3.0 kg/m²). Microalbuminuria was found in six (20%) diabetic patients at baseline, three of them (10%) after three months, and only one patient (3.33%) at the end of the study period. A significant correlation was found for urinary albumin excretion at baseline both with sulfhydryl-groups and catalase, but not for urinary albumin excretion with MDA and glutathione. The prevalence of microalbuminuria tended to decrease after six months of aerobic exercise in type 2 diabetic patients, independently of any improvement in insulin resistance and oxidative stress parameters. Neither between-group nor within-group changes were found for urinary PC-1, APN, and NAGA activity. Serum NAGA was significantly increased (p < 0.05) over the control level in diabetic patients at baseline, but it decreased to the normal level after six months of exercise. This study has shown that a six-month aerobic exercise, without any change in the medication, tended to decrease microalbuminuria without changing enzymuria. However, further studies are needed not only to confirm those findings, but to elucidate potential mechanisms that would clarify the beneficial effects of exercise.     

Urinary N-Acetyl B Glucosaminidase as an Earlier Marker of Diabetic Nephropathy and Influence of Low-Dose Perindopril/Indapamide Combination

Introduction. Tubulointerstitial injury is both a key feature of diabetic nephropathy and an important predictor of renal dysfunction. N-Acetyl B glucosaminidase (NAG) is derived from proximal tubular cells and is widely used to evaluate tubular renal function. Objective. The objective of this study is whether NAG can be used as an early marker of diabetic nephropathy by comparing the urinary NAG levels between healthy controls and diabetic patients and determining changes in urinary NAG excretion after treatment with low-dose combination perindopril (2 mg)/indapamide (0.625 mg)/o.d. Materials and Methods. A total of 50 patients (29 female) with type II diabetes mellitus applying to our diabetes outpatient clinics for the first time were included in our study (Group 1). Diabetic patients were classified into three subgroups on the basis of their duration of diabetes: Group 1_A (n = 15) ≤3 years, Group 1_B (n = 19) 3 to 5 years, and Group 1_C (n = 16) >5 years. The inclusion criteria were no prior use of antihypertensive agents; blood pressure <130/85 mmHg; urinary albumin excretion <30 mg/day; and absence of renal failure, diabetietes, and hypertensive retinopathy. A total of 30 healthy individuals (16 female) (Group 2) were assessed as the control group. Systolic and diastolic blood pressures, HbA1c, body mass index, 24-h microalbuminuria (MAU), and NAG measurements in urine samples were performed by using colorimetric assay method in an analyzer (Roche Cobas Mira). The assay defined as fragmentation of 3-cresolsulfonphthaleinyl-N-acetyl-β-D-glucosaminide molecule by NAG to 3-cresolsulphonphthalein and N-acetylglucosamine molecules and serum creatinine were measured in all groups. Type II diabetic patients were administered perindopril (2 mg)/indapamide (0.625 mg) combination once daily for 4 months, and urinary NAG levels were measured at the end of treatment. Results. Statistically significant differences were observed between the groups 1 and 2 with respect to the levels of NAG and HbA1c (p < 0.05). In the treatment group, NAG levels decreased significantly (p < 0.05), whereas blood pressure and HbA1c levels did not change significantly (p > 0.05). In diabetic patients, pretreatment NAG were lowest in Group 1_A and highest in Group 1_C, although the difference between the treatment subgroups was not statistically significant (p > 0.05). Conclusion. Urinary NAG excretion is elevated in type II diabetic patients as compared with the healthy individuals. Perindopril/indapamide administration is effective in reducing urinary NAG excretion in these patients, and this effect seems to be independent from blood pressure and glycemia control. Presence of tubular proteinuria may be an early indicator of diabetic renal disease in patients without microalbuminuria. Perindopril (2 mg)/indapamide (0.625 mg)/o.d. treatment may have beneficial effect on the tubulointerstitial damage in diabetic kidney disease.     

Effect of enalapril on proteinuria, phosphaturia, and calciuria in insulin-dependent diabetes

Elevated urinary calcium and phosphate excretion have been observed in children with insulin-dependent diabetes mellitus (IDDM). This may be related to a defect in tubular reabsorption. It is well known that converting enzyme inhibition decreases microalbuminuria and may prevent or retard diabetic nephropathy. We investigated whether enalapril also improves the defect in calcium and phosphate reabsorption. We studied 16 children and young adults (age 12–21 years) with IDDM and persistent microalbuminuria before and during 12 weeks of enalapril treatment. Before treatment microalbuminuria, urinary calcium excretion, and fractional tubular phosphorus reabsorption (TPR) were 153±53 μg/min, 5.5±0.9 mg/kg per day, and 71.4±3.6%, respectively. At the end of the 12th week, microalbuminuria had decreased to 20.3±7.9 μg/min and calcium excretion to 3.3±0.4 mg/kg per day (P<0.01), while the TPR increased to 80.1±3.8% (NS). The renal threshold phosphate concentration increased from 1.8±0.15 to 2.92±0.23 mg/dl (P<0.01). The fasting serum glucose and hemoglobin A_lc levels did not change significantly during the study. Systolic and diastolic blood pressures were 120.4±2.2/79.3±1.4 mm Hg and 110.5±1.8/ 71.3±0.9 mm Hg before and after 12 weeks, respectively. We conclude that enalapril treatment improves not only microalbuminuria but also abnormal calcium and phosphate excretion in microalbuminuric children with IDDM. Received February 10, 1997; received in revised form December 29, 1997; accepted January 2, 1998     

The Course of Hypercalciuria and Related Markers of Bone Metabolism Parameters Associated with Corticosteroid Treatment

Background and objective: Prolonged corticosteroid (CS) use induces osteoporosis; the pathogenesis of this condition is multifactorial and includes CS-induced hypercalciuria. We investigated the course of hypercalciuria and related markers of bone metabolism parameters during and after the CS treatment. Materials and Methods: We recruited 42 patients who were taking at least 10 mg/day of methylprednisolone or an equivalent dose of CSs for at least 30 days. The 24-h urinary calcium and sodium, a spot urinary calcium/creatinine ratio, and urinary deoxypyridinoline were measured prior to the treatment, at day 7, at days 30–60, and after the cessation of the treatment. Additionally, the serum levels of phosphorus, calcium, alkaline phosphatase (ALP), albumin, creatinine, osteocalcin, and parathyroid hormone (PTH) were analyzed. Results: The 24-h urinary calcium excretion was significantly increased at day 7 (182.2 ± 158.6 mg/day; p < 0.001) and at days 30–60 (196.9 ± 167.8 mg/day; p < 0.001) compared with baseline (98.7 ± 88.1 mg/day) and returned to basal level after the cessation of the CSs (118.9 ± 90.2 mg/day; p = 0.725). The urinary deoxypyridinoline level was significantly higher at days 30–60 compared with basal level. The serum osteocalcin level was decreased at days 30–60 when compared with day 7. No significant changes were detected in the PTH, phosphorus, creatinine, and ALP levels. Conclusions: CS treatment induces hypercalciuria just after starting the treatment until the end of it. CS-induced hypercalciuria promptly improved after cessation of the treatment. By days 30–60, the excretion of urinary deoxypyridinoline was accompanied by hypercalciuria. The serum osteocalcin level was decreased at days 30–60 when compared with day 7.     

Treatment of diabetic nephropathy with angiotensin II receptor antagonist

Type 2 diabetes is an ever-growing problem worldwide. Approximately 40% of the patients with type 2 diabetes will develop diabetic kidney disease. In the United States, diabetes has become the most common single cause of endstage renal disease defined by the need for dialysis or transplantation. Patients with type 2 diabetes and diabetic nephropathy have a dramatically increased cardiovascular risk. The Irbesartan Diabetic Nephropathy Trial was designed to determine whether the use of irbesartan or a calcium channel blocker would provide protection against the progression of nephropathy due to type 2 diabetes beyond that attributable to the lowering of blood pressure. In that study, 1715 hypertensive patients with nephropathy due to type 2 diabetes were randomly assigned to irbesartan 300 mg/day or amlodipine 10 mg/day, or placebo. All patients randomized in this trial had more than 900 mg of protein in their urine and serum creatinines between 1.0 mg/dl and 3.0 mg/dl. The target blood pressure was 135/85 mmHg or less in all groups. The primary outcome was time to a combined endpoint of doubling of their baseline serum creatinine concentration, the development of endstage renal disease, or death from any cause. The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite endpoint that was 20% lower than that in the placebo group (P = 0.02) and 23% lower than that in the amlodipine group (P = 0.006). The risk of doubling of the serum creatinine concentration was 33% lower in the irbesartan group than in the placebo group (P = 0.003) and 37% lower in the irbesartan group than in the amlodipine group (P < 0.001). Treatment with irbesartan was associated with a relative risk of endstage renal disease that was 23% lower than that in both other groups. These differences were not accounted for by differences in the blood pressures that were achieved. Proteinuria was reduced on average by 33% in the irbesartan group as compared with 6% in the amlodipine group and 10% in the placebo group. The angiotensin II receptor blocker irbesartan was shown to be effective in protecting against the progression of nephropathy due to type 2 diabetes. In a study done in patients with type 2 diabetes and early nephropathy as manifested by microalbuminuria, 590 hypertensive patients with type 2 diabetes and microalbuminuria were randomized to receive either irbesartan 150 mg/day or irbesartan 300 mg/day and followed for 2 years. The primary outcome in that trial was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was more than 200 mg/min or at least 30% higher than the baseline level. The irbesartan 150 mg/day group demonstrated a 39% relative risk reduction versus the control group in the development of overt proteinuria. The irbesartan 300 mg/day group demonstrated a highly significant 70% risk reduction versus the control group (P < 0.001). The albumin excretion rate was reduced in the two irbesartan groups throughout the study (−11% and −38% at 24 months compared with baseline in the irbesartan 150-mg and 300-mg groups, respectively). The albumin excretion rate remained unchanged in the control group. Irbesartan was demonstrated in the above study to be renoprotective, independent of its blood pressure-lowering effect, in patients with type 2 diabetes and microalbuminuria. Thus, irbesartan, an angiotensin receptor blocker, was demonstrated to be significantly renoprotective in patients with type 2 diabetes with either early nephropathy (microalbuminuria) or late nephropathy (proteinuria). The renoprotective effects of irbesartan were above and beyond the effects irbesartan had on systemic blood pressure. Patients with type 2 diabetes and either early or late diabetic nephropathy should be treated with the angiotensin II receptor blocker irbesartan. Received: October 18, 2002 / Accepted: December 17, 2002 Correspondence to:E.J. Lewis     

Is Serum Cystatin C an Accurate Endogenous Marker of Glomerular Filteration Rate for Detection of Early Renal Impairment in Patients with Type 2 Diabetes Mellitus?

Background. Researches have recently reported that serum cystatin C is a more sensitive marker of changes in glomerular filtration rate (GFR) than serum creatinine. We conducted this study to evaluate the significance of serum cystatin C as a more sensitive marker of GFR for early detection of renal impairment in special groups of patients with type 2 diabetes mellitus (DM). Methods. The present study included 40 patients with type 2 DM divided into four equal groups based on their urinary albumin excretion and renal function: group 1 was normoalbuminuric, group 2 was microalbuminuric, group 3 was macroalbuminuric, and group 4 was macroalbuminuric with renal dysfunction. All patients underwent a thorough history, full clinical examination, fasting, and renal function tests. Post-prandial blood glucose levels, glycosylated hemoglobin A1c (HbA1c), proteins, albumin in 24 hr urine, and serum cystatin C were collected. Results. Serum cystatin C and creatinine were significantly higher in macrolbuminuric type 2 diabetic patients with renal dysfunction (group 4: 2.26 ± 1.28, 4.21 ± 2.38 mg/dl, respectively; p < 0.001) than macrolbuminuric type 2 diabetic patients with normal renal function (group 3: 1.04 ± 0.24, 0.96 ± 0.20 mg/dl, respectively), the microalbuminuric group (0.87 ± 0.28, 0.71 ± 0.12 mg/dl, respectively), as well as the normoalbuminuric group (0.55 ± 0.41, 0.60 ± 0.18 mg/dl, respectively). ROC plots demonstrated that area under the curve (AUC) of cystatin C (0.74) was greater than that for creatinine clearance (cr.cl) (0.67) and serum creatinine (s‐cr) (0.74); therefore, the sensitivity and diagnostic accuracy of cystatin c was better than cr. cl., and both were better than s-cr. Serum cystatin C showed significant correlation in groups 2–4 with s-cr, cr.cl, and 24 hr urine albumin, but no correlation was found in group 1. Conclusion. Serum cystatin C is a reliable and easily performed marker for GFR to detect renal impairment in patients with type 2 DM.     

Diurnal Rhythm of Urinary Calcium Excretion in Adults

Twenty-four-hour urinary calcium excretion is normally the equivalent of daily calcium intake, and varies between 200–300 mg/dL with a calcium/creatinine ratio of 0.07–0.15. In this study, we aimed to investigate the diurnal rhythm of calcium excretion in healthy individual. Forty subjects (30 male, 10 female) were involved into the study. The spot urine samples were taken at 08:00, 14:00, and 22:00 together with a 24-hour collection. Mean spot urinary calcium levels at 08:00, 14:00, and 22:00 were 12.39 ± 8.19, 12.97 ± 8.37, and 16.95 ± 10.39 mg/dL, with calcium/creatinine ratios of 0.104 ± 5.26l, 0.119 ± 7.85, and 0.133 ± 8.17, respectively. Twenty-four-hour urinary calcium excretion was 12.74 ± 7.31 mg/dL with a calcium/creatinine ratio of 0.111 ± 5.41. The values at 08:00, 14:00, and of 24-hour collection were statistically similar (p > 0.05), but the nighttime values were significantly elevated (p < 0.05). In conclusion, calcium excretion is increased at night, and urinary calcium measurements should be interpreted accordingly.     

Parental hypertension and 24 h-blood pressure in children prior to diabetic nephropathy

In a search for predictors of nephropathy development, albumin excretion rate (AER), ambulatory blood pressure, and parental hypertension were assessed in 40 type 1 diabetic patients and 27 normal siblings (age<18 years) during a 2-year follow-up period. A double-antibody kit and an automated device were used for measuring 24-h AER and ambulatory blood pressure monitoring (ABPM), respectively. Patients had higher 24-h and daytime diastolic blood pressure (DBP), diastolic load, and daytime heart rate than siblings. Patients with hypertensive parents had higher 24-h DBP and diastolic load than patients with normotensive parents and all siblings. Non-dipping was more frequent in children with hypertensive parents (P<0.05). Both diabetes (P<0.001) and parental hypertension (P<0.05) had independent effects on longitudinal AER (average AER during follow-up). Patients with intermittent or persistent microalbuminuria showed a trend towards higher diastolic load (P<0.05); the latter group had higher 24-h DBP (P<0.01). Longitudinal AER correlated with 24-h DBP (P<0.01) and maternal mean blood pressure (P<0.05). Since changes in blood pressure preceded persistent microalbuminuria, ABPM might help to identify diabetic children prone to nephropathy. Received: 18 June 2001 / Revised: 1 October 2001 / Accepted: 4 October 2001     

Urinary N-acetyl-β-D-glucosaminidase activity in rabbits with experimental hypercalciuria

Routinely used renal function tests remain normal in uncomplicated hypercalciuria. The aim of this study was to assess the value of N-acetyl-β-D-glucosaminidase (NAG), a sensitive marker of renal proximal tubular damage, in experimental hypercalciuria. Oral calcium providing 75 mg/kg per day elementary calcium and 20,000 IU/day vitamin D₃ was administered for 15 days to 7 rabbits (Orytolagus cuniculus-New Zealand white) and 7 rabbits were given placebo as a control group. Serum calcium, phosphorus, and alkaline phosphatase, daily urinary calcium excretion and NAG/creatinine ratio were measured before and after drug administration. Kidneys were examined macroscopically and microscopically following the study period. Serum calcium, phosphorus and urinary calcium excretion increased, while alkaline phosphatase decreased significantly in response to drug treatment [10.8±1.5 vs. 12.2±1.3 mg/dl, 4.6±0.6 vs. 6.7±0.7 mg/dl, 22.3±8.3 vs. 46.8±22.5 mg/kg per day, and 138.0±57.1 vs. 70.1±33.1 IU/l, respectively (P <0.05)]. The NAG/creatinine ratio prior to the study (0.5±0.1 mU/mg) was significantly different from that after the study (5.4±1.5 mU/mg, P <0.01). In the control group, changes in serum and urinary parameters were not significant (P >0.05). The relationship between the urinary NAG/creatinine ratio and the daily urinary calcium excretion was statistically significant (r = 0.67, P <0.05). In the study group, nephrocalcinosis was present in all rabbits except 1 (85.7%), whereas none of the control group rabbits had nephrocalcinosis. In conclusion, in rabbits urinary NAG excretion increases significantly in nephrocalcinosis induced by hypercalciuria. Received February 12, 1996; received in revised form November 25, 1996; accepted November 27, 1996     

Effects of the angiotensin II type 1 receptor antagonist candesartan,compared with angiotensin-converting enzyme inhibitors,on the urinary excretion of albumin and type IV collagen in patients with diabetic nephropathy

Background. We previously reported that the angiotensin II type 1 receptor antagonist candesartan was effective in reducing blood pressure and microalbuminuria in hypertensive patients with diabetic nephropathy after angiotensin-converting enzyme (ACE) inhibitors were replaced due to side effects. In the present study, the clinical effects of candesartan were investigated and compared with ACE inhibitors in patients with stage 2 or 3A diabetic nephropathy, mainly with respect to the effects on the urinary excretion of albumin and type IV collagen. Methods. Forty-nine patients (26 males/23 females) with diabetic nephropathy (stage 2 or 3A), including normotensive patients, were the study subjects. The patients were treated with either an ACE inhibitor (23 patients) or candesartan (26 patients) for 11 ± 3 months. The urinary excretion of albumin and urinary type IV collagen was measured. Results. Posttreatment blood pressure tended to decrease, but such a decrease did not reach a statistically significant level, nor did it show any intergroup difference. The urinary albumin excretion was positively correlated with pretreatment mean blood pressure and left ventricular mass index, but the urinary type IV collagen excretion did not show such correlations. The urinary albumin excretion decreased significantly after treatment to a similar extent in both groups, whereas the urinary type IV collagen excretion decreased significantly only in the candesartan group. Conclusion. It was revealed that ACE inhibitors and candesartan reduced urinary albumin excretion to a similar extent in patients with diabetic nephropathy. From the results of the present study, it is inferred that the renoprotective effect of candesartan in diabetic nephropathy may partially differ from that of ACE inhibitors.     

Relationship between urinary albumin excretion and glomerular filtration rate in normotensive, nonproteinuric patients with type 2 diabetes mellitus

BACKGROUND/AIM: In patients with type 2 diabetes mellitus, the relationship between glomerular filtration rate (GFR) and urinary albumin excretion remains an unresolved issue. In order to investigate the early renal function abnormalities, GFR and urinary albumin excretion were assessed, and their relationship was examined in normotensive patients with type 2 diabetes mellitus. METHODS: In a cross-sectional study of 85 nonhypertensive Japanese patients with type 2 diabetes mellitus not showing overt proteinuria, the GFR was measured using (99m)Tc-diethylenetriamine pentaacetate renography. Fifty-one diabetic patients lacked microalbuminuria (albumin excretion <30 mg/day), while 34 patients showed microalbuminuria (between 30 and 300 mg/day). Fifteen healthy subjects served as controls. RESULTS: The three groups were well matched with regard to gender, age, and body mass index. The GFR in microalbuminuric patients (134 +/- 23 ml/min/1.48 m(2)) was significantly higher than in patients without microalbuminuria (108 +/- 21 ml/min/1.48 m(2)) and in controls (109 +/- 18 ml/min/1.48 m(2); p < 0.0001). In type 2 diabetic patients, the GFR positively correlated with the logarithmically transformed urinary albumin excretion. Multiple regression analysis showed that the urinary albumin excretion was significantly and independently affected by GFR (beta = 0.548), duration of diabetes (beta = 0.297), and systolic blood pressure (beta = 0.232; R(2) = 0.409; p < 0.0001). CONCLUSION: It is suggested that one of the mechanisms underlying increased urinary albumin excretion in early nephropathy in normotensive type 2 diabetes is glomerular hyperfiltration.     

Evaluation of lithogenic elements in urine of healthy newborns

The determination of urinary excretion of lithogenic elements in healthy newborns involves factors ranging from urine collection and data handling to maternal influences, which can cause difficulties in analyzing the results. The objective of this study was to determine normal values of parameters related to lithogenesis, such as calcium, uric acid, citrate, and oxalate, in urine of healthy newborns using isolated samples, focusing on variations according to gender, weight, milk ingestion, and family history of lithiasis. Parameters measured in isolated urine samples from 104 healthy newborns (77 males and 27 females) were corrected by creatinine. The ratios were expressed as milligram/milligram of creatinine: calcium/creatinine of 0.10±0.01 (X±SE), uric acid/ creatinine of 1.10±0.10, citrate/creatinine of 0.56±0.04, and oxalate/creatinine of 0.07±0.01. Differences were observed between males and females, in terms of uric acid (0.80±0.07 vs. 1.10±0.10 mg/mg, P<0.05), citrate (0.05±0.06 vs. 0.17±0.05, P<0.05), sodium (0.17± 0.01 vs. 0.05±0.01, P<0.001), and potassium (0.05± 0.01 vs. 0.20±0.02, P<0.001). Interestingly, the urinary concentration of protector factors such citrate and potassium was higher in females than in males with low sodium excretion. Artificial milk feeding leads to higher calcium (0.10±0.06 vs. 0.06±0.01), uric acid (1.40±0.20 vs. 0.90±0.09, P<0.05), citrate (0.90±0.09 vs. 0.50±0.04, P<0.001), and oxalate (0.17±0.03 vs. 0.05±0.01, P<0.001) excretion when compared with breast feeding. There was higher excretion of calcium and sodium in patients under 3 kg. Children with familial antecedents presented some differences in urinary excretion, with higher uric acid (1.50±0.30 vs. 0.80±0.08, P<0.05) but lower calcium (0.05±0.02 vs. 0.10±0.01, P<0.05) and sodium (0.15±0.02 vs. 0.20±0.02, P<0.05) excretion, respectively. This report provides urinary parameters obtained in healthy newborns and correlates them with factors that could be involved in the genesis of osteopenia, renal stones, and/or nephrocalcinosis. Received: 8 May 2000 / Revised: 7 June 2001 / Accepted: 12 June 2001     

Combination therapy of trandolapril and candesartan cilexetil reduces microalbuminuria and urinary endothelin-1 excretion in patients with type 2 diabetes

Background. Angiotensin (AT)-converting enzyme inhibitors (ACEIs) and AT1-receptor blockers (ARBs) are widely used to reduce urinary albumin excretion (UAE) and slow the progression of diabetic nephropathy. The aim of the present study was to determine whether treatment with trandolapril (an ACEI) and candesartan cilexetil (an ARB) in combination has more effect on UAE and urinary endothelin (ET)-1 excretion than treatment with trandolapril or candesartan cilexetil alone in patients with type 2 diabetes. Methods. Sixty normotensive type 2 diabetes patients with microalbuminuria were randomly assigned to four treatment groups: (A) treatreatment with trandolapril at 2 mg/day (n = 15), (B) treatment with candesartan cilexetil at 8 mg/day (n = 15), (C) treatment with trandolapril at 2 mg/day and candesartan cilexetil at 8 mg/day (n = 15), and (D) treatment with placebo (n = 15). The study period was 18 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in the patients before treatment and after 12 and 18 months of treatment. Results. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little between the four groups. Trandolapril and candesartan cilexetil administered alone reduced UAE and urinary ET-1 excretion to a similar extent (12 months; P < 0.05 and 18 months; P < 0.01). When trandolapril and candesartan cilexetil were coadministered, UAE and urinary ET-1 excretion decreased to a significantly greater extent at 12 and 18 months (P < 0.05) than with trandolapril or candesartan cilexetil alone. However, plasma ET-1 and systemic blood pressure levels were not affected. Conclusions. The data suggest that combination therapy with trandolapril and candesartan cilexetil has an additive effect on the reduction of microalbuminuria in microalbuminuric normotensive type 2 diabetes patients. Received: December 19, 2001 / Accepted: June 12, 2002     

Diagnostic Value of the Aminopeptidase N,N-Acetyl-β-D-Glucosaminidase and Dipeptidylpeptidase IV in Evaluating Tubular Dysfunction in Patients with Glomerulopathies

Aim. The aim of the present study was to investigate the value of the urine cell glycoprotein 1 (PC-1), aminopeptidase N (APN), N-acetyl-β-D-glucosaminidase (NAGA), and dipeptidylpeptidase IV (DPP IV) in the evaluation of tubular damage in patients with primary glomerulonephritis, diabetic nephropathy, and lupus nephritis. Subjects and Methods. PC-1, APN, NAGA, and DPP IV activities were determined in serum, urine, and lymphocytes of 178 subjects, including 10 patients with membranous nephropathy, 38 with IgA nephropathy, 29 with lupus nephritis, 51 with diabetic nephropathy, and 50 control subjects. Results. Urinary PC-1 excretion in IgA nephropathy group was significantly higher (p < 0.05) than in controls. Urinary NAGA excretion was markedly (p < 0.01) higher in membranous nephropathy group, and APN excretion in diabetic nephropathy group was significantly higher (p < 0.01) than in healthy controls. Urinary APN activity was significantly (p < 0.01) higher in both type 1 and type 2 diabetic patients with microalbuminuria, as well as urinary NAGA and DPP IV activities in type 2 diabetics with microalbuminuria (p < 0.01 and p < 0.05, respectively) compared to controls. Serum PC-1 and APN activities were significantly higher than the control level in membranous nephropathy group, as well as serum PC-1 and DPP IV activities in IgA nephropathy patients (p < 0.05). However, significantly lower serum DPP IV and APN activity was observed in type 2 diabetics with microalbuminuria compared to controls (p < 0.05). Conclusion. Damage of tubules in primary glomerulonephritis, lupus nephritis, and diabetic nephropathy is accompanied by a release of several tubular enzymes, with possible diagnostic and prognostic significance. Increased serum PC-1, APN, and DPP IV activities could be also of diagnostic significance.     

Inhibitory effect of ibudilast on urinary albumin excretion in type 2 diabetes mellitus with microalbuminuria

To evaluate the clinical effect of ibudilast, a prostacyclin-mediated vasodilator and antiplatelet agent, on diabetic nephropathy, 8 nonhypertensive patients with type 2 diabetes mellitus (DM; 4 men and 4 women, mean age: 58.9 +/- 11.4 years, duration of diabetes: 16.9 +/- 3.2 years) with microalbuminuria [20-200 mg/g creatinine (Cr)] were administered ibudilast (30 mg/day) for 18 months (ibudilast group). The urinary albumin excretion index (UAE, mg albumin/g Cr) was compared with 8 age-matched type 2 DM with microalbuminuria (control group). During the study, the UAE significantly decreased in the ibudilast group, while it significantly increased in the control group. After 18 months, the UAE (52 +/- 19 mg/g Cr) in the ibudilast group was significantly (p < 0.05) lower than that (99 +/- 46 mg/g Cr) in the control group. These results suggest that ibudilast may inhibit the progression of early diabetic nephropathy in type 2 DM.     

Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus

Background. Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained. Methods. We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years. Results. In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5±2.9 and 12.6±2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3±2.3 vs 8.6±1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5±2.1 vs 9.0±2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric. Conclusions. Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.     

Asymmetric Dimethylarginine (ADMA) and Progression of Nephropathy in Patients with Type 2 Diabetes

Diabetic nephropathy is the leading cause of kidney failure all over the world. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. ADMA is in part eliminated via urinary excretion. It is found to be elevated in end stage renal disease. Identification of the plasma concentrations of ADMA in patients with different stages of diabetic nephropathy compared with healthy age-matched control subjects for estimation of the role of ADMA as a marker of progression of kidney disease in diabetic patients. Seventy-five diabetic patients were divided into five groups: Group I: patients with normoalbuminuria (urinary albumin excretion UAE < 30 mg/d), Group II: patients with microalbuminuria (UAE: 30–300 mg/d), Group III: patients with macroalbuminuria (UAE > 300 mg/d), Group IV: patients one month after renal transplantation and Group V: patients on haemodialysis. Patients were compared to 15 healthy control subjects matched for age and sex. All subjects subjected to thorough clinical examination and laboratory investigations including: serum albumin, urea, creatinine, fasting and postprandial blood glucose, UAE, urinary albumin/creatinine ratio and serum ADMA level. All patients groups had significantly higher levels of ADMA when compared to control group P < 0.01. The levels of ADMA were positively correlated with disease progression and degree of proteinuria. ADMA can be used as a marker of progression of kidney disease among diabetic patients.