Blood sugar control reverses the increase in urinary excretion of prostaglandin D synthase in diabetic patients

BACKGROUND/AIMS: We investigated basal levels of serum and urinary lipocalin-type prostaglandin D synthase/beta-trace (L-PGDS) in type-2 diabetic patients and explored whether glycemic control affects L-PGDS status in another 55 diabetic inpatients with normoalbuminuria. METHODS: Fifty-five type-2 diabetic outpatients (HbA1c, 9.14 +/- 0.20%; creatinine (Cr), 85.1 +/- 2.4 micromol/l), and 55 age-matched healthy control subjects were recruited. Serum and urinary levels of L-PGDS were determined with respect to the stage of diabetic nephropathy. The L-PGDS was localized by immunohistochemistry. RESULTS: The urinary L-PGDS index increased in diabetic patients, compared with the controls (234.8 +/- 27.4 vs. 73.8 +/- 7.8 microg/mmol Cr, p < 0.001). Even in normoalbuminuric patients as well as in microalbuminuric patients, urinary L-PGDS indexes were higher than the controls (166.0 +/- 21.1, p < 0.0001 and 338.6 +/- 62.5 microg/mmol Cr, p < 0.0001, respectively), although the serum L-PGDS level was equal to that in the control subjects. Multiple regression analysis revealed that the urinary L-PGDS index was predicted solely by glucose levels and type-IV collagen index, whereas the serum L-PGDS was determined mainly by age and serum Cr. Glycemic control reduced the urinary L-PGDS index towards the normal range in diabetic patients with normoalbuminuria (172.3 +/- 6.6 vs. 118.1 +/- 2.6 (SE) microg/mmol Cr, p < 0.0001). Immunohistochemistry showed that L-PGDS was uniquely present in the renal tubules in diabetes while in nondiabetics, L-PGDS occurred solely in the peritubular interstitium, not in the tubular cells. CONCLUSION: Inadequate glycemic control is responsible for urinary L-PGDS excretion in the diabetic patients. Urinary L-PGDS is useful to predict subclinical renal injury associated with type-2 diabetes.     

Increased serum high-molecular-weight complex of adiponectin in type 2 diabetic patients with impaired renal function

BACKGROUND/AIM: Adiponectin, an adipocyte-derived protein, has been shown to exert antidiabetic, anti-inflammatory, and antiatherosclerotic effects. Although recent reports show an increase in the total adiponectin levels in chronic kidney disease patients and in patients with end-stage renal disease, the nature of biodegradation and renal involvement of adiponectin is largely unknown. We aimed at determining whether the high-molecular-weight (HMW) complex of adiponectin is associated with renal insufficiency in type 2 diabetic patients. METHODS: A total of 179 type 2 diabetic patients were selected from among outpatients and divided into four groups according to their albumin-to-creatinine ratio: patients with normoalbuminuria (n = 86), patients with microalbuminuria (n = 44), patients with macroalbuminuria (n = 23), and patients on hemodialysis (n = 26). The serum HMW adiponectin was specifically assayed with a commercially available enzyme-linked immunosorbent assay kit. RESULTS: The HMW adiponectin levels were higher in patients on hemodialysis (17.1 +/- 8.2 microg/ml) and in those with macroalbuminuria (14.3 +/- 8.7 microg/ml) than in patients with normoalbuminuria (7.2 +/- 5.6 microg/ml) and microalbuminuria (10.8 +/- 7.0 microg/ml). Univariate linear regression analysis showed that the HMW adiponectin concentrations correlated negatively with the estimated glomerular filtration rate in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria (r = -0.42, p < 0.001). Multiple stepwise regression analysis disclosed that estimated glomerular filtration rate, pioglitazone therapy, gender differences, and systolic blood pressure were independently associated with HMW adiponectin levels (r = 0.56). CONCLUSIONS: The serum HMW adiponectin concentrations are higher in type 2 diabetic patients with nephropathy, and these levels are also associated with renal insufficiency.     

Evaluation of tests for microalbuminuria screening in patients with diabetes.

BACKGROUND: The first step in the diagnosis of diabetic nephropathy is to measure albumin in a spot urine sample. The aim of this study was to assess the accuracy of urinary albumin concentration (UAC), urinary albumin-to-creatinine ratio (UACR), and the Micral-Test II in a random urine specimen (RUS) for microalbuminuria screening in diabetes mellitus. METHODS: Two hundred and seventy-eight patients collected 24 h timed urine specimens followed by RUS. Albumin (immunoturbidimetry) and creatinine were measured in protein-negative (Combur-Test) urine samples. Samples were classified as normoalbuminuric [24 h urinary albumin excretion rate (UAER) <20 microg/min; n = 189] and microalbuminuric (UAER =20-199 microg/min; n = 89). Micral-Test II readings were performed in 130 RUS. Receiver operating characteristics (ROC) curves were constructed using UAER as the reference standard. RESULTS: The areas under the ROC curves were similar for UAC (0.934+/-0.032) and UACR (0.920+/-0.035; P = 0.626), but the Micral-Test II had lower accuracy to diagnose microalbuminuria (area = 0.846+/-0.047) than UAC (P = 0.014). The first cutoff point with 100% sensitivity for UAC was 14.4 mg/l (specificity =77.2%), and 15.7 mg/g for UACR (specificity =73.0%). Concerning the Micral-Test II, sensitivity and specificity for the 20 mg/l cutoff point were 90.0 and 46.0%, respectively. The agreement between UAER and the Micral-Test II for microalbuminuria diagnosis was 55.8% (kappa = 0.22; P < 0.001). The cost of diagnosing microalbuminuria was 1.74 dollars(UAC), 2.00 dollars (UACR) and 4.09 dollars (Micral-Test II) per patient. CONCLUSIONS: Measurement of UAC in a RUS was the best choice for the diagnosis screening of microalbuminuria in diabetic patients, considering cost and accuracy.     

Urinary albumin excretion rate and its determinants after 6 years in non-insulin-dependent diabetic patients

BACKGROUND.: The present study was undertaken to clarify the progressionof urinary albumin excretion rate (UAER) in non-insulin-dependentdiabetic (NIDD) patients 6 years after diagnosis, and to elucidatethe risk factors of nephropathy. METHODS.: This is a population-based controlled (base-line) cohort study.The prospective evaluation utilized the diabetic patients asinternal controls. The setting was an urban primary health carecentre. Main outcome measures were the UAER-24 h and fractionalurinary albumin excretion rate (FAC) and their relation to meanblood pressure, haemoglobin A1c, fasting serum insulin and cholesteroland renal size. RESULTS.: UAER (mg/24 h) was increased (geometric mean, quartile 1 and3) in the diabetic patients at baseline, compared to the non-diabeticcontrol subjects; 21(10 and 33) versus 12 (8 and 15), P=0.0001(Wilcoxon's rank test). The UAER-24 h was not increased in diabeticsubjects at follow-up; 24 (7 and 49) P=0.3791 versus diabeticsubjects at baseline. Eighteen per cent of normoalbuminuric(UAER <30 mg/24 h) patients developed microalbuminuria (UAER=30–300mg/24 h) and 3% clinical nephropathy (UAER>300 mg/24 h).Of the microalbuminuric subjects 19% progressed to clinicalnephropathy, 46% remained microalbuminuric and 35% remittedto normoalbuminuria. Serum insulin concentration, after assessmentof confounding factors, measured at the baseline predicted theUAER for all diabetic subjects at follow-up in multiple linearregression analysis in an independent and significant way (P=0.01).Serum insulin concentration (P=0.034) and diuretic therapy (P=0.050)at baseline independently predicted the outcome of the categoricalvariable progressor/nonprogressor (n=22/86) based on the UAER-24h at baseline and at follow-up. CONCLUSIONS.: Progression of the UAER during the first 6 years is found amongapproximately every fifth NIDD subject who develops either microalbuminuria(from normoalbuminuria) or clinical nephropathy (from microalbuminuria).The role of serum insulin (insulin resistance) or some factorassociated with it, is suggestive in the genesis of kidney disease.     

The early natural history of nephropathy in Type 1 Diabetes: III. Predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients

Predictors of albumin excretion rate (AER) abnormalities could provide earlier indicators of diabetic nephropathy risk. Data from the Natural History Study, a prospective 5-year observation of renal structure and function in young type 1 diabetic patients, were examined for predictors of AER patterns in normoalbuminuric type 1 diabetic patients. Included were 170 patients (96 females) (aged 16.7 +/- 5.9 years, duration of diabetes 8.0 +/- 4.3 years) with normal blood pressure, normoalbuminuria (AER <20 microg/min), and eight or more follow-up visits over 5 years. AER, blood pressure, and HbA1c (A1C) were determined quarterly and glomerular filtration rate (GFR) annually. Persistent microalbuminuria (PMA) was defined as 20-200 microg/min in two of three consecutive values within 6-12 months. Four different AER patterns were identified. Group 1 (n = 99): all values <20 microg/min. Group 2 (n = 49): intermittent levels >20 microg/min but not meeting microalbuminuria criteria. Group 3 (n = 14): PMA during follow-up but normoalbuminuria at study exit. Group 4 (n = 8): microalbuminuria at study exit. Group 4 (497 +/- 95 nm, P < 0.01) and group 3 (464 +/- 113 nm, P = 0.03) patients had greater baseline glomerular basement membrane (GBM) width versus group 1 (418 +/- 67 nm). Baseline GFR in group 4 (163 +/- 37 ml.min(-1). 1.73 m(-2)) was higher than group 1 (143 +/- 28 ml.min(-1) . 1.73 m(-2), P = 0.04). A1C was higher in group 2 (9.0 +/- 1.2%) than group 1 (8.4 +/- 1.1%, P = 0.008). Thus, greater increases in GBM width and GFR were predictors of PMA. Since 64% of the patients that developed microalbuminuria reverted to normoalbuminuria, the risk of diabetic nephropathy as defined by current microalbuminuria criteria is unclear.     

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.     

Effects of the C677T and A1298C polymorphisms of the MTHFR gene on the genetic predisposition for diabetic nephropathy.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a regulatory enzyme of homocysteine metabolism. The C677T polymorphism of the MTHFR gene has been reported to be associated with elevated plasma homocysteine in patients with low folic acid intake. A recently reported second common polymorphism, A1298C, may increase homocysteine, but only in individuals carrying the T677 allele. This study aimed to investigate the influence of the C677T and A1298C polymorphisms of the MTHFR gene on the development of diabetic nephropathy in Caucasian patients with type 2 diabetes. METHODS: We genotyped 429 type 2 diabetic patients for the C677T and A1298C polymorphisms using standard PCR-based protocols, and divided them into three groups based on renal status: 159 patients with normoalbuminuria, 149 with microalbuminuria, and 121 with persistent proteinuria and chronic renal failure (CRF). The C677T and A1298C genotype frequencies were compared among the three groups. RESULTS: Although the frequencies of the CT and TT genotypes of the C677T polymorphism tended to increase with each stage of diabetic nephropathy (53, 56 and 63% in normoalbuminuria, microalbuminuria and proteinuria/CRF, respectively), these differences were not significant. When male and female patients were analysed separately, the effect was seen only in males. The CT + TT genotype was present in 46% of male patients with normoalbuminuria, in 57% with microalbuminuria and in 68% with proteinuria/CRF (OR = 2.46; 95% CI 1.13-5.38). There were no differ-ences in the A1298C polymorphism among the three groups. CONCLUSIONS: These findings indicate that the C677T polymorphism is a risk factor for diabetic nephrop-athy in male patients with type 2 diabetes.     

Association between mannose-binding lectin and vascular complications in type 1 diabetes

Complement activation and inflammation have been suggested in the pathogenesis of diabetic vascular lesions. We investigated serum mannose-binding lectin (MBL) levels and polymorphisms in the MBL gene in type 1 diabetic patients with and without diabetic nephropathy and associated macrovascular complications. Polymorphisms in the MBL gene and serum MBL levels were determined in 199 type 1 diabetic patients with overt nephropathy and 192 type 1 diabetic patients with persistent normoalbuminuria matched for age, sex, and duration of diabetes, as well as in 100 healthy control subjects. The frequencies of high- and low-expression MBL genotypes were similar in patients with type 1 diabetic and healthy control subjects. High MBL genotypes were significantly more frequent in diabetic patients with nephropathy than in the normoalbuminuric group, and the risk of having nephropathy given a high MBL genotype assessed by odds ratio (OR) was 1.52 (1.02-2.27, P = 0.04). Median serum MBL concentrations were significantly higher in patients with nephropathy than in patients with normoalbuminuria: 2,306 microg/l (interquartile range [IQR] 753-4,867 microg/l) vs. 1,491 microg/l (577-2,944 microg/l), P = 0.0003. In addition, even when comparing patients with identical genotypes, serum MBL levels were higher in the nephropathy group than in the normoalbuminuric group. Patients with a history of cardiovascular disease had significantly elevated MBL levels independent of nephropathy status (3,178 microg/l [IQR 636-5,231 microg/l] vs. 1,741 microg/l [656-3,149 microg/l], P = 0.02). The differences in MBL levels between patients with and without vascular complications were driven primarily by pronounced differences among carriers of high MBL genotypes (P < 0.0001). Our findings suggest that MBL may be involved in the pathogenesis of micro- and macrovascular complications in type 1 diabetes, and that determination of MBL status might be used to identify patients at increased risk of developing these complications.     

Prevention and treatment of diabetic nephropathy with blood pressure lowering drugs

Summary: Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 h), a relentless decline in glomerular filtration rate (GFR), and raised arterial blood pressure. the prevalence of abnormal elevated albumin excretion rate (>30 mg/24 h) is approximately 40% in insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) patients. Diabetes has become the leading cause of end-stage renal failure in the United States of America and Japan and it remains the second leading cause in Europe. Patients suffering from diabetic nephropathy have an enormous increase in morbidity and mortality from cardiovascular disease in addition to renal death. Elevated blood pressure is an early and frequent phenomenon and furthermore accelerates the course of diabetic nephropathy. Studies in humans suggest that angiotensin-converting enzyme (ACE) inhibitors postpone and may even prevent progression to clinical overt diabetic nephropathy in normotensive IDDM and NIDDM patients with persistent microalbuminuria. Conventional antihypertensive therapy and ACE inhibition usually combined with a diuretic reduces albuminuria and postpones renal insufficiency in hypertensive IDDM patients with overt nephropathy. A more beneficial effect on the rate of decline in glomerular filtration rate has been demonstrated by ACE inhibitors compared to conventional antihypertensive treatment in IDDM patients with diabetic nephropathy and reduced kidney function (serum creatinine >133 mmol/L). These findings suggest that ACE inhibition causes renal protection (i.e. a beneficial effect on kidney function [structure] above and beyond what would be expected from blood pressure lowering effect alone). Finally, it should be stressed that ACE inhibition and conventional antihypertensive treatment postpone end-stage renal failure and improve survival in diabetic nephropathy.     

Urinary excretion of type IV collagen as a specific indicator of the progression of diabetic nephropathy

AIMS AND METHODS: This study was carried out to clarify whether the urinary excretion of type IV collagen (u-IV collagen) detected by specific radioimmunoassay, can be used as an indicator for the progression of diabetic nephropathy. RESULTS: u-IV collagen was higher in diabetic subjects with microalbuminuria and overt proteinuria than those with normoalbuminuria, IgA nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, or control normal subjects. u-IV collagen was positively correlated with serum and urinary beta(2)-microglobulin and negatively with creatinine clearance only in diabetic patients, but not in patients with other glomerular diseases. The serum type IV collagen was not different between all the groups, and not correlated with its urinary excretion. In the advanced diabetic nephropathy, immunoreactive type IV collagen was detected in glomerular basement membrane (GBM), tubular basement membrane and Bowman's capsule much more than that in the normal kidney. CONCLUSION: These findings indicated increased production and degeneration of type IV collagen in diabetic nephropathy. It is suggested that augmented turnover of type IV collagen in GBM and tubular basement membrane results in increased concentrations of free u-IV collagen. Therefore, measurement of u-IV collagen may be a useful, specific indicator of the progression of diabetic nephropathy.     

Clinical predictors of non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus

Background: Several studies had suggested that non-diabetic renal disease (NDRD) was common among non-insulin dependent diabetes mellitus (NIDDM) patients with renal involvement. Methods: We prospectively studied the prevalence of NDRD among a Chinese NIDDM population. Renal biopsy specimens were evaluated with light-, immunohistological and electron-microscopy. The cohort consisted of 51 patients who had NIDDM and proteinuria >1 g/24 h. Results: Patients with both isolated diabetic nephropathy (DN, n=34) and NDRD (n=17) had comparable duration of DM, creatinine clearance, serum creatinine, albumin and glycosylated haemoglobin levels, as well as incidences of retinopathy, neuropathy and hypertension. Significantly more patients with NDRD had microscopic haematuria (P=0.043) or non-nephrotic proteinuria (P=0.004). IgA nephropathy accounted for 59% of the NDRD identified. Conclusions: In this study, microscopic haematuria and non-nephrotic proteinuria predicted the presence of NDRD among NIDDM patients presenting with renal disease.     

Correlation of uric acid and urinary albumin excretion rate in patients with type 2 diabetes mellitus in Taiwan

BACKGROUND: Uric acid is detrimental to the kidneys in animal models. However, its role in human diabetic nephropathy has not been extensively studied. This study evaluated the association between serum uric acid and urinary albumin-to-creatinine ratio (ACR) among patients with type 2 diabetes mellitus in Taiwan. METHODS: A total of 343 patients (144 men and 199 women), aged 62.8 +/- 10.8 years and not using uric acid-lowering agents, diuretics, or alcohol, were recruited. Serum uric acid and urinary ACR were determined. Normoalbuminuria, microalbuminuria, and macroalbuminuria were defined as ACR <30.0, 30.0 to 299.9, and > or =300.0 microg/mg, respectively. RESULTS: The respective uric acid levels for normoalbuminuria (N= 166), microalbuminuria (N= 130), and macroalbuminuria (N= 47) were 5.2 +/- 1.6 mg/dL, 5.6 +/- 1.9 mg/dL, and 6.7 +/- 2.1 mg/dL (P < 0.001). The mean +/- SD (minimum-maximum) values of uric acid for the first to the fourth quartile were 3.4 +/- 0.6 (1.7-4.2), 4.9 +/- 0.4 (4.3-5.4), 6.0 +/- 0.3 (5.5-6.5), and 8.1 +/- 1.2 (6.6-12.2), respectively. Prevalence of abnormal albuminuria (microalbuminuria plus macroalbuminuria) for the respective quartiles were 38.4%, 51.2%, 50.6%, and 66.3% (P trend <0.01). In men, uric acid correlated positively with triglycerides and natural logarithmic [ln (ACR)] (gamma= 0.168, P < 0.05). In women, uric acid correlated positively with triglycerides, ln (ACR) (gamma= 0.277, P < 0.01) and body mass index (borderline significant P < 0.1), but negatively with calculated creatinine clearance. The standardized regression coefficient for ln (ACR) and the odds ratio for abnormal albuminuria for every 1 mg/dL increment of uric acid after adjusting for calculated creatinine clearance and other confounders were 0.138 (P < 0.05) and 1.183 (1.025-1.364), respectively. The results after excluding 127 cases with a history of hypertension were similar. CONCLUSION: Serum uric acid is an independent correlate of urinary ACR in Taiwanese patients with type 2 diabetes mellitus.     

Increased serum advanced glycation end products are associated with impairment in HDL antioxidative capacity in diabetic nephropathy.

BACKGROUND: Advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications. Recent data suggest that AGEs may also interfere with the function of HDL and the reverse cholesterol transport pathway. We have investigated whether serum AGE level is associated with impairment in the antioxidative capacity of HDL and in the ability of serum to induce cholesterol efflux in type 2 diabetic patients with and without nephropathy. METHODS: A total of 167 controls and 264 diabetic patients was recruited. The ability of serum to induce cellular cholesterol efflux and the capacity of HDL to inhibit LDL oxidation ex vivo was determined. Serum AGEs were assayed by competitive ELISA using a polyclonal rabbit antisera raised against AGE-RNase. RESULTS: Diabetic subjects were subdivided into three groups (normoalbuminuria, microalbuminuria and proteinuria). Serum AGEs were significantly increased in diabetic patients with microalbuminuria or proteinuria (P < 0.001). Cholesterol efflux was significantly decreased in all three groups of diabetic patients compared to controls (P < 0.001) whereas the antioxidative capacity of HDL was significantly impaired in patients with microalbuminuria or proteinuria (P < 0.01). No relationship between serum AGEs and cholesterol efflux was found. However, serum AGE concentration was significantly associated with the antioxidative capacity of HDL and this was partly due to the adverse effect of AGEs on paraoxonase-1 activity. CONCLUSION: In type 2 diabetic patients with incipient or overt nephropathy, increased serum concentration of AGEs was associated with impairment in the antioxidative capacity of HDL. Cholesterol efflux to serum was also reduced but was not related to serum AGEs.     

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.     

Albuminuria as a predictor of cardiovascular and renal outcomes in people with known atherosclerotic cardiovascular disease

BACKGROUND: Microalbuminuria predicts elevated cardiovascular risk in those with and without diabetes. In diabetes, microalbuminuria also heralds overt diabetic nephropathy. The predictive value of albuminuria below the microalbuminuria cutoff, and the development of overt nephropathy in nondiabetics with microalbuminuria, have not been well studied. We review findings of the HOPE Study. METHODS: The HOPE Study database includes data on first morning urine albumin/creatinine ratio (ACR) in 9043 participants at baseline, and in 7674 participants at baseline and at last follow-up. Inclusion criteria were known vascular disease or diabetes, plus one other cardiovascular risk factor; exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (> 1+), and serum-creatinine > 2.3 mg/dL (200 micromol/L). Microalbuminuria was defined as an ACR > or = 2 mg/mmol. RESULTS: Microalbuminuria at baseline approximately doubled the relative risk (RR) of the primary outcome (myocardial infarction, stroke, or CV death). For every 1 mg/mmol rise of ACR, even below the level of microalbuminuria, the adjusted hazard of the primary outcome increased by about 15%. Baseline microalbuminuria predicted subsequent clinical proteinuria, RR 17.5, similarly in participants without and with diabetes. New microalbuminuria developed in 1542 participants, and clinical proteinuria in 317. CONCLUSION: Albuminuria is a continuous risk factor for CV events even below the level of microalbuminuria. Microalbuminuria predicts clinical proteinuria in nondiabetics.     

Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria.

BACKGROUND: Intervention studies in microalbuminuric type 2 diabetic patients have demonstrated that it is possible to avoid progression to overt diabetic nephropathy and even to achieve regression to normoalbuminuria. However, the long-term impact of stabilization/regression in albuminuria on decline in glomerular filtration rate (GFR) has not been established. METHODS: 151 patients with type 2 diabetes and microalbuminuria at baseline in whom GFR was measured at least three times during 7.8 years of follow-up were divided into three groups according to the level of albuminuria during follow-up. Overt nephropathy was diagnosed as a urinary albumin excretion rate (AER) >300 mg/24 h and remission to normoalbuminuria was defined as an AER <30 mg/24 h at the last examination. RESULTS: During follow-up, 46 patients achieved remission to normoalbuminuria, 58 remained microalbuminuric and 47 patients progressed to overt nephropathy. The mean (+/- SE) yearly decline in GFR was lowest (2.3+/-0.4 ml/min/year) in patients who obtained remission, in comparison with patients remaining microalbuminuric, in whom the decline was 3.7+/-0.4 ml/min/year, and patients progressing to overt nephropathy, who had a decline in GFR of 5.4+/-0.5 ml/min/year (ANOVA, P<0.001). Start of antihypertensive treatment during follow-up was strongly associated with remission to normoalbuminuria [odds ratio: 2.32; 95% confidence interval (CI): 1.09-4.93] whereas a decrease in HbA(1c) by 1% increased the probability for remission (odds ratio: 1.48; 95% CI: 1.11-1.97). CONCLUSIONS: Remission to normoalbuminuria was associated with a decreased GFR decline during 7.8 years of follow-up in type 2 diabetic patients with microalbuminuria. Antihypertensive therapy and improved glycaemic control were independent predictors for remission.     

ACE DD genotype is more susceptible than ACE II and ID genotypes to the antiproteinuric effect of ACE inhibitors in patients with proteinuric non-insulin-dependent diabetes mellitus.

BACKGROUND: ACE polymorphism, especially genotype DD or D allele, may be involved in the progression of diabetic nephropathy. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. We investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (Benazepril 10 mg/day or Perindopril 4 mg/day) in 83 NIDDM patients with overt proteinuria (urinary protein excretion over 500 mg/day). METHODS: We recruited NIDDM patients with overt proteinuria from our renal clinic. Before entry, previously used ACE inhibitors were withdrawn for at least 2 weeks and baseline proteinuria and albuminuria were measured. Patients were classified into three groups in accordance with ACE genotypes (17 DD; 33 ID; 33 II) and prospectively followed up for 3 months. Various clinical parameters including age, DM duration, body mass index (BMI), 24-h urine sodium, protein and albumin, BUN, serum creatinine, creatinine clearance (Ccr), mean arterial pressure (MAP), and HbA(1c) were measured in the pre- and post-treatment periods. ACE genotypes were determined by polymerase chain reaction. RESULTS: There were no significant differences in the clinical parameters such as age, DM duration, BMI, BUN, serum creatinine, Ccr, MAP, HbA(1c), and daily urinary excretion of sodium, protein and albumin among three groups (P>0.05). After the 3-month treatment period using ACE inhibitors, there were no significant differences in the reduction of MAP and Ccr among the three groups (P>0.05). However, the percentage reductions in urinary excretion of protein and albumin for DD genotype were significantly higher than in ID and II genotypes (50.9+/-19.2% vs 19.2+/-16.0%, 20.2+/-20.4%; 52.6+/-23.6% vs. 13.5+/-51.8%, 24.8+/-23.9%, P<0.05). There were no statistically significant correlations between the levels of baseline proteinuria and albuminuria and the magnitudes of the reduction of proteinuria and albuminuria under ACE inhibition (P>0.05). CONCLUSIONS: Our results suggest that the ACE gene polymorphism might have a role in determining the responsiveness to the antiproteinuric effect of ACE inhibition in proteinuric NIDDM patients.     

Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus

BACKGROUND: The plasma concentrations of total homocysteine (tHcy) and total cysteine (tCys) are determined by intracellular metabolism and by renal plasma clearance, and we hypothesized that glomerular filtration is a major determinant of plasma tHcy and tCys. We studied the relationships between the glomerular filtration rate (GFR) and plasma tHcy and tCys in populations of diabetic patients with particularly wide ranges of GFR. METHODS: We measured GFR, urine albumin excretion rate (UAER), plasma tHcy, tCys, methionine, vitamin B12, folate, C-peptide, and routine parameters in 50 insulin-dependent diabetes mellitus (IDDM) and 30 non-insulin-dependent diabetes mellitus (NIDDM) patients. All patients underwent intensive insulin treatment and had a serum creatinine concentration below 115 micromol/liter. RESULTS: Mean plasma tHcy in diabetic patients (0.1 micromol/liter) was lower than in normal persons (11.1 micromol/liter, P = 0.0014). Mean plasma tCys in diabetic patients (266.1 micromol/liter) was also lower than in normal persons (281.9 micromol/liter, P = 0.0005). Seventy-three percent of the diabetic patients had relative hyperfiltration. Plasma tHcy and tCys were closely and independently associated with GFR, serum folate, and serum B12. However, plasma tHcy was not independently associated with any of the 22 other variables tested, including age, serum creatinine concentration, UAER, total daily insulin dose, and glycemic control. CONCLUSIONS: Glomerular filtration rate is an independent determinant of plasma tHcy and tCys concentrations, and GFR is rate limiting for renal clearance of both homocysteine and cysteine in diabetic patients without overt nephropathy. Declining GFR explains the age-related increase in plasma tHcy, and hyperfiltration explains the lower than normal mean plasma tHcy and tCys concentrations in populations of diabetic patients.     

Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: a prospective study

Angiotensin-I converting enzyme (ACE) regulates renal hemodynamics. Its insertion/deletion (I/D) polymorphism, which determines most of ACE interindividual variance, was proposed as a genetic marker for diabetic nephropathy. A substitution (M235T) polymorphism in angiotensinogen (AGT) may interact with ACE I/D polymorphism for the risk of diabetic nephropathy, but their prognostic values have to be established by follow-up studies. A total of 310 type 1 diabetes mellitus patients who attended the diabetic clinic in Angers (France) took part in a prospective, observational, follow-up study. Glycohemoglobin, BP, plasma creatinine, and urinary albumin excretion were determined periodically. Nephropathy was classified as absent, incipient (microalbuminuria), established (proteinuria), advanced (plasma creatinine > or = 150 micromol/L), and terminal (renal replacement therapy). The main end point was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) had established nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT polymorphisms were in Hardy-Weinberg equilibrium in the patients. The median duration of follow-up was 6 yr (range, 2 to 9 yr). The occurrence of renal events was significantly influenced by ACE genotype (log-rank II versus ID versus DD, P < 0.03) with a dominant deleterious effect of the D allele: ID or DD versus II (adjusted hazard ratio, 5.0; 95% confidence interval, 1.5 to 16.6). Other contributors were high glycohemoglobin and systolic BP. In the patients who initially were free of nephropathy, baseline plasma ACE concentration was higher in patients who progressed to microalbuminuria (571 +/- 231 versus 466 +/- 181 microg/L; P = 0.0032); the D allele independently favored the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95% confidence interval, 1.1 to 19.4); other contributors were male gender, baseline systolic BP, and urinary albumin excretion. The AGT M235T polymorphism was not associated with renal events. The D allele of the ACE I/D polymorphism is an independent risk factor for both the onset and the progression of diabetic nephropathy in type 1 diabetes mellitus patients.     

Non-albuminuric renal disease among subjects with advanced stages of chronic kidney failure related to type 2 diabetes mellitus

Urinary albumin excretion has been consistently found to be normal in a significant number of subjects with early stages of diabetic kidney disease. This study was aimed to estimate the prevalence and characteristics of non-albuminuric chronic kidney disease associated with type 2 diabetes mellitus among subjects who reach advanced stages of renal failure. Study population was composed of incident patients with advanced chronic kidney disease (glomerular filtration rate <30?mL/min) related to type 2 diabetes in a tertiary hospital from Gran Canaria (Spain) during a period of 2 years. Subjects were classified as normoalbuminuric (urinary albumin-to-creatine ratio [UACR] <30?mg/g), microalbuminuric (UACR ≥30 and <300?mg/g), or proteinuric (UACR ≥300?mg/g). Of 78 eligible patients, 21.8% had normoalbuminuria, 20.5% had microalbuminuria, and 57.7% had proteinuria. Individuals with normoalbuminuria were mostly women and had a lower prevalence of smoking and polyneuropathy than subjects with microalbuminuria or proteinuria. They also presented greater measures of body mass index and waist circumference, higher values of total and LDL cholesterol, and lower values of HbA_1c and serum creatinine than subjects with microalbuminuria or proteinuria. Multivariate analysis demonstrated that female sex (positively) and HbA_1c and polyneuropathy (negatively) were independently associated with absence of albuminuria. In conclusion, around 20% of subjects with diabetes-related advanced chronic kidney disease, characteristically women, have normal urinary albumin excretion. HbA_1c and polyneuropathy are inversely related to this non-albuminuric form of nephropathy.