Urinary albumin excretion rate is associated with increased ambulatory blood pressure in normoalbuminuric type 2 diabetic patients

OBJECTIVE: To evaluate the 24-h blood pressure profile in normoalbuminuric type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted in 90 type 2 diabetic patients with a urinary albumin excretion rate (UAER) <20 microg/min on two occasions, 6 months apart (immunoturbidimetry). Patients underwent clinical and laboratory evaluations. Ambulatory blood pressure monitoring and echocardiograms were also performed. RESULTS: UAER was found to correlate positively with systolic doctor's office blood pressure measurements (r = 0.243, P = 0.021) and ambulatory blood pressure (24 h: r = 0.280, P = 0.008) and left ventricular posterior wall thickness (r = 0.359, P = 0.010). Patients were divided into four groups according to UAER (<5, > or =5-10, > or =10-15, and > or =15-20 microg/min). Systolic blood pressure parameters for the 1st, 2nd, 3rd, and 4th groups, respectively, were 123.0 +/- 10.6, 132.5 +/- 15.0, 139.0 +/- 23.4, and 130.7 +/- 8.0 mmHg for 24-h blood pressure (ANOVA P = 0.004) and 48.4 +/- 6.0, 54.5 +/- 11.2, 58.8 +/- 15.6, and 57.6 +/- 8.0 mmHg for 24-h pulse pressure (ANOVA P = 0.003). A progressive increase in the prevalence of diabetic retinopathy was observed from the 1st to the 4th UAER group: 27.3, 43.8, 45.5, and 66.7% (P = 0.029 for trend). CONCLUSIONS: In type 2 diabetic patients, UAER in the normoalbuminuric range is positively associated with systolic ambulatory blood pressure indexes, left ventricular posterior wall thickness, and diabetic retinopathy, suggesting that intensive blood pressure treatment may prevent diabetes complications in these patients.     

Effect of a chicken-based diet on renal function and lipid profile in patients with type 2 diabetes: a randomized crossover trial

OBJECTIVE: To assess the effect of replacing red meat with chicken in the usual diet and the effect of a low-protein diet on glomerular filtration rate (GFR), urinary albumin excretion rate (UAER), and lipid levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized, crossover, controlled trial was conducted with 28 patients with type 2 diabetes (seven women; mean age 58.1 years): 15 patients were normoalbuminuric (UAER <20 microg/min), and 13 patients were microalbuminuric (UAER 20-200 microg/min). A chicken-based diet (red meat replaced with chicken) and a low-protein diet were compared with the patients' usual diet. Patients followed each diet for 4 weeks with a 4-week washout period between. GFR ((51)Cr-EDTA single-injection technique), 24-h UAER (immunoturbidimetry), apolipoprotein B, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were measured after each diet. RESULTS: Normoalbuminuric and microalbuminuric patients with diabetes were analyzed separately. In normoalbuminuric patients, GFR after the chicken (101.3 +/- 22.9 ml x min(-1) x 1.73 m(-2)) and low-protein diets (93.8 +/- 20.5 ml x min(-1) x m(-2)) was lower than after the usual diet (113.4 +/- 31.4 ml x min(-1) x 1.73 m(-2); P < 0.05). In microalbuminuric patients, apolipoprotein B levels were lower after the chicken (113.5 +/- 36.0 mg/dl) and low-protein diets (103.5 +/- 40.1 mg/dl) than after the usual diet (134.3 +/- 30.7 mg/dl; P < 0.05). Only the chicken diet reduced UAER (median 34.3 microg/min) compared with the low-protein (median 52.3 microg/min) and usual (median 63.8 microg/min) diets (P < 0.05). Glycemic control and blood pressure did not change after the diets. CONCLUSIONS: A normoproteic diet with chicken as the only source of meat may represent an alternative strategy for treatment of patients with type 2 diabetes and microalbuminuria.     

Early disturbances of ambulatory blood pressure load in normotensive type I diabetic patients with microalbuminuria.

OBJECTIVE--To compare 24-h ABP in normotensive type 1 diabetic patients with and without microalbuminuria. RESEARCH DESIGN AND METHODS--The study was a retrospective comparison of cases and matched control subjects. The first phase included 35 type 1 diabetic patients, normotensive by OMS criteria. The 23 patients with normoalbuminuria (< 15 micrograms/min) were compared with 12 patients with microalbuminuria (> or = 15 micrograms/min). In the second phase, the 12 microalbuminuric patients were paired by sex- and age-matched with 12 normoalbuminuric patients and 12 nondiabetic healthy control subjects. We measured casual systolic and diastolic BP and HR, 24-h ABP and AHR (recorded with a Spacelabs automatic recorder), and microalbuminuria. RESULTS--No correlation between microalbuminuria and casual BP was observed. Microalbuminuria was correlated significantly with diastolic 24-h APR and nocturnal systolic and diastolic ABP (r = 0.35, 0.38, and 0.33, respectively; P < 0.05) and with AHR during all time periods (24-h, r = 0.46; day, r = 0.39; night, r = 0.39; P < 0.05). Normo- and microalbuminuric patients did not differ in casual BP and HR. However, microalbuminuric patients had a significant increase in systolic 24-h ABP (119.1 +/- 8.2 vs. 113.1 +/- 8.1, P = 0.05), diastolic 24-h ABP (74.9 +/- 7.5 vs. 70.2 +/- 5.7, P = 0.04), nocturnal systolic ABP (112.8 +/- 7.1 vs. 105.8 +/- 7.9, P = 0.01), and AHR during all time periods. The same results were observed when patients were paired by age and sex. CONCLUSIONS--Normotensive microalbuminuric type 1 patients, although strictly comparable with normoalbuminuric patients for casual BP and HR, have an increased ABP and HR, especially during the night. This difference might reflect dysautonomia. Ambulatory measurement of BP and HR is more appropriate than casual measurements in hemodynamic studies of incipient diabetic nephropathies and could be proposed as an interesting tool for an early prediction of diabetic nephropathy.     

Autonomic dysfunction and urinary albumin excretion rate are associated with an abnormal blood pressure pattern in normotensive normoalbuminuric type 1 diabetic patients

OBJECTIVE: To analyze the role of autonomic function and other possible factors associated with a blunted fall in nocturnal blood pressure. RESEARCH DESIGN AND METHODS: A total of 39 normotensive normnoalbuminuric type 1 diabetic patients were studied. Glomerular filtration rate (51Cr-EDTA technique), extracellular volume (51Cr-EDTA distribution volume), and urinary albumin excretion rate (UAER) (by radioimmunoassay) were measured. The subjects' 24-h ambulatory blood pressure and a 24-h electrocardiogram were recorded simultaneously Heart rate variability was calculated in the time domain for 24 h, in the frequency domain at night, at rest in the supine position, and during tilt. Patients were classified according to diastolic blood pressure (dBP) night/day ratio as dipper patients (< or =0.9) and nondipper patients (>0.9). RESULTS: Nondipper patients presented a higher low-frequency (LF) component (a sympathetic index) and higher LF/high-frequency (HF) ratio during sleep than dipper patients (0.29 +/- 0.12 vs. 0.19 +/- 0.10 normalized units [n.u.], P = 0.008; and 0.98 +/- 0.53 vs. 0.55 +/- 0.45 n.u., P = 0.007, respectively). At rest, the LF component in nondipper patients (0.38 +/- 0.13 n.u.) was higher than in dipper patients (0.27 +/- 0.12 n.u., P = 0.04). After the tilt, nondipper patients did not show an increase in the LF component (P = 0.32), but in dipper patients, the increase was significant (P = 0.001). In both groups, tilting promoted a decrease in the HF component (a parasympathetic index). In a stepwise multiple linear regression analysis, the LF component during sleep and the UAER accounted for 24% of the variability in the dBP night/day ratio. CONCLUSIONS: The predominance of sympathetic activity and increased levels of UAER, although within the normal range, are associated with a blunted fall in nocturnal dBP in normoalbuminuric normotensive type 1 diabetic patients.     

胱抑素C及同型半胱氨酸的血清含量与糖尿病肾病患者肾小球滤过率的相关性研究

目的:通过检测血胱抑素C(CystatinC,CysC)、同型半胱氨酸(Homocysteine,Hcy)浓度及尿白蛋白清除率(urinealbumin excretionrate,UAER)在糖尿病肾病(diabetic nephropathy,DN)进程中的变化以及与肾小球滤过率(glomerular filtration rate,GFR)的相关性,探讨其在DN诊断中的价值。方法:共47例患者,根据肾小球滤过率将其分为早期糖尿病肾病组(early-DN组,GFR≥60mL/min)及晚期糖尿病肾病组(end-DN组,GFR<60mL/min),比较两组间CysC、Hcy的变化以及与肾小球滤过率的相关性。结果:end-DN组CysC、UAER均高于early-DN组(P<0.01)。相关分析显示肾小球滤过率与CysC、Hcy、UAER负相关(r=-0.584,P=0.000;r=-0.547,P=0.000;r=-0.507,P=0.000),在慢性肾脏病(chronic kidney disease,CKD)Ⅱ、Ⅲ期,肾小球滤过率与CysC、Hcy负相关(r=-0.617,P=0.000;r=-0.431,P=0.018)。结论:糖尿病患者中,伴随慢性肾脏病进程,CysC、Hcy、UAER逐渐升高,尤其在CKDⅡ、Ⅲ期,CysC、Hcy联合检测与UAER比较,能更好的反应糖尿病肾病肾小球滤过功能异常。     

Monitoring kidney function in type 2 diabetic patients with incipient and overt diabetic nephropathy

OBJECTIVE: The purpose of this study was to assess agreement between glomerular filtration rate (GFR) and the decline in GFR estimated with the Modification of Diet in Renal Disease (MDRD) Study Group equation or the Cockcroft-Gault formula and measured by the plasma clearance of 51Cr-EDTA. RESEARCH DESIGN AND METHODS: We followed a cohort of 156 microalbuminuric type 2 diabetic patients for 8 years with four measurements of GFR and another cohort of 227 type 2 diabetic patients with overt diabetic nephropathy for 6.5 (range 3-17) years with seven (3-22) measurements of GFR. RESULTS: For patients with microalbuminuria, mean +/- SD baseline GFR was 117 +/- 24 measured, 92 +/- 20 estimated (MDRD equation), or 103 +/- 24 ml x min(-1) per 1.73 m2 estimated (Cockcroft-Gault formula) (both P < 0.001); 95% limits of agreement were -66.1 to 20.3 (MDRD equation) and -58.7 to 30.7 (Cockcroft-Gault formula). The rate of decline in GFR was 4.1 +/- 4.2 measured, 2.9 +/- 2.8 estimated (MDRD equation), or 3.4 +/- 3.2 ml x min(-1) per 1.73 m2 estimated (Cockcroft-Gault formula) (both P < 0.001). For patients with overt nephropathy, baseline GFR was 84 +/- 30 measured, 73 +/- 24 estimated (MDRD equation), or 81 +/- 28 ml x min(-1) per 1.73 m2 estimated (Cockcroft-Gault formula) (both P < 0.001) with 95% limits of agreement -47 to 25 (MDRD equation) and -39 to 33 (Cockcroft-Gault formula). The rate of decline in GFR was 5.2 +/- 4.1 measured, 4.2 +/- 3.8 estimated (MDRD equation), and 4.6 +/- 4.1 ml x min(-1) per 1.73 m2 estimated (Cockcroft-Gault formula) (both P < 0.001). CONCLUSIONS: Particularly in microalbuminuric (hyperfiltering) patients, GFR is significantly underestimated with wide limits of agreement by the MDRD equation as well as by the Cockcroft-Gault formula. The rate of decline in GFR is also significantly underestimated with both equations. This makes GFR estimations based upon these equations unacceptable for monitoring kidney function in type 2 diabetic patients with incipient and overt diabetic nephropathy.     

Autoregulation of glomerular filtration rate in patients with type 2 diabetes during isradipine therapy

OBJECTIVE: Calcium-channel blockade impairs renal autoregulation in animals. Impaired renal autoregulation leads to transmission of the systemic blood pressure (BP) into the glomerulus, resulting in capillary hypertension. Information on the impact of calcium antagonist treatment on renal autoregulation in humans is lacking. This study examines the effect of isradipine treatment on the autoregulation of the glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS: We performed a randomized double-blind crossover study with 5 mg o.d. isradipine retard and matching placebo in 16 hypertensive patients with type 2 diabetes. Each treatment arm lasted 4 weeks. On the last day of each treatment period, GFR (single-shot 51Cr-EDTA plasma clearance technique for 4 h) was measured twice between 8:00 A.M. and 5:00 P.M., first without clonidine and then after intravenous injection of 75 micro g clonidine. BP was measured every 10 min (Takeda TM2420; A&D, Tokyo). RESULTS: Clonidine reduced mean arterial BP (MABP) by 15 +/- 1 vs. 11 +/- 1 mmHg (means +/- SE) during placebo and isradipine treatment, respectively (P < 0.05). GFR was reduced from 102 +/- 4 to 99 +/- 4 ml. min(-1). 1.73 m(-2) with placebo (P < 0.01) and from 106 +/- 5 to 98 +/- 5 ml. min(-1). 1.73 m(-2) during treatment with isradipine (P < 0.01). Mean difference (95% CI) between changes in GFR with placebo and isradipine was -4.6 ml. min(-1). 1.73 m(-2) (-10.0 to 0.6) (P = 0.08). Six patients had a reduction in GFR >13% (exceeding the normal limit of autoregulation) combined with a complete pressure-passive vasculature (defined as DeltaMABP% < or = DeltaGFR%) during isradipine treatment versus none during the placebo treatment (P < 0.05). CONCLUSIONS: Isradipine impairs GFR autoregulation in a sizeable proportion of hypertensive type 2 diabetic patients.     

Glomerular filtration rate and kidney volume in normoalbuminuric non-insulin-dependent diabetics--lack of glomerular hyperfiltration and renal hypertrophy in uncomplicated NIDDM

Glomerular filtration rate (GFR) and kidney volume were evaluated in 18 healthy normoalbuminuric non-insulin-dependent diabetic patients and compared to 12 healthy controls matched for sex, age and body mass index (BMI). The patients (12 males, six females) were 61.6 +/- 3.4 (mean +/- SD) years old, the known diabetes duration was 5 +/- 4.8 years, fasting plasma glucose 8.6 +/- 2.3 mmol/l, urinary albumin excretion rate 7.9 x/divided by 2.0 micrograms/min, BMI 26.8 +/- 2.8 kg/m2 and blood pressure systolic/diastolic 145 +/- 19/82 +/- 7 mmHg. The GFR was measured by the plasma clearance of [51Cr]EDTA, using a single shot procedure. The kidney volume was measured by ultrasonic scanning. The GFR was not increased in diabetics: 100.4 +/- 16.7 ml/min/1.73 m2 as compared to controls: 93.8 +/- 11.4 ml/min/1.73 m2. The kidney volume was similar in the two groups. Diabetics: 231.1 +/- 33.4 ml/1.73 m2. Controls: 236.3 +/- 45.7 ml/1.73 m2. There was a borderline significant correlation between kidney volume and GFR (r = 0.40, p = 0.10) in diabetics. No correlation between glycosylated haemoglobin and GFR was found in diabetics. In contrast to the findings in insulin-dependent diabetes renal hypertrophy and hyperfunction were not characteristic features in this series of non-insulin-dependent diabetics. It is suggested that diabetic glomerulopathy is not always a consequence of long-standing hyperfiltration.     

Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study

OBJECTIVE: To evaluate kidney function 7 years after the end of treatment with cyclosporine A (CsA) (initial dosage of 9.3 tapered off to 7.0 mg.kg-1.day-1) in young patients (mean age 20 years) with newly diagnosed type 1 diabetes participating in a randomized, double-blind, placebo-controlled CsA trial. RESEARCH DESIGN AND METHODS: In this study, 21 patients received CsA for 12.5 +/- 4.0 months (mean +/- SD) and 19 patients received placebo for 14.4 +/- 3.8 months. The two groups were similar with regard to mean arterial blood pressure (BP), urinary albumin excretion rate (UAER), serum creatinine, and estimated glomerular filtration rate (GFR [Cockcroft and Gault]) at initiation of CsA treatment (baseline). HbA1c (mean +/- SEM) during 7 years of follow-up was also the same: 8.7 +/- 0.4 vs. 8.3 +/- 0.4% in the CsA and placebo groups, respectively. RESULTS: During the 7 years after cessation of study medication, two CsA group patients and one control patient were lost to follow-up. One placebo-treated patient developed IgA nephropathy (biopsy proven) and was excluded. Four CsA-treated patients developed persistently elevated UAER > 30 mg/24 h (n = 3 with microalbuminuria), whereas all the 17 placebo-treated patients had normal UAER (< 30 mg/24 h) after 7 years of follow-up. At the end of follow-up, the CsA group had a more pronounced rise in UAER: 2.5-fold (95% CI 1.4-4.5) higher than baseline value vs. 1.1-fold (0.7-1.7) in the placebo-treated group (P < 0.05). Estimated GFR (ml.min-1.1.73 m-2) declined from baseline to end of follow-up (1994) by 6.3 +/- 6.0 in the former CsA group, whereas it rose by 7.4 +/- 5.0 in the placebo group (P = 0.05). In 1994, 24-h blood pressure was nearly the same: 131/77 +/- 4/2 vs. 127/75 +/- 2/2 mmHg (NS) in the CsA and placebo groups, respectively. Five randomly selected CsA-treated patients had a kidney biopsy performed shortly after the CsA treatment was stopped. Interstitial fibrosis/tubular atrophy and/or arteriolopathy were present in two subjects who both subsequently developed persistent microalbuminuria. CONCLUSIONS: The results of our 7-year follow-up study suggested that short-lasting CsA treatment in young, newly diagnosed type 1 diabetic patients accelerated the rate of progression in UAER and tended to induce a loss in kidney function. Longer term follow-up is mandatory to clarify whether CsA-treated patients are at increased risk of developing clinical nephropathy.     

The impact of glycaemic control on autoregulation of glomerular filtration rate in patients with non-insulin dependent diabetes

The ability of the kidney to maintain constancy of glomerular filtration rate (GFR) over a wide range of renal perfusion pressures is termed autoregulation. Defective autoregulation of GFR has been demonstrated in patients with diabetic and non-diabetic nephropathy and in streptozotocin diabetic rats during hyperglycaemia. Information on the potential impact of acute changes in glycaemic control on autoregulation of GFR in diabetic patients is lacking. Therefore the aim of our study was to evaluate the effect of acute lowering of blood pressure (BP) on GFR during normoglycaemia and hyperglycaemia. We investigated 14 (12m/2f) normoalbuminuric patients with non-insulin dependent diabetes (NIDDM). The patients were examined in random order on two separate days with blood glucose (BG)<10 mmol/L or with BG>15 mmol/L. GFR (single shot [51Cr] EDTA plasma clearance technique) was measured twice each day; first without clonidine (baseline) followed by intravenous injection of clonidine 100-150 microg. We measured BG (One Touch 2), and BP (Takeda TM2420) several times during each GFR measurement. Clonidine reduced mean arterial blood pressure with 20 (1.4) vs. 16 (1.2) mmHg (mean (SE)) with BG<10mmol/L and with BG>15 mmol/L, respectively (p=0.053). GFR diminished in average from 92 (3.1) to 86 (3.7) ml/min/1.73m2 with BG<10 mmol/L (p<0.05), and from 102 (4.1) to 98 (4.2) ml/min/1.73 m2 with BG> 15 mmol/L, NS. Mean difference between changes in GFR (95% confidence interval) between the examination with BG<10 mmol/L and with BG>15 mmol/L were 2.3 (-1.3 to 5.9) ml/min/1.73 m2 (NS). The mean BG during normoglycaemia was 6.9 (0.3) vs.16.9 (0.4) during hyperglycaemia. CONCLUSION: Our study suggests that acute changes in glycaemic control have no detectable effect on autoregulation of GFR in NIDDM patients. Hyperglycaemia enhances GFR.     

Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patients with type 1 diabetes

OBJECTIVE: To study whether administration of 1.25 and 5.0 mg ramipril daily, compared with placebo treatment, reduces the urinary albumin excretion rate (UAER) in normotensive patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Ramipril was administered double blind at two different doses (1.25 [n = 19] and 5.0 mg [n = 18]), and compared with placebo (n = 18) after a single-blind placebo period of 1-4 weeks. The patients (total, n = 55; women, n = 14) were followed for 2 years. To document an effect on the renin-angiotensin system, ACE activity and plasma-renin activity (PRA) were measured. In addition, 24-h ambulatory blood pressure (BP) was recorded at baseline and repeated after 1 and 2 years using a Spacelab 90207 ambulatory BP recording device (Spacelab, Redmont, CA). RESULTS: Both doses of ramipril were sufficient to reduce ACE activity and to increase PRA significantly as compared with placebo (P < 0.05 for both). On the other hand, neither ambulatory nor clinic BP was affected by either dose of ramipril compared with the placebo group. There was no progression of UAER in the placebo group during the 2 years of the study. Analysis of covariance showed no differences in UAER between the three treatment groups at year 1 (P = 0.94) or year 2 (P = 0.97), after adjusting for baseline. Furthermore, there were no statistically significant changes from baseline UAER within any of the three treatment groups. CONCLUSIONS: Treatment with ramipril did not affect microalbuminuria or clinic or ambulatory BP in this study. On the basis of the present study, we question the clinical use of ACE inhibitors in stably normotensive patients with type 1 diabetes and microalbuminuria in whom a concomitant reduction in BP is not demonstrated.     

PC-1 amino acid variant Q121 is associated with a lower glomerular filtration rate in type 2 diabetic patients with abnormal albumin excretion rates

OBJECTIVE: To study the relationships between the PC-1 K121Q variant and diabetic nephropathy (DN) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 125 patients with type 2 diabetes and abnormal albumin excretion rate (AER) (range 20-5416 microg/min) were followed up for 4 years with repeated measurements of glomerular filtration rate (GFR). Genomic DNA was extracted from all patients, and the PC-1 K121Q polymorphism was determined by the PCR AvaII restriction enzyme. A subset of 64 patients underwent a percutaneous kidney biopsy at baseline, and glomerular structure was analyzed by electron microscopic morphometric analysis. At baseline, age (56 +/- 8 vs. 59 +/- 7 years), BMI (28.3 +/- 4.3 vs. 28.6 +/- 3.7 kg/m(2)), known duration of type 2 diabetes (11.1 +/- 7 vs. 11.9 +/- 8 years), and HbA(1c) (8.6 +/- 1.8 vs. 8.4 +/- 1.7%) were similar in K121K (KK, n = 87, 73 men/14 women) and XQ (35 K121Q + 3 Q121Q, n = 38, 27 men/11 women) patients. Baseline GFR was 96 +/- 28 ml. min(-1). 1.73 m(-2) and was related (P = 0.01-0.001) to age, known diabetes duration, and systolic blood pressure. RESULTS: XQ patients had lower GFR (P < 0.05) than KK patients (88 +/- 30 vs. 100 +/- 26 ml. min(-1). 1.73 m(-2)); this difference persisted also after factoring in age and known diabetes duration. The rate of progression of DN was similar in KK and XQ patients: %deltaGFR was 4.1/year (median, range: 22.9-30.6) vs. 4.2/year (9.8-26.7). Morphometric parameters of diabetic glomerulopathy were similar in the two genotype groups. CONCLUSIONS: Among patients with type 2 diabetes with abnormal AER, those carrying the Q PC-1 genotype have more severe DN but not a faster GFR decline than KK patients, thus suggesting faster DN development since diabetes diagnosis in XQ patients.     

Fatty acid composition of serum lipid fractions in type 2 diabetic patients with microalbuminuria

OBJECTIVE: To determine the fatty acid composition of serum phospholipid, triglyceride, and cholesterol ester fractions and to analyze the lipid profile of microalbuminuric type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A case-control study was conducted with 72 patients: 37 were normoalbuminuric (urinary albumin excretion rate [UAER] <20 microg/min), and 35 were microalbuminuric (UAER 20-200 microg/min). After 4 weeks of a standardized diet, the fatty acid composition of phospholipid, triglyceride, and cholesterol ester fractions was determined by gas chromatography. Total cholesterol and triglycerides were measured by enzymatic-colorimetric methods; cholesterol HDL by double precipitation with heparin, MnCl(2), and dextran sulfate; and apolipoprotein B by immunoturbidimetry. RESULTS: Microalbuminuric patients showed a lower proportion of polyunsaturated fatty acids (24.8 +/- 11.0%), especially of the n-6 family (21.7 +/- 10.5%), in triglyceride fraction than normoalbuminuric patients (34.1 +/- 11.3%, P = 0.001 and 31.4 +/- 11.5%, P < 0.001, respectively). Patients with microalbuminuria also presented higher levels of saturated fatty acids in triglyceride fraction (43.4 +/- 18.0% vs. 34.7 +/- 13.1%, P = 0.022). In the logistic regression analysis, only the proportion of polyunsaturated fatty acids in triglyceride fraction remained significantly associated with microalbuminuria (odds ratio [OR] 0.92, 95% CI 0.85-0.98, P = 0.019). Total cholesterol, HDL cholesterol, triglyceride, and apolipoprotein B levels were similar in normo- and microalbuminuric patients. CONCLUSION: Microalbuminuria in type 2 diabetic patients is associated with low polyunsaturated fatty acid contents in serum triglyceride fraction. This association may represent a risk factor for cardiovascular disease and may contribute to the progression of renal disease.     

Glucose control influences glomerular filtration rate and its prediction in diabetic subjects

OBJECTIVE: Hyperglycemia increases glomerular filtration rate (GFR), but the influence of HbA(1c) (A1C) on GFR and GFR's prediction by recommended equations remains to be determined. RESEARCH DESIGN AND METHODS: In 193 diabetic patients, we searched for an association between A1C and isotopically measured GFR (51Cr-EDTA) and their predictions by the Cockcroft and Gault formula (CG) and the modification of diet in renal disease (MDRD) equation. Their accuracy for the diagnosis of moderate (GFR <60 ml/min per 1.73 m(2)) or severe (GFR <30 ml/min per 1.73 m(2)) renal failure was compared from receiver operating characteristic (ROC) curves, before and after categorizing the patients as well (A1C 8%. The MDRD equation was more accurate and robust in diabetic patients with impaired renal function.     

Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy

OBJECTIVE: To compare the long-term effect on kidney function of a long-acting calcium antagonist (nisoldipine) versus a long-acting ACE inhibitor (lisinopril) in hypertensive type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: We performed a 4-year prospective, randomized, double-dummy controlled study comparing nisoldipine (20-40 mg once a day) with lisinopril (10-20 mg once a day). The study was double-blinded for the first year and single-blinded thereafter. The study included 51 hypertensive type 1 diabetic patients with diabetic nephropathy. Three patients dropped out during the first month; results for the remaining 48 patients are presented. RESULTS: At baseline, the two groups were comparable: glomerular filtration rate (GFR) was 85 +/- 5 and 85 +/- 6 ml x min(-1) x [1.73 m](-2); mean 24-h ambulatory blood pressure was 108 +/- 3 and 105 +/- 2 mmHg, and albuminuria was 1,554 mg/24 h (95% CI 980-2,465) and 1,033 mg/24 h (760-1,406) in the lisinopril and nisoldipine groups, respectively. Mean 24-h arterial blood pressure during the study did not differ between the lisinopril and nisoldipine groups (100 +/- 2 and 103 +/- 1 mmHg, respectively). The time-course of albuminuria differed between groups (P < 0.001). Whereas initiation of treatment with lisinopril resulted in a reduction from baseline albuminuria by 52% (95% CI 14-73), albuminuria in the nisoldipine group did not change throughout the study GFR declined in a biphasic manner with an initial (0-6 months) reduction of 1.3 +/- 0.3 ml x min(-1) x month(-1) in the lisinopril group compared with 0.2 +/- 0.4 ml x min(-1) x month(-1) in the nisoldipine group (P < 0.01). The subsequent sustained decline (6 to 48 months or the end of treatment) was identical in the two groups: 0.5 +/- 0.1 ml min(-1) x month(-1) (NS). Two patients in the lisinopril group and three patients in the nisoldipine group entered therapy for end-stage renal failure. CONCLUSIONS: Long-term treatment with lisinopril or nisoldipine has similar beneficial effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients.     

Randomized placebo-controlled trial of perindopril in normotensive, normoalbuminuric patients with type 1 diabetes mellitus

Diabetic nephropathy is one of the leading causes of end-stage renal disease. We examined whether ACE inhibitor treatment may have a nephroprotective effect in normotensive insulin-dependent diabetic patients without microalbuminuria and with normal glomerular filtration rate (GFR), and whether any effect was associated with the ACE genotype. In a prospective double-blind randomized study, normotensive patients with type 1 diabetes mellitus with normal serum creatinine and no microalbuminuria were treated with either placebo or perindopril, an ACE inhibitor. Urine albumine/creatinine ratio (ACR), mean blood pressure (MBP) and index of glomerular filtration rate (GFR) based on S-creatinine were determined. ACE genotype was determined by electrophoresis. ACR was higher in the placebo group than in the perindopril group after 4 months, and continued to increase during the study period. After 36 months of observation, ACR in the placebo group was 1.7+/-1.1 mg/mmol, and 0.6+/-0.2 mg/mmol in the ACE-inhibitor-treated group (p<0.001, Mann-Whitney test). During treatment, a significant increase in ACR in the placebo group (p=0.007), Wilcoxon matched paired test) was observed. There were no differences between the groups regarding MBP or GFR. The nephroprotective effects of ACE inhibitor treatment was not associated with the ACE genotype (II, ID, DD).     

Low-dose dopamine infusion, renal haemodynamics and urinary albumin excretion rate in insulin-dependent diabetics and in normal man

The effect of experimental renal vasodilatation by means of low-dose (2.0 micrograms/kg/min) intravenous dopamine infusion was investigated in 28 insulin-dependent diabetes mellitus (IDDM) patients with normal basal urinary albumin excretion rate (UAE) (less than 15 micrograms/min), 9 IDDM patients with UAE between 15-200 micrograms/min (microalbuminuria), and 7 normal subjects. Glomerular filtration rate (GFR) (thalamate clearance) showed a small increase with dopamine infusion, in the normoalbuminuric IDDM patients from 140 +/- 20 to 146 +/- 20 ml/min (2p less than 0.01), in the microalbuminuric IDDM patients from 146 to 151 ml/min (NS), and in normal subjects from 115 +/- 16 to 122 +/- 15 (2p less than 0.05). A marked increase in renal plasma flow (RPF) (hippuran clearance) was seen in all three groups--533 +/- 82 to 724 +/- 120 ml/min (2p less than 0.01), 574 +/- 69 to 777 +/- 140 ml/min (2p less than 0.01) and 523 +/- 87 to 749 +/- 145 ml/min (2p less than 0.05), respectively. Urinary albumin excretion rate (radioimmunoassay) increased from 5.3 x/divide 1.5 (tolerance factor) to 6.5 x/divide 1.8 micrograms/min (2p less than 0.05) in the normoalbuminuric IDDM patients and from 6.1 x/divide 2.1 to 7.8 x/divide 2.3 micrograms/min (2p less than 0.05) in the normal subjects, while no significant change was seen in the microalbuminuric group of diabetics. Kidney volume (ultrasonic scanning) was significantly enhanced in IDDM patients (294 +/- 73 ml vs. 196 +/- 49 ml). There was no significant correlation between kidney volume and the renal haemodynamic response to dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion

BACKGROUND: Glomerular hyperfiltration plays a role in the pathophysiology of diabetic nephropathy. An increase in the glomerular filtration rate (GFR) could result from primary actions at the glomerular/vascular level or could be the consequence of a primary increase in proximal tubular sodium reabsorption resulting in systemic volume expansion. Recently it was hypothesized that an increase in sodium reabsorption may lead to glomerular hyperfiltration through the tubulo-glomerular feedback mechanism (tubular-hypothesis) without volume expansion. DESIGN: We have studied 54 normoalbuminuric patients with type 1 diabetes. The GFR was measured by inulin clearance. Proximal and distal sodium reabsorption were calculated according to standard formulas using the free water clearance technique. Plasma volume, measured by the (125)I-albumin method, atrial natriuretic peptide (ANP) and the second messenger cyclic guanosine-3,5-monophosphate (c-GMP) were used as markers of extracellular volume expansion. RESULTS: Glomerular hyperfiltration (GFR >or= 130 mL min(-1) 1.73 m(-2)) was present in 14 out of 55 patients with diabetes (25%). There were no differences in plasma volume between normo-(NF) and hyper-filtrating (HF) patients (2933 +/- 423 in NF vs. 3026 +/- 562 mL in HF, NS). Also plasma ANP and c-GMP levels were not significantly different between the groups. The fractional proximal reabsorption of sodium was significantly increased in HF [fPRNa(+) (%) 90.1 +/- 2.0 vs. 91.5 +/- 1.6, P = 0.02]. There were no differences in distal sodium reabsorption or distal sodium load (approximately macula densa concentration of NaCl) in both groups. CONCLUSIONS: Our data suggest that the primary event in diabetic glomerular hyperfiltration is an increase in proximal tubular sodium reabsorption. They do not support the hypothesis that systemic volume expansion or ANP mediate glomerular hyperfiltration in patients with normoalbuminuric type 1 diabetes. As such, changes in tubular sodium handling most probably influence tubulo-glomerular feedback.     

Nonalbuminuric renal insufficiency in type 2 diabetes

OBJECTIVE: To determine the prevalence and characteristics of patients with type 2 diabetes who have impaired renal function, defined as a glomerular filtration rate (GFR) <60 ml. min(-1). 1.73 m(-2), and normoalbuminuria. RESEARCH DESIGN AND METHODS: A cross-sectional survey of 301 outpatients attending a single tertiary referral center using the plasma disappearance of isotopic (99m)Tc-diethylene-triamine-penta-acetic acid to measure GFR and at least two measurements of urinary albumin excretion rate (AER) over 24 h to determine albuminuria. RESULTS: A total of 109 patients (36%) had a GFR <60 ml. min(-1). 1.73 m(-2). The overall prevalence of normo-, micro-, and macroalbuminuria was 43 of 109 (39%), 38 of 109 (35%), and 28 of 109 (26%), respectively. Compared with patients with macroalbuminuria, those with normoalbuminuria were more likely to be older and female. After excluding patients whose normoalbuminuric status was possibly related to the initiation of a renin-angiotensin system (RAS) inhibitor before the start of the study, the prevalence of a GFR <60 ml. min(-1). 1.73 m(-2) and normoalbuminuria was 23%. Temporal changes in GFR in a subset of 34 of 109 (32%) unselected patients with impaired renal function were available for comparison over a 3- to 10-year period. The rates of decline in GFR (ml. min(-1). 1.73 m(-2). year(-1)) of -4.6 +/- 1.0, -2.8 +/- 1.0, and -3.0 +/- 07 were not significantly different for normo- (n = 12), micro- (n = 12), and macroalbuminuric (n = 10) patients, respectively. CONCLUSIONS: These results suggest that patients with type 2 diabetes can commonly progress to a significant degree of renal impairment while remaining normoalbuminuric.     

A longitudinal evaluation of urinary glycosaminoglycan excretion in normoalbuminuric type 1 diabetic patients.

BACKGROUND: Previously, we found high urinary glycosaminoglycan (GAG) concentration, together with an altered electrophoretic pattern, in normoalbuminuric type 1 diabetic subjects with hemoglobin A(1c) (HbA(1c)) > or =8.0%. The purpose of this study was long-term evaluation of GAG excretion variations in these patients compared to those with HbA(1c) < 8.0% at baseline who maintained better metabolic control over time. METHODS: We enrolled 26 normotensive, normoalbuminuric type 1 diabetic patients and divided them into two groups according to mean HbA(1c) levels during the follow-up period. GAGs were isolated from 24-h urine samples on two separate occasions, at baseline and after a mean (+/-SD) follow-up of 6.8+/-1.1 years. RESULTS: All patients remained normoalbuminuric at follow-up, and had normal urinary alpha(1)-microglobulin levels. In patients with HbA(1c) <8.0%, total GAG levels and low sulfated chondroitin sulfate-proteoglycan/chondroitin sulfate ratio were almost unchanged during the follow-up period. In contrast, these increased in patients with HbA(1c) > or =8.0% and were significantly related to both HbA(1c) levels and the duration of poor glycemic control. CONCLUSIONS: Our results show a strong influence of hyperglycemic environment on GAG metabolism in diabetes and indicate that the distribution pattern of urinary GAGs, besides their total concentration, may be predictive of altered GAG metabolism in type 1 diabetes.