Familial factors determine the development of diabetic nephropathy in patients with IDDM

Summary To evaluate familial factors in the development of diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) we examined concordance for diabetic nephropathy in families with multiple IDDM siblings. Families (n=110) were identified through Joslin Clinic patients (probands) with a sibling having IDDM. To be eligible, the probands' and siblings' ages at IDDM diagnosis were less than 21 years, and IDDM duration was more than 15 years for probands and more than 10 years for siblings. Mean post-pubertal diabetes duration was 23 years for probands (n=110) and 21 years for siblings (n=125). Nephropathy history was determined by medical record review for deceased patients and those with persistent proteinuria or end-stage renal disease to ascertain the date of onset of persistent proteinuria. For patients without documented nephropathy, the albumin/creatinine ratio was measured in multiple urine samples. The cumulative incidence of persistent proteinuria according to post-pubertal duration of IDDM was determined by life-table analysis. For probands and siblings combined, the cumulative incidence of advanced diabetic nephropathy after 30 years of IDDM was 35%, but the risk in siblings varied according to the proband's renal status. The cumulative risk in siblings after 25 years of IDDM (post-puberty) was 71.5% if the proband had persistent proteinuria but only 25.4% if the proband did not (p<0.001). A difference of nearly 50% in the risk to IDDM siblings, depending upon the IDDM proband's renal status, is consistent with a major gene effect that predisposes an individual with IDDM to develop advanced diabetic nephropathy.Abbreviations IDDM Insulin-dependent diabetes mellitus - C.I. confidence interval     

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

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

Renal functional reserve in IDDM patients

Summary The aim of this study was to determine whether renal functional reserve (RFR) is altered in insulin-dependent diabetic (IDDM) patients according to the stage of diabetic nephropathy. RFR was examined in 33 IDDM patients in similar glycaemic and metabolic control and compared to 12 healthy control subjects, during eight 1 h clearance periods prior to, during and after a 3-h stimulation by amino acid infusion (4.5 mg · kg⁻¹· min⁻¹). RFR was calculated as the difference between stimulated and baseline glomerular filtration rates (GFR). In 14 early normotensive diabetic patients with normal urinary albumin excretion, mean baseline GFR (133 ± 3 ml · min⁻¹· 1.73 m⁻²) was higher whereas RFR (10 ± 4 ml · min⁻¹· 1.73 m⁻²) was lower (p < 0.05) than in control subjects (113 ± 4 and 28 ± 2 ml · min⁻¹· 1.73 m⁻², respectively). In 10 normotensive patients who had lived with IDDM for 16 years and who had microalbuminuria, baseline GFR and RFR (109 ± 7 and 24 ± 6 ml · min⁻¹· 1.73 m⁻², respectively) were similar to those in control subjects. In 9 patients who had suffered IDDM for 23 years and had developed macroalbuminuria and hypertension, baseline GFR (78 ± 8 ml · min⁻¹· 1.73 m⁻²) was lower than in control subjects (p < 0.05) and RFR (8 ± 4 ml · min⁻¹· 1.73 m⁻²) was not significant. In addition, renal vascular resistance decreased significantly during infusion (p < 0.05) in microalbuminuric normotensive patients as well as in control subjects (by 9 ± 4 and 11 ± 4 mm Hg · l⁻¹· min⁻¹· 1.73 m⁻², respectively) but not in normoalbuminuric normotensive or macroalbuminuric hypertensive patients. These results indicate that microalbuminuric normotensive patients retain a normal RFR, whereas RFR is reduced or suppressed at two opposite stages of the disease: in normoalbuminuric normotensive patients with a high GFR and in macroalbuminuric hypertensive patients with a decreased GFR. This dissimilar impairment reveals permanent glomerular hyperfiltration in both early IDDM without nephropathy and IDDM with overt diabetic nephropathy, but not in IDDM with incipient nephropathy. [Diabetologia (1998) 41: 86–93] Received: 12 February 1997 and in final revised form: 28 August 1997     

Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria

Summary In insulin-dependent diabetes mellitus (IDDM), microalbuminuria predicts renal and cardiovascular disease. We report a combined analysis of 235 normotensive IDDM patients with microalbuminuria who participated in two 24-month double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. Of the 225 patients who were evaluable on an intent to treat basis, 25 of 114 placebo-treated patients (21.9%) and 8 of 111 captopril-treated patients (7.2%) progressed to persistent clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p=0.004) with a risk reduction of 69.2% (95% confidence interval (CI): 31.7 to 86.1%). This degree of risk reduction remained at the same level (62.9% [16.1–83.6%], p=0.017) after adjustment for differences in time-varying mean arterial blood pressure. Albumin excretion rate increased by an average of 14.2% [3.1–26.5%] per year in the placebo-treated group compared with a reduction of 9.6% [–18.6–0.4%] per year in the captopril-treated group (p=0.002). The rate of fall of creatinine clearance tended to be faster in the placebo-treated group than in the captopril-treated group (–6.4 [–10.2––2.5] vs –1.4 [–5.3–2.6] ml · min^–1 · 1.73 m^–2, p=0.07). Baseline albumin excretion rate (p<0.0001) and glycated haemoglobin (p=0.03) were independent predictors of progression to clinical albuminuria and changes in mean arterial blood pressure (p=0.02) and serum cholesterol level (p=0.003) were significantly associated with percentage changes in albumin excretion rate. Captopril reduces the risk of progression to overt nephropathy in IDDM patients with microalbuminuria, an effect partly independent of its blood pressure-lowering effects.Abbreviations ACE Angiotensin converting enzyme - IDDM insulin-dependent diabetes mellitus - GFR glomerular filtration rate - C captopril - P placebo - AER albumin excretion rate - MAP mean arterial pressure Corresponding author: Professor G.C. Viberti, Unit for Metabolic Medicine, United Medical and Dental Schools of Guy's and St. Thomas' Hospitals, Guy's Hospital, London SE1 9RT, UKMembership of the Study Group is listed in the Acknowledgement section     

Enhanced erythrocyte Na + /H + exchange predicts diabetic nephropathy in patients with IDDM

Summary Diabetic nephropathy develops in a subset of patients with an apparently hereditary predisposition. Microalbuminuria and elevated arterial pressure have been proposed as predictors of nephropathy but both appear when renal damage is impending. Enhanced sodium-hydrogen exchange in the cell membranes of diabetic patients is an early marker of diabetic nephropathy but its predictive value has not been assessed. In this study, sodium-hydrogen exchange was measured in erythrocytes as an initial velocity of amiloride-inhibited H ⁺ efflux (pH 6.35–6.45) into a Na ⁺ -containing medium (pH 7.95–8.05) in 156 non-microalbuminuric insulin-treated diabetic patients (98 women, 58 men, age 33 ± 8 years, diabetes duration prior to enrollment 15 ± 4 years) during 8 years of follow-up. Enhanced erythrocyte sodium-hydrogen exchange predicted diabetic nephropathy alone and in association with a familial tendency to hypertension/nephropathy with 86 and 96 % sensitivity, and 80 % specificity. Thus, sodium-hydrogen exchange appears to detect a subset of diabetic patients prone to develop renal damage, in whom a more intensive treatment modality might be considered. [Diabetologia (1998) 41: 201–205] Received: 23 April 1997 and in final revised form: 15 September 1997     

Synergistic effect of angiotensin II type 1 receptor genotype and poor glycaemic control on risk of nephropathy in IDDM

Summary We investigated the contribution of polymorphisms in the angiotensin II type 1 receptor gene (AGTR1) to renal complications in an inception cohort of 152 insulin-dependent diabetic (IDDM) patients examined 15–21 years after diabetes onset. This nested case-control study included 79 normoalbuminuric control subjects and 73 cases with evidence of nephropathy ranging from microalbuminuria to overt proteinuria. Subjects were genotyped for two AGTR1 polymorphisms (T⁵⁷³→C and A¹¹⁶⁶→C), and an adjacent CA repeat microsatellite. Allele C¹¹⁶⁶ and the 140 bp allele of the microsatellite were more frequent among nephropathy cases than normoalbuminuric control subjects (0.322 vs 0.247, and 0.618 vs 0.521, respectively), but these differences were not statistically significant. Although not significant by themselves, the AGTR1 polymorphisms contributed significantly to the risk of diabetic nephropathy when accompanied by poor glycaemic control. Among patients with frequent severe hyperglycaemia during the first decade of diabetes, the relative risk of nephropathy among allele C¹¹⁶⁶ carriers was 12.1 (95 % CI: 3.7–39.8), whereas it was only 1.4 (95 % CI: 0.6–3.5) among allele A¹¹⁶⁶ homozygotes. The difference between relative risks was highly significant (χ ² = 8.25, p = 0.004 with 1 df). A similar pattern of higher risk of microalbuminuria, specifically among those carriers of allele C¹¹⁶⁶ who had poor glycaemic control was also found in an independent study of a cross-sectional sample of 551 IDDM individuals, although the effect was smaller in magnitude. We conclude that DNA sequence differences in the AGTR1 gene may modify the noxious effects of hyperglycaemia on the kidney. Allele C¹¹⁶⁶ carriers might especially benefit from nephropathy prevention programmes. [Diabetologia (1997) 40: 1293–1299] Received: 4 March 1997 and in revised form: 18 June 1997     

Latent overhydration and nocturnal hypertension in diabetic nephropathy

Summary With the aim of studying the diurnal variation in blood pressure in relation to degree of fluid retention, 24-h ambulatory blood pressure monitoring was performed in 31 insulin-dependent diabetic patients with nephropathy. The extracellular volume was calculated from the distribution volume of ⁵¹Cr-EDTA after a single injection. The study population was arbitrarily divided into two groups, depending on their extracellular volume. Group 1 included 15 patients with a lower extracellular volume and group 2, 16 patients with a higher extracellular volume. Ambulatory blood pressure was measured with a portable monitor using an oscillometric technique. In all patients, the mean ±SD 24-h ambulatory blood pressure was 135/79±14/7 mm Hg. Day and night-time blood pressures were 136/81±14/7 and 133/75±17/8, respectively (p<0.02). The ambulatory blood pressure was 135/80±14/7 in group 1 and 136/78±15/6 mm Hg in group 2. The nocturnal change in blood pressure was significantly greater in group 1 than in group 2, –9/–9±10/5 mm Hg and 1/–3±10/6 mm Hg, respectively (p=0.005/0.01). There were no other significant differences between the groups than the diurnal blood pressure pattern. There were significant correlations between day ambulatory blood pressure and night ambulatory blood pressure and 24-h ambulatory blood pressure and urinary albumin excretion. There was no correlation between auscultatory clinic blood pressure on the one hand and albuminuria on the other. Latent fluid retention therefore may contribute to nocturnal hypertension in diabetic nephropathy.Abbreviations ECV Extracellular volume - IDDM insulin-dependent diabetes mellitus - ABP ambulatory blood pressure     

Monitoring kidney function in diabetic nephropathy

Summary Progression in diabetic nephropathy is usually determined by repeated measurements of glomerular filtration rate and expressed as rate of decline in glomerular filtration rate. Our aim was to evaluate the agreement between rate of decline in glomerular filtration rate estimated from the Cockroft-Gault formula: (140-age)^*K^*body weight^* (1/S-creatinine) and measured by the plasma clearance of ⁵¹CrEDTA. All insulin-dependent diabetic patients with diabetic nephropathy followed-up for at least 5 years with at least 5 simultaneous measurements of glomerular filtration rate, s-creatinine, and weight were included in the study. Forty-three patients (32 male/11 female), age 31 (18–61) years were enrolled. Observation period: 6.6 (5.1–9.9) years and number of investigations per patient 6 (5–16) (median(range)). Baseline glomerular filtration rate (ml/min) was 97 (30) measured and 107 (37) estimated (mean(SD))(p<0.001) and the 95% limits of agreement were –42.0 to 20.8 ml/min. Measured and estimated glomerular filtration rate correlated significantly (r = 0.91, p<0.00001). Rate of decline in kidney function ml · min^–1 · year^–1 was 4.7 (3.3) measured and 4.8 (3.5) estimated (mean(SD)) (NS), but the 95% limits of agreement showed a wide range –3.9 to 3.5 ml · min^–1 · year^–1. A significant correlation between rate of decline in measured and estimated glomerular filtration rate was present (r = 0.84, p<0.00001). In conclusion, glomerular filtration rate is overestimated by the Cockroft-Gault formula. The mean rates of decline in glomerular filtration rate are comparable, but the limits of agreement are wide, which make the Cockroft-Gault method unacceptable for clinical purposes, i.e. monitoring progression in kidney function in the individual patient. However, the estimated glomerular filtration rate may be used for comparison of groups in observational studies and in clinical trials with a long observation period.Abbreviations GFR Glomerular filtration rate - ⁵¹Cr-ED-TA ⁵¹Chromium ethylene diamine tetra-acetic acid - IDDM insulin-dependent diabetes mellitus     

Cytokine overproduction in healthy first degree relatives of patients with IDDM

Summary Healthy family members of patients with insulin-dependent diabetes mellitus (IDDM) are known to share a number of immunological abnormalities with their affected relatives. Since monocyte and type 1 T-cell-derived cytokines contribute to the pathogenesis of IDDM, we studied the production of these cytokines in the healthy first degree relatives of 29 children with IDDM. We report that circulating tumour necrosis factor-α (TNF-α) and soluble interleukin-2 (sIL-2) receptor were present in increased amounts in non-diabetic family members at levels similar to those found in the diabetic children (duration of disease 3 months–5 years). Furthermore, marked hypersecretion of IL-1α and TNF-α by mitogen-stimulated peripheral blood mononuclear cells was found in both diabetic and healthy family members. Abnormalities of cytokine production in healthy relatives did not correlate with the presence of islet cell antibodies or with HLA DR type. These data indicate that healthy family members of patients with IDDM exhibit overproduction of a number of cytokines that have been implicated in diabetogenesis. [Diabetologia (1998) 41: 343–349] Received: 26 August 1997 and in revised form: 24 October 1997     

Insertion/deletion polymorphism in the angiotensin-l-converting enzyme gene is associated with coronary heart disease in IDDM patients with diabetic nephropathy

Summary Insulin-dependent diabetic (IDDM) patients with diabetic nephropathy have a highly increased morbidity and mortality from coronary heart disease. An insertion (I) /deletion (D) polymorphism in the angiotensin-I-converting enzyme (ACE) gene has been shown to be associated with coronary heart disease. Therefore, we have investigated the role of this ACE/ID polymorphism in 198 IDDM patients with diabetic nephropathy and 190 normoalbuminuric IDDM patients. The prevalence of myocardial infarction and other coronary heart disease was significantly elevated in patients with nephropathy, 19 % (38/198) vs 8 % (15/190), p < 0.001. In the nephropathic group 12 of 63 (19 %), 23 of 95 (24 %), and 3 of 40 (7.5 %) patients with the DD, ID and II genotypes, respectively had a history of coronary heart disease, II vs DD and ID, p < 0.05 when compared to nephropathic patients without coronary heart disease. Multiple logistic regression analysis of the risk factors associated with coronary heart disease in univariate analysis revealed that the II genotype acts as an independent protective factor against coronary heart disease, odds ratio II/DD + ID 0.27 (95 % confidence interval 0.07–0.97, p < 0.05). There was no difference in genotype or allele frequency (D/I) between patients with and without nephropathy, 0.56/0.44 in both groups, but plasma ACE concentration was elevated in patients with nephropathy 609 (151–1504) ng/ml as compared to patients with normoalbuminuria, 428 (55–1630) ng/ml, p < 0.001. We suggest that ACE/ID polymorphism may influence the frequency of life-threatening cardiac complications in IDDM patients suffering from diabetic nephropathy, a condition characterized by increased plasma ACE concentration. [Diabetologia (1995) 38: 798–803] Received: 10 October 1994 and in revised form: 20 December 1994     

Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM

Summary Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n=242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n=187); a geographically defined cohort of newly diagnosed diabetic patients (n=341); and IDDM patients with long duration of disease (>15 years) and no evidence of overt nephropathy (n=166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p=0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p=0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.Abbreviations IDDM Insulin-dependent diabetes mellitus - ACE angiotensin converting enzyme - PCR polymerase chain reaction - LDNN long duration-non-nephropathy group - I/D insertion/deletion - RAS renin-angiotension system     

糖尿病视网膜病变合并糖尿病肾病的危险因素及其预测价值

目的探讨糖尿病视网膜病变(DR)合并糖尿病肾病(DN)的危险因素及预测价值。方法回顾性分析2017年5月至2018年5月南京医科大学附属无锡市人民医院内分泌科收治的2型糖尿病(T2DM)患者1 969例,其中糖尿病视网膜病变(DR)合并糖尿病肾病(DN)患者609例,单纯DR患者746例,未并发DN和DR患者614例,比较3组患者的血糖、血压、肝功能和肾功能指标水平,分析DR合并DN的危险因素及预测价值。采用SPSS 18.0统计软件对数据进行分析。组间比较采用单因素方差分析或χ~2检验。多因素logistic回归分析DR合并DN的危险因素。受试者工作特征(ROC)曲线分析因素预测DR合并DN的价值。结果除高密度脂蛋白胆固醇(HDL-C)水平和左侧颈动脉内膜中层厚度(IMT)外,3组患者其余指标差异均具有统计学意义(P0.05)。多因素logistic回归分析结果显示年龄(OR=0.966,95%CI 0.932～1.000; P=0.049)、白蛋白(ALB)(OR=0.872,95%CI 0.837～0.908; P0.001)、服用他汀类药物(OR=0.400,95%CI 0.265～0.606; P0.001)是DR合并DN的保护因素,高血压病程(OR=1.021,95%CI 1.005～1.037; P=0.011)、收缩压(OR=1.018,95%CI 1.007～1.029; P=0.002)、空腹血糖(OR=1.054,95%CI 1.002～1.108; P=0.040)、甘油三酯(OR=1.133,95%CI 1.021～1.256;P=0.019)、低密度脂蛋白胆固醇(OR=1.355,95%CI 1.017～1.805; P=0.038)、血尿酸(OR=1.124,95%CI 1.016～1.244;P=0.023)、胱抑素C(OR=2.466,95%CI 1.495～4.068; P0.001)、眼底评分(OR=1.275,95%CI 1.088～1.494; P=0.003)、左室后壁厚度(OR=1.306,95%CI 1.051～1.622; P=0.016)和颈动脉粥样斑块形成(OR=1.578,95%CI 1.051～2.370;P=0.028)为危险因素。ROC曲线分析结果表明胱抑素C预测DR合并DN价值最高,AUC为0.677。结论 T2DM患者DR合并DN的患病率较高,其发生与多种因素相关,其中,胱抑素C预测DR合并DN价值最高。     

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

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

2型糖尿病患者高敏C-反应蛋白与糖尿病肾病的关系

目的:探讨2型糖尿病肾病(DN)不同时期血清高敏C-反应蛋白(hs-CRP)的浓度变化与DN的关系。方法:采用速率散射比浊法测定144例2型糖尿病患者和49名正常对照的血清hs-CRP水平。根据尿白蛋白排泄率(UAER)将2型糖尿病患者分为3组:正常蛋白尿组53例、微量白蛋白尿组57例和临床蛋白尿组34例。结果:(1)2型糖尿病组的血清hs-CRP值较对照组显著升高(U=1458.5,P<0.001);(2)hs-CRP值随UAER的增加而增加(H=74.068,P<0.001);(3)hs-CRP值与空腹血糖、血尿酸、纤维蛋白原成正相关(r=0.26、0.33、0.30,P均<0.001),与高密度脂蛋白呈负相关(r=-0.14,P<0.05)。结论:C-反应蛋白可能参与了2型糖尿病和糖尿病肾病的发生发展。     

肥胖与2型糖尿病肾病

肥胖不仅是糖尿病、冠心病、高血压的高危因素,还可能导致肾脏损害。糖尿病肾病是糖尿病常见的慢性微血管并发症,是造成终末期肾病的主要原因。已有研究证明肥胖的2型糖尿病患者具有明显的多种代谢异常,能促进糖尿病肾病的发生发展。本文就肥胖导致糖尿病患者肾脏的损伤机制及糖尿病肾病的相关药物治疗做一综述。     

Arterial hypertension and microalbuminuria in IDDM: The Italian Microalbuminuria Study

Summary Arterial hypertension and poor glycaemic control are central to the development of microalbuminuria in insulin-dependent diabetes mellitus (IDDM). Recent consensus has established sensitive criteria for their detection and treatment, although the proportion of patients who may benefit is unclear. Between 1988 and 1990, we measured urinary albumin to creatinine concentration ratio (A/C) in 3,636 adult out-patients with IDDM of more than 3 years duration, serum creatinine under 133 mol/l and who were not undergoing antihypertensive treatment. A/C indicating microalbuminuria (2.38/ 2.96 mg/mmol, male/female) was found in 620 of 3,451 patients without proteinuria, and associated with hypertension (blood pressure 140 and/or 90 mm Hg; p=0.0016; rate: 39.6%), independent of diabetes duration (p=0.0082) and male gender (p=0.0350; relative risk=1.16; 95% confidence interval: 1.01–1.32). Hypertension was less common among those with normal A/C (27.5%, p<0.0001) but was positively related with diabetes duration. Of the 1,015 patients with A/C>2.0 mg/mmol 529 were reexamined. Glycated haemoglobin levels exceeded 3 SD above the mean of normal in 84.3% of the 198 microalbuminuric patients (AER=20–200 g/min), but were comparably poor (79.2%) in normoalbuminuria. Duration of diabetes was inversely related to glycated haemoglobin only in microalbuminuria (0.05<p<0.1). Intervention to lower blood pressure remains mainly restricted to those patients with long-term diabetes and slower development of kidney disease. Near-normalisation of glycaemia remains the priority for the majority of patients with microalbuminuria.Abbreviations UAlb Urinary albumin concentration - A/C urinary albumin to creatinine concentration ratio - AER urinary albumin excretion rate - C. I. confidence interval - df degrees of freedom     

Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy

Summary The Steno hypothesis suggests that albuminuria reflects widespread vascular damage (proliferative retinopathy and severe macroangiopathy) due to a generalized vascular (endothelial) dysfunction. We assessed this concept in NIDDM (non-insulin-dependent diabetic) patients with (13 female/39 male, age 60 ± 7 years, group 1) and without (12 female/41 male, age 61 ± 7 years, group 2) diabetic nephropathy compared to matched non-diabetic subjects (7 female/15 male, age 58 ± 8 years, group 3). A 12-lead ECG was recorded and coded blindly using the Minnesota Rating Scale; the World Health Organization cardiovascular questionnaire was used to assess past and present evidence of myocardial infarction, angina pectoris, stroke, and peripheral vascular disease (digital systolic blood pressure determination). The degree of diabetic retinopathy was scored from fundus photography. The following variables were measured: transcapillary escape rate of albumin (initial disappearance of intravenously injected ¹²⁵I-labelled human serum albumin), plasma concentrations of prorenin (radioimmunoassay) and serum concentrations of von Willebrand factor (enzyme-linked immunoadsorbent assay). Prevalence of ischaemic heart disease (ECG reading) (49/20/5)% and peripheral vascular disease as indicated by reduced systolic blood pressure on big toe (69/30/14)% was significantly higher in group 1 vs group 2 (p < 0.01) and in group 2 vs group 3 (p < 0.01), respectively. The prevalence and severity of retinopathy was higher in group 1 vs 2 (p < 0.01). Transcapillary escape rate of albumin (%/h) was elevated in group 1 and 2 as compared to control subjects: 7.9 (4.3–13.7); 7.4 (3.7–16.4) vs 6.0 (3.4–8.7), (p < 0.005), respectively. Plasma prorenin activity (IU/ml) was raised in group 1 and group 2 as compared to group 3: 272 (59–2405); 192 (18–813), and 85 (28–246), p < 0.001, respectively. Serum von Willebrand factor (IU/ml)was elevated in group 1 as compared to group 2 and 3: 2.07 (0.83–4.34); 1.60 (0.30–2.99) and 1.50 (1.00–2.38), p < 0.001, respectively. Our study demonstrated that NIDDM patients with and without albuminuria had increased transcapillary escape of albumin and raised prorenin activity, whereas only those with albuminuria had increased von Willebrand factor. Patients with NIDDM may have abnormal endothelial function in the absence of albuminuria. [Diabetologia (1996) 39: 1590–1597]     

Uptake mechanisms for ascorbate and dehydroascorbate in lymphoblasts from diabetic nephropathy and hypertensive patients

Summary In diabetic nephropathy and hypertension, a major cause of mortality is from cardiovascular disease. Since low levels of antioxidants such as vitamin C have been associated with such complications, we have examined the uptake mechanisms for ascorbic acid (AA) and dehydroascorbic acid (DHA) in lymphoblasts from normal control subjects (CON), normoalbuminuric insulin-dependent diabetic (IDDM) patients (DCON), patients with IDDM and nephropathy (DN) and hypertensive patients (HT) using mass assays of uptake and measuring AA using high-performance liquid chromatography. Precautions were taken to prevent oxidation of AA and to take into account the instability of DHA in buffers. DHA uptake was the major mechanism in all four groups of subjects, and the V_max (maximal uptake rate) was significantly lower in the DN cells (24.7 ± 1.0 nmol [95 % confidence intervals CI 22.5, 26.3] 10⁶ cells^–1 h^–1) compared to CON and DCON cells (33.9 ± 2.1 [95 % CI 29.4, 38.4] and 37.0 ± 2.2 [95 % CI 32.2, 41.8] nmol 10⁶ cells^–1 h^–1, respectively, p < 0.001 for both). DHA V_max was also lower in the HT group (23.2 ± 1.1 [95 % CI 20.7, 25.7] nmol 10⁶ cells^–1 h^–1) compared to the CON group (p < 0.001). There were no significant differences in the K_m or passive membrane permeability for DHA or the AA uptake. DHA uptake showed a negative correlation to systolic blood pressure (r _s = –0.49, p < 0.001). These findings suggest that impaired DHA uptake may be one component of the phenotype expressed by DN cells that may persist in culture. Impaired DHA uptake in vivo, especially in the presence of hyperglycaemia, leads to impaired regeneration of AA and depletion of anti-oxidant defences, exposing such individuals to increased risk of cardiovascular disease. [Diabetologia (1998) 41: 435–442] Received: 10 July 1997 and in final revised form: 24 November 1997     

Prevalence of left ventricular hypertrophy in Type I diabetic patients with diabetic nephropathy

Summary The increased mortality of patients with diabetic nephropathy is mainly due to cardiovascular disease and end stage renal failure. Left ventricular hypertrophy is an independent risk factor for myocardial ischaemia and sudden death. The aim of our cross-sectional study was to evaluate left ventricular structure and function in Type I (insulin-dependent) diabetic patients with diabetic nephropathy. M-mode and Doppler echocardiography were done on 105 Type I diabetic patients with diabetic nephropathy [61 men, age (means ± SD) 44 ± 9 years, and albuminuria [median(range)] 567(10–8188) mg/24 h, serum creatinine 109 (53–558) μmol/l], and 140 Type I diabetic patients with persistent normoalbuminuria [79 men, 47 ± 10 years, urinary albumin excretion rate 8 (0–30) mg/24 h, and serum creatinine 81 (55–121) μmol/l]. Patients with and without nephropathy were comparable with respect to sex, body mass index, and duration of diabetes. Arterial blood pressure was slightly higher in patients with nephropathy: 140/79 ± 17/9 mm Hg vs 134/78 ± 15/8 mm Hg, p < 0.01, and the majority of proteinuric patients received antihypertensive drugs, 84 vs 17 %, respectively, p < 0.001. Left ventricular mass index was increased in the nephropathic group (means ± SD) 100.6 ± 23.9 g/m² compared with the normoalbuminuric group 91.4 ± 21.9 g/m², p = 0.002. Left ventricular hypertrophy was found more often in patients with nephropathy 23 (14–31)% compared with patients with normoalbuminuria 9 (5–14)%, p < 0.005. Diastolic function, assessed by the ratio between the peak diastolic velocity and the peak atrial systolic velocity (E/A ratio) and isovolumic relaxation time, was reduced in patients with vs without nephropathy: 1.17 ± 0.29 vs 1.34 ± 0.32, and 81.7 ± 16.5 vs 74.6 ± 14.5, p < 0.001 and p = 0.002, respectively. Systolic function was about the same and normal in both groups. Our study suggests that an increase in left ventricular mass index and a decrease in diastolic function occurs early in the course of diabetic nephropathy. [Diabetologia (1999) 42: 76–80] Received: 16 April 1998 and in final revised form: 5 August 1998     

Monitoring kidney function in diabetic nephropathy

We investigated the validity of a one plasma sample method (I) compared with a multiple plasma sample method (II) for routine clinical determination of glomerular filtration rate (GFR) in 35 insulin-dependent diabetic patients suffering from nephropathy. GFR was measured after an intravenous bolus injection of 100 microCi 51Cr-EDTA by determination of plasma radioactivity in venous blood samples taken from the other arm 180, 200, 220 and 240 min after the injection (II). The plasma radioactivity in the sample drawn 240 min after injection was used in method I. During the mean investigation period of 32 months (12-62 months) a total of 184 GFR determinations were performed. The average interval between the GFR measurements was 6 months (1-21 months). In 127/184 of the study intervals method I indicated a decrease in GFR. The corresponding figure for method II was almost identical, 130/184. The mean decline in GFR was 8.1 +/- 7.2 and 7.8 +/- 6.9 ml year-1 1.73 m-2 using methods I and II, respectively (NS). The methods essentially provided the same GFR values in absolute terms (r = 0.98, P less than 0.001). We conclude that the one plasma sample method can be used as a valid routine technique in non-uraemic patients with nephropathy.