A quantitative ultrastructural study of juxtaglomerular arterioles in IDDM patients with micro- and normoalbuminuria

Summary Hyalinization of juxtaglomerular arterioles is prominent in advanced diabetic nephropathy and may have important functional consequences. We studied the early stages of diabetic renal disease using kidney biopsy material from insulin-dependent diabetic patients, 8 with normal albumin excretion rate (<15 /min) and 16 with microalbuminuria (15–200 g/min). Ten living non-diabetic kidney donors served as a control group. Median duration of diabetes was 9.5 years (range 5–31) in patients with normoalbuminuria, and 12 years (7–22) in patients with microalbuminuria (p=0.27). The tissue was sectioned systematically, 1-m thick sections for light microscopy at 10-m intervals, and thin sections for electron microscopy taken at 60-m intervals. The arterioles were identified as afferent or efferent, and total profiles were photographed (magnification 7500×), providing a systematic independent sample for measurements using standard stereological methods. Patients with microalbuminuria had significantly increased arteriole parameters compared with the control group: for afferent and efferent arterioles the volume fraction of matrix/media, means and (coefficient of variation, CV), was 0.47 (0.16) vs 0.33 (0.19) (p=0.0009), and 0.62 (0.14) vs 0.45 (0.23) (p=0.0004) and matrix-T, expressing amount of matrix per unit arteriolar surface, 2.38 (0.38) m vs 1.44 (0.30) m (p=0.004), and 1.62 (0.28) m vs 1.03 (0.34) (p=0.0009). Patients with normoalbuminuria showed no significant differences from the control group, and had lower values than microalbuminuric patients for all parameters except the afferent matrix-T. In the normoalbuminuric group a correlation was found between parameters for afferent arterioles and those for glomerular structure. In conclusion there is arteriolar accumulation of extracellular material in the early phase of diabetic nephropathy, concomitant with early glomerulopathy.Abbreviations IDDM Insulin-dependent diabetes mellitus - GFR glomerular filtration rate - AER albumin excretion rate - matrix-T matrix thickness - ND non-diabetic subjects - D_NA IDDM patients with normal albumin excretion rate - D_MI IDDM patients with microalbuminuria - RPF renal plasma flow - CV coefficient of variation     

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     

Effect of angiotensin converting enzyme inhibitor or beta blocker on glomerular structural changes in young microalbuminuric patients with Type I (insulin-dependent) diabetes mellitus

Aims/hypothesis. To investigate the influence of angiotensin converting enzyme inhibitors and beta blockers on the progression of early diabetic glomerulopathy. Methods. Thirteen patients with Type I (insulin-dependent) diabetes mellitus (mean age 18.8 years) with microalbuminuria 31 (19–160) μg/min were randomised to treatment with enalapril (group 1, n = 7) or metoprolol (group 2, n = 6). Renal biopsies were taken before and after 38 (36–48) months of treatment. Albumin excretion rate, blood pressure and HbA_{1 c} were measured every third month. A reference group without antihypertensive treatment (group 3, n = 9), with similar age, diabetes duration and degree of microalbuminuria as group 1 and 2, had baseline and follow-up renal biopsies taken previously with an interval of 26–34 months, analysed at the same laboratory. Glomerular structures were measured by stereological methods. Results. Measurements of basement membrane thickness, mesangial and matrix volume fractions were similar among groups at baseline. Structural variables were only increased in group 3 at follow-up. Delta values in basement membrane thickness and diabetic glomerulopathy index per 24 months were lower in group 1 and 2 than in group 3 (p < 0.05). Microalbuminuria returned to normal in group 1 and 2 only. Decreased albumin excretion rate tended to inversely correlate with increased basement membrane thickness (p = 0.08) and diabetic glomerulopathy index (p = 0.05). Mean HbA_{1 c} was similar between groups. Mean diastolic blood pressure was lower in group 1 and 2 than in group 3 (p < 0.01). Mean HbA_{1 c} and mean diastolic blood pressure correlated to changes in basement membrane thickness, mesangial volume fraction and diabetic glomerulopathy index (p < 0.05). Conclusion/interpretation. Contrary to findings in the group without antihypertensive treatment, no progression of glomerulopathy was seen in those treated with enalapril or metoprolol. [Diabetologia (1999) 42: 589–595] Received: 11 November 1998 and in revised form: 21 December 1998     

The number of glomeruli in Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients

Summary The number of glomeruli per kidney in Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients was estimated by an unbiased stereological method: the fractionator. No significant differences were observed between Type 1 and Type 2 diabetic patients without severe diabetic glomerulopathy and non-diabetic patients. Diabetic patients with proteinuria who were in the early stages of diabetic nephropathy also had a normal number of glomeruli. On the other hand, a subgroup classified as Type 1 diabetic patients with severe diabetic glomerulopathy had significantly less glomeruli compared with Type 1 diabetic patients with mild or no glomerulopathy. A probable explanation is that Type 1 diabetic patients lose glomeruli in relation to the progression of diabetic glomerulopathy. A more theoretical alternative is, however, that development of diabetic glomerulopathy is facilitated by a low number of glomeruli.Presented in part at the first meeting of the European Diabetic Nephropathy Study Group, Pisa, Italy, April 1988, and at the 23rd annual meeting of the Scandinavian Society for the Study of Diabetes, Bergen, Norway, May 1988     

Population-based survey and analysis of trends in the prevalence of diabetic nephropathy in Type 1 diabetes.

AIMS: To determine the prevalence of the various stages of diabetic nephropathy in Type 1 diabetes in a population-based survey. To make direct comparison with results from previous published studies to assess current trends. METHODS: Identification of all Type 1 patients using a population-based diabetes register. Urine samples for albumin assay were obtained at clinic visit and by postal request. Prevalence rates were calculated specifically for direct comparisons with previously published surveys. RESULTS: This study and European data from the 1990s show a clear reduction in the cumulative prevalence of microalbuminuria and established nephropathy compared with surveys from Copenhagen (1985), Pittsburgh (1986-8) and Boston (1992). In North Wales in 1999 the overall cumulative prevalence of microalbuminuria was 27.2% (95% confidence interval (CI) 24.3-30.1%) and established nephropathy was 9.6% (7.7-11.5%). Comparisons with data from EURODIAB and from Spain indicated similar results, although the prevalence of microalbuminuria was lower in North Wales than in the EURODIAB study. Significantly lower rates of nephropathy were seen in more recent Swedish cohorts. Diabetic nephropathy remains more common in males. Microalbuminuria before 10 years duration of diabetes was seen at all post-pubertal ages. CONCLUSIONS: Rates of nephropathy in Europe in the 1990s are lower than a decade ago. Modern methods of management are therefore associated with demonstrable benefit at the population level. The lowest rates of nephropathy are associated with optimum glycaemic control in Swedish data, indicating the importance of metabolic in addition to haemodynamic factors.     

Lack of synergism between long-term poor glycaemic control and three gene polymorphisms of the renin angiotensin system on risk of developing diabetic nephropathy in Type I diabetic patients

Aims/hypothesis. Reports on a putative synergism between poor glycaemic control and carriage of the angiotensin II type 1 receptor (AGTR1) C¹¹⁶⁶-allele and risk of diabetic nephropathy have been conflicting. Therefore, we investigated the interaction between long-term glycaemic control and three polymorphisms in the genes coding for AGTR1 (A¹¹⁶⁶→C), angiotensin converting enzyme (ACE/ID) and angiotensinogen (M235T) on risk of developing diabetic nephropathy. Furthermore, we investigated the relation between a random measurement and long-term measurements of haemoglobin A_{1 c} (HbA_{1 c}).¶Methods. We studied Caucasian patients with Type I (insulin-dependent) diabetes mellitus and nephropathy (120 men 74 women, age 41.1 ± 9.6 years, diabetes duration 28 ± 8 years) and long-standing Type I diabetic patients with persistent normoalbuminuria (112 men 69 women, age 42.5 ± 10.0 years, diabetes duration 27 ± 9 years). Genotyping was PCR-based and metabolic control estimated from all measurements of HbA_{1 c} done in each patient [average (range) n = 31 (6–74)]. The median observation time (range) was 13.5 (2–14) years.¶Results. Type I diabetic patients with a history of poor glycaemic control (HbA_{1 c} above the median, 8.7 %) had an increased risk of diabetic nephropathy compared with patients with a better metabolic control, OR (95 % CI): 9.2 (5.8–14.7). The magnitude of this risk was similar in carriers and non-carriers of the mutations. The risk of nephropathy in patients with HbA_{1 c} above compared with below the median in carriers of the mutant C¹¹⁶⁶-allele, D-allele, or T235-allele were 7.6 (95 % CI: 3.9–14.8), 10.4 (6.0–17.8) and 9.8 (5.4–17.9), respectively. A significant correlation (r = 0.74, p < 0.001) existed between a random and long-term measurements of HbA_{1 c} with a small mean difference (limits of agreement) [0.2 (–1.8 to 2.1) %] between the two estimates.¶Conclusion/interpretation. Poor metabolic control is a major risk factor for diabetic nephropathy in Caucasian Type I diabetic patients. This risk was similar in carriers and non-carriers of the mutant alleles of the AGTR1(A¹¹⁶⁶→C), ACE/ID and angiotensinogen-M235T polymorphisms. The HbA_{1 c} value measured at random reflects rather closely average long-term HbA_{1 c} values. [Diabetologia (2000) 43: 794–799]     

糖尿病患者经皮肾穿刺活检术的安全性评估及其临床意义

目的:动态监测糖尿病(DM)患者行经皮肾穿刺活检术后并发症的发生率及其特点,结合肾活检病理检查结果,阐述糖尿病肾病(DN)患者肾活检的意义。方法:观察行肾活检穿刺的DM患者111例。肾活检采用实时B超引导下斜角进针负压吸引法。术后进行B超动态监测,分别观察肾活检术后第4h、8h、24h、48h、72h肾周血肿、肉眼血尿、严重腹痛、低血压、血红蛋白下降等并发症的发生情况。结果:(1)本研究观察到的并发症主要包括肾周血肿、肉眼血尿。其中,单纯肾周血肿24例,单纯肉眼血尿7例,4例既有肉眼血尿又有肾周血肿,肾周血肿总发生率为25.23%,肉眼血尿总发生率为9.91%,均无需特殊处理可自行缓解。28例中8例肾周血肿(7.21%)面积大于4cm2,20例(18.02%)为面积2～4cm2的小血肿。其中症状性血肿3例,发生率为2.7%。8例大血肿患者中5例为DN(3例肾功能不全,SCr114.9～152.9μmol/L),2例合并IgA肾病(IgAN),1例合并膜增生性肾小球肾炎。大血肿集中发生在4h内。发生肉眼血尿的11例患者中,6例为DN(4例为肾功能不全患者),4例合并IgAN,1例合并微型多动脉炎。患者肾活检针数有5例超过2针。发生时间集中在8h内。(2)111例患者肾活检病理结果示DN占72.07%,非糖尿病肾病占27.93%,其中IgAN占18.02%,膜性肾病占7.21%,其他类肾脏疾病类型占2.7%。结论:DM患者肾活检术后常见并发症为肾周血肿、肉眼血尿,主要发生在8h内,尤以4h内多见。这些并发症无需特殊处理,均可自行缓解。患者SCr升高,穿刺针数增加及合并IgAN和系统性血管炎者出血风险增加。DM患者肾活检术后并发症的发生率并不高于其他慢性肾脏疾病。正确掌握肾活检适应证,强调术前全面检查和提高肾活检操作技术水平,是保证肾活检安全性的关键,也是提高DN诊治水平必不可少的检查。     

Glomerular structure and function in proteinuric Type 2 (non-insulin-dependent) diabetic patients

Summary Glomerular ultrastructure was examined in a series of 20 Type 2 (non-insulin-dependent) diabetic patients with proteinuria. Reference was made to data previously obtained in non-diabetic kidney donors and in Type 1 (insulindependent) diabetic patients with similar degrees of proteinuria. The Type 2 diabetic patients demonstrated the changes which characterize the diabetic glomerulopathy seen in Type 1 diabetic patients: basement membrane thickening, and increase in the mesangium and mesangial matrix expressed as fraction of the glomerular volume. Among the Type 2 diabetic patients there was more variation then among the Type 1 diabetic patients, as this group included subjects with normal parameters. The group means and coefficients of variation (=SD/mean) of the glomerulopathy parameters combined in the glomerulopathy index=basement membrane thickness/10+V_v(matrix/glom)·100 were 81 (0.30) and 92 (0.15) in the two diabetic groups, clearly different from the non-diabetic index, 42 (0.16). All Type 2 diabetic patients who also had retinopathy had a glomerulopathy index above the normal range. Similar changes in glomerular composition were seen in the two diabetic groups: with increasing glomerulopathy the volume of matrix dominated over the peripheral basement membrane, and a shift in the ratio of interfaces was seen: mesangial surface towards capillary lumen increased relative to the urinary surface, and peripheral capillary surface comprised less of the total capillary surface. Data indicated marked glomerular hypertrophy, which correlated with the mesangial volume fraction, thus encompassing preserved filtration surface per glomerulus. An inverse correlation obtained between the index of glomerulopathy and current glomerular filtration rate, as well as the ensuing rate of decline in glomerular filtration rate, as well as the ensuing rate of decline in glomerular filtration rate: (index (glomerulopathy) vs rate of decline in glomerular filtration rater=0.84,p<0.0001). No correlation was found between glomerular volume and the ensuing rate of decline in glomerular filtration rate.     

The long-term renal and retinal outcome of childhood-onset Type 1 diabetes.

AIMS: To quantify the influence of childhood onset on long-term renal and retinal outcome in Type 1 diabetes. METHODS: We used a population-based diabetes register to identify all Type 1 patients diagnosed before age 15 from 1960 to 1982 and resident in a defined catchment area in 1999. Those diagnosed before age 5, aged 5-9 and 10-14 years were compared with a reference group diagnosed at age 21-25 years over the same period. RESULTS: Compared with adult-onset controls, proteinuria occurred earlier (P = 0.02) and nephropathy outcome was worse (P = 0.008) in childhood-onset diabetes. The risk of developing microalbuminuria was greater in childhood-onset diabetes: odds ratio 2.6 (95% confidence interval 1.4-4.9, P = 0.003). The relative risk of established nephropathy was 3.8 (1.5-9.4, P = 0.005) with childhood onset. The number developing background retinopathy did not differ with age at onset but younger onset patients were more likely to need laser treatment: relative risk 2.1 (1.1-3.8, P = 0.02). This maintained visual outcome which was not significantly different between the various age at onset groups. CONCLUSIONS: Patients with onset of Type 1 diabetes before age 15 have substantially worse renal outcome and require more laser treatment than adult-onset patients. Differences between those with onset before age 5, onset at 5-9 and 10-14 years are small compared with the difference between childhood onset and adult onset. Events in the teenage years therefore appear to have a major adverse effect on the risk of developing long-term microvascular complications.     

糖尿病肾病患者肾小球基因表达谱及其与病情进展的关系

目的 :研究糖尿病肾病 (diabeticnephropathy ,DN)患者肾小球基因表达谱与正常人之间的差异 ,及其在DN病程进展中的变化。　 方法 :选择分别处于微量白蛋白尿期 ,临床蛋白尿期及伴有肾功能损害期的 3例DN患者 ,并以性别、年龄与患者匹配的 2例正常供肾组织作为对照。首次应用显微微分离法获取肾活检标本中的肾小球 ,进行肾小球细胞数目扩增 ,利用AffymetrixU133A基因芯片技术检测其基因表达谱的变化 ,以生物信息学工具作聚类分析。　 结果 :与正常对照组相比 ,DN患者肾小球内表达水平显著上升或下降的基因共有 182条(P <0 0 1)。聚类分析将显著差异表达基因群分为表达水平显著升高、表达水平下降和持续性显著下降三个特殊亚群。功能分析发现 ,DN患者肾小球基因表达谱的变化突出表现在某些与细胞内异常糖和脂质代谢、细胞增殖、细胞外基质合成和细胞因子相关基因上 ,特别是脂质代谢相关基因。部分基因的表达变化与DN病情进展有一定相关性 ,存在随病情进展表达水平逐渐增加、在DN病程早期应答和随病情进展表达水平逐渐下降的三组基因。未发现转化生长因子 β1在DN患者肾小球细胞内mRNA表达水平呈现显著变化。　 结论 :与正常人相比 ,DN患者肾小球基因表达谱的变化突出表现在某些与细胞内异常糖和脂质代谢     

Short-term moderate sodium restriction induces relative hyperfiltration in normotensive normoalbuminuric Type I diabetes mellitus

Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is associated with an increased extracellular volume. Sodium restriction might seem a logical form of treatment but data on its renal effects is conflicting. We therefore studied the effects of sodium restriction on renal haemodynamics in uncomplicated Type I diabetes mellitus. Methods. Uncomplicated Type I diabetic patients (n = 24) and matched control subjects (n = 24) were studied twice in random order: after a week of 50 mmol or after 200 mmol sodium intake, respectively. The diabetic patients were studied under normoglycaemic clamp conditions. Glomerular filtration rate and effective renal plasma flow were measured as the clearances of iothalamate and hippuran, respectively. Results. During liberal sodium intake, glomerular filtration, effective renal plasma flow and filtration fraction were similar between the diabetic patients and the control subjects. Sodium restriction decreased the effective renal plasma flow in both groups, whereas glomerular filtration rate only decreased in the control subjects. Consequently, in the diabetic patients, the filtration fraction was increased on low sodium (4.1 ± 8.4 %, p < 0.05 vs liberal sodium). As a consequence, filtration fraction (24.0 ± 2.6 vs 22.1 ± 2.0 %, p < 0.05) and glomerular filtration (119 ± 14 vs 110 ± 13 ml/min, p < 0.05) were higher in the diabetic patients than in the control subjects during sodium restriction. Conclusion/interpretation. Short-term moderate sodium restriction induces relative hyperfiltration in uncomplicated Type I diabetes. This could indicate an increased intraglomerular pressure. Sodium restriction could be an unfavourable preventive approach in diabetes mellitus but its long-term effects are not known. [Diabetologia (2002) 45: ▪–▪] Received: 17 September 2001 and in revised form: 7 November 2001     

Human leucocyte antigen and insulin gene regions and nephropathy in Type I diabetes

Abstract Aims/hypothesis. Diabetic nephropathy seems to have a strong genetic component. Genes involved in the genetic susceptibility to Type I (insulin-dependent) diabetes have been suggested to have a role in the development of diabetic nephropathy. This study aimed to examine the role of human leucocyte antigen and insulin genes in susceptibility to nephropathy in patients with Type I diabetes. Methods. We carried out a genetic association study examining insulin gene polymorphisms using three large cohorts of patients with Type I diabetes: nephropathy (n = 258), long duration non-nephropathy (n = 153) and a recently diagnosed (sporadic) diabetic cohort (n = 264). Human leucocyte antigen typing results were obtained in a smaller number due to assay failures (n = 182, 126 and 200 respectively). Results. No significant difference was seen in the distribution of human leucocyte antigen A, B, C, DR, DQA1 and DQB1 haplotypes and alleles between the three diabetic cohorts. No significant difference was seen in insulin ’ + ' and ’–' genotypes and alleles between the three diabetic cohorts. Conclusion/interpretation. Human leucocyte antigen and insulin gene loci are unlikely to have a major role in the susceptibility to nephropathy in Caucasian patients with Type I diabetes in the United Kingdom. [Diabetologia (1999) 42: 1017–1020] Received: 6 November 1998 and in final revised form: 31 March 1999     

2型糖尿病伴肾脏病变患者肾活检指征探讨

目的 研究2型糖尿病(DM)伴肾脏病变怀疑合并非糖尿病肾病(NDN)患者肾活检的指征及临床特征.方法 对53例2型糖尿病患者[因①急性肾衰竭7例;②突出的肾小球源性血尿6例;③糖尿病病程＜5年而蛋白尿＞0.5 g/24h者29例;④糖尿病病程＞5年、大量蛋白尿而血压正常者(肾活检指征)11例]行肾活检、眼底和常规实验室检查.24例因其他原因肾活检、住院期间发现2型糖尿病的患者做对照.结果 糖尿病肾病(DN)占51%,非糖尿病肾病占49%,其中系膜增生性肾炎最多见占1/3.病程越长,糖尿病肾病发生率越高;伴有糖尿病眼部病变[糖尿病视网膜病、白内障、晶体或(和玻璃体)浑浊]者肾活检均为糖尿病肾病.非糖尿病肾病患者糖尿病眼部病变少,糖尿病肾病病程短.肾活检指征②非糖尿病肾病的检出率最高(83.3%),指征④最低(18.2%).结论 糖尿病眼部病变预测糖尿病肾病的特异性为100%;2型糖尿病合并非糖尿病肾病患者血尿突出,糖尿病病程短,糖尿病眼部病变少见.     

Glucose-induced changes in renal haemodynamics in proteinuric Type 1 (insulin-dependent) diabetic patients: inhibition by acetylsalicilic acid infusion

Summary The effect of hyperglycaemia on renal function in diabetic nephropathy remains poorly understood. We investigated the renal haemodynamic response to an acute plasma glucose rise from sustained euglycaemia to sustained hyperglycaemia in eight persistently proteinuric Type 1 (insulin-dependent) diabetic patients. Studies were performed in a double-blind cross-over manner after i.v. injection of 450 mg lysine acetylsalicilate (equivalent to 250 mg acetylsalicilic acid) or equal volume of 0.9% NaCl (isotonic saline). In the isotonic saline experiments hyperglycaemia produced a significant rise, by approximately 35%, in glomerular filtration rate in all patients from 41.5±5.2 to 55±6 ml·min^–1·1.73 m^–2 (p<0.005) and an increase in sodium paraminohippurate clearance from 178±22.7 to 220±20.0 ml·min^–1·1.73 m^–2 (p<0.05). These changes took place within the first 30 min of glucose infusion and were maintained for a 90 min hyperglycaemic period. Filtration fraction did not change significantly. Infusion of lysine acetylsalicilate lowered baseline glomerular filtration rate (isotonic saline vs lysine acetylsalicilate 41.5±5.2 vs 30.0±5.7 ml·min^–1·1.73 m^–2; p<0.05) and significantly blunted the rise in glomerular filtration rate during hyperglycaemia (glomerular filtration rate increment: saline vs lysine acetylsalicilate: 13.6±2.8 vs 5.3±1.8 ml·min^–1 ·1.73 m^–2; p<0.005). The effects on renal plasma flow were similarly blunted. In five additional patients, time- and volume-controlled isotonic saline experiments during sustained euglycaemia showed no significant changes in glomerular filtration rate and sodium paraminohippurate clearance. In Type 1 diabetic patients with advanced renal failure, acute hyperglycaemia induces a significant elevation in glomerular filtration rate and renal plasma flow which is likely to be mediated by renal prostaglandin production.     

How often is NIDDM complicated with non-diabetic renal disease? An analysis of renal biopsies and the literature

Summary According to extensive autopsy studies, non-diabetic renal disease seems to be rare in diabetes mellitus, but recent publications suggest a significant prevalence of non-diabetic renal disease in non-insulin-dependent diabetic (NIDDM) patients, especially in the absence of retinopathy. The purpose of this study was to evaluate the prevalence of non-diabetic renal disease in NIDDM patients in renal biopsies from clinical practice, in patients suspected of having non-diabetic renal disease. In addition we systematically reviewed the literature. Biopsies were evaluated at the University Department of Pathology, Aarhus, Denmark, but had been collected at several departments of nephrology. In total 33 consecutive biopsies were available from 1988–1995 (mean age of patients: 62 years (range 39–75) (mean known diabetes duration 8 years (range 1–25); the main clinical reason for a biopsy was proteinuria. Renal function changes ranged from slight elevation of serum creatinine to uraemia. In addition 9 original papers, including our own material 580 patients were examined. On the basis of careful morphological evaluation according to international criteria, no patient exhibited an unequivocal sign of non-diabetic glomerular disease. Two patients had strongly but not completely convincing evidence of glomerulonephritis. One patient had some evidence of glomerulonephritis. These 3 patients also exhibited diabetic lesions. One patient with end-stage renal disease showed evidence of interstitial nephropathy without glomerular lesions. Thus, in 4 patients evidence of non-diabetic lesions was found. In the remaining 29 patients typical diffuse (n = 9) or nodular (n = 20) diabetic lesions were found. Twenty patients showed evidence of diabetic retinopathy. One of the patients with evidence of non-diabetic renal disease had simplex retinopathy. In the literature a considerable bias exists towards including patients with non-diabetic renal disease. In non-biased materials with proteinuria the prevalence of non-diabetic renal disease is very similar to our series. In microalbuminuric patients non-diabetic renal disease seems to be very rare. It can be concluded that in our material non-diabetic renal disease is uncommon in NIDDM patients, even if a clinician has suggested renal disease of other origin. A considerable bias towards including non-diabetic renal disease in NIDDM patients exists in the literature. The indication for biopsy should be evaluated carefully, and biopsy should by no means be routinely performed in NIDDM patients with proteinuria. [Diabetologia (1996) 39: 1638–1645]     

Low prevalence of cardiac autonomic neuropathy in Type 1 diabetic patients without nephropathy.

AIM: To assess the prevalence of cardiac autonomic neuropathy (CAN) in Type 1 diabetic patients with and without nephropathy. METHODS: Sixty-six consecutive patients without nephropathy (n = 24), with incipient (n = 26) or overt nephropathy (n = 16) and a diabetes duration between 21 and 31 years were examined. Heart rate variability (HRV) as measure for CAN was investigated with short-term spectral analysis in the low-frequency (LF) band (0.06-0.15 Hz), reflecting sympathetic and vagal activity, and high-frequency (HF) band (0.15-0.50 Hz), reflecting vagal activity. HRV was expressed as spectral power (ms2, log-transformed). Normal, age-corresponding reference values were established in 184 controls. QTc intervals and dispersion were measured. RESULTS: After adjustment for age, there was no significant difference between healthy controls and patients without nephropathy. After further adjustment for diabetes duration, HbA1c, hypertension and treatment with beta-blockers, HRV in both frequency bands decreased with evidence of nephropathy. LF band (supine): patients without nephropathy 5.56 (4.89-6.21) (least squares means and 95% confidence interval (CI)), incipient nephropathy 5.72 (5.15-6.29) and overt nephropathy 4.11 (3.27-4.96). HF band (supine): without nephropathy 5.93 (5.26-6.60), incipient nephropathy 5.99 (5.41-6.57) and overt nephropathy 4.84 (4.00-5.68). Significant differences were found for patients without and with incipient nephropathy compared with those with overt nephropathy in the LF band and between patients with incipient nephropathy compared with those with overt nephropathy in the HF band. QTc intervals and QTc dispersion increased significantly with increasing nephropathy. CONCLUSIONS: Long-term Type 1 diabetes without nephropathy was not associated with impaired cardiac autonomic function in our study. However, in those with nephropathy, a loss of both vagal and sympathetic activity was present, and the severity of CAN correlated positively with more advanced nephropathy.     

Characteristics of Type 1 diabetes of over 50 years duration (the Golden Years Cohort).

BACKGROUND: Type 1 diabetes mellitus is associated with high levels of premature morbidity and mortality. Prolonged survival is possible, however, and some patients appear to be protected from the long-term complications of this condition. METHODS: Diabetes UK awards medals to patients who have had Type 1 diabetes for 50 years or more. By examining medal-holders, we have established the clinical and biochemical features of a group of 400 subjects (54% male) with Type 1 diabetes of long duration. RESULTS: Mean age of the subjects was 68.9 years and mean age-at-onset of diabetes 13.7 years. Features of long duration diabetes in this cohort include normal body mass (mean BMI 25.0 kg m-2), low insulin dose (mean 0.52 units kg-2) and greatly elevated HDL-cholesterol (mean 1.84 mmol/l). Mean HbA1c was 7.6% (normal range 3.8-5.0%) and no patient had a normal HbA1c at the time of venesection. As a group, they have long-lived parents and consume moderate amounts of alcohol. Medical contact has often been sporadic. A significant proportion (29%) were taking anti-hypertensive medication. Screening for micro- and macroalbuminuria was positive in 35.7%. CONCLUSIONS: Patients with long-duration (> 50 years) Type 1 diabetes are relatively protected from clinical diabetic nephropathy and large vessel disease; our data are consistent with protection possibly being genetically determined in part via elevated HDL-cholesterol levels. An abnormal urinary albumin/creatinine ratio is common in these patients, despite their low risk of significant renal deterioration; this may have implications for microalbuminuria screening programmes.