Possible participation of a prostaglandin E1 analogue in the aggravation of diabetic nephropathy.

A relation between the progression of diabetic nephropathy and glomerular hyperfiltration has been speculated. We describe two cases of non-insulin-dependent diabetic males aged 55 and 59 years in whom diabetic nephropathy was aggravated during the administration of limaprost, a a prostaglandin E1 analogue with a vasodilatory action. We also observed a short-term effect of limaprost on renal hemodynamics in three cases with diabetic nephropathy. In case 1, one year after limaprost administration the serum albumin level fell from 3.6 to 2.6 g/dl and the serum creatinine level rose from 1.0 to 1.6 mg/dl. In case 2, 9 months after limaprost administration the serum albumin level fell from 3.6 to 2.9 g/dl and the serum creatinine level rose from 1.8 to 2.3 mg/dl. In the latter stages of limaprost administration, the downslopes of reciprocal serum creatinine against time appeared to be augmented in the two cases. After the 3-day administration of limaprost, the peripheral and renal blood flows, and the glomerular filtration rate (GFR) were observed to rise, but the filtration fraction (FF) and urinary protein output were elevated. Keeping in mind the pre-existing renal damage, the increases in GFR and FF suggested acceleration of compensatory glomerular hyperfiltration in less damaged surviving glomeruli. The sustained acceleration of hyperfiltration with long-term administration of limaprost as an exogenous vasodilatory prostaglandin was assumed to eventuate in the aggravation of diabetic nephropathy. Attention should be paid to drugs which increase GFR in patients with established diabetic nephropathy.     

Protein C levels in nephrotic syndrome: use of a new enzyme-linked immunoadsorbent assay for protein C antigen

Activated protein C is a potent, physiologic anticoagulant that inactivates the activated forms of factors V and VIII as well as facilitates in vivo fibrinolysis. We developed a competitive protein-binding enzyme-linked immunoadsorbent assay (ELISA) for protein C that was utilized to investigate if the hypercoagulability of the nephrotic syndrome is related to a deficiency of circulating plasma protein C. Protein C was measured in plasma of 11 patients with nephrotic syndrome (24 hr protein 8.4 +/- 1.6 g, SEM; serum creatinine 4.2 +/- .74 mg/dl, SEM). Ten azotemic nonnephrotic patients were employed as controls (serum creatinine 6.0 +/- 1.25 mg/dl, SEM). No significant reduction of protein C values was observed (mean 108%, range 65-200%) in nephrotic patients when compared with the controls (mean 127%, range 100-200%) even though protein C antigen was present in all nephrotic urine samples tested. Also, no correlation existed between blood levels of urea nitrogen, creatinine, albumin, total protein, or 24-hr urine protein excretion and the observed protein C values. These results suggest that in patients with the nephrotic syndrome, a hypercoagulable state may not be related to a deficiency of protein C and that the level of this zymogen in nephrotic syndrome reflects a dynamic balance between urinary losses and systemic production.     

RENAL DISEASE IN DIABETICS—WHICH PATIENTS HAVE DIABETIC NEPHROPATHY AND WHAT IS THEIR OUTCOME?*

From August 1974 to January 1985, 53 patients (26 men; seven Maoris) mean age 45 (SD 15) years, with diabetes mellitus for a mean of 12 (SD nine) years had a renal biopsy and were followed. Indications for biopsy were nephrotic syndrome (24), proteinuria (23), renal impairment (five) and hematuria (one). Mean plasma creatinine concentration was 0.22 (SD 0.18) mmol/L and protein excretion 3.4 (SD 2.5) g/24 h. Diabetic nephropathy was demonstrated in 39 patients and significantly associated with retinopathy and insulin dependent diabetes mellitus (IDDM). Of the 39 patients followed for 25.7 (SD 22.8) months, 18 had died (nine myocardial infarction, six uremia, two sepsis, one stroke) and nine had begun dialysis. The five-year cumulative renal survival was 28%. The presence of the nephrotic syndrome and the plasma creatinine concentration at presentation were the best predictors of survival. Diabetics with IDDM of 20 years duration, retinopathy and heavy proteinuria, who survive the other complications of their disease, are likely to have diabetic nephropathy requiring renal replacement therapy.     

Successful treatment of nephrotic syndrome due to FMF amyloidosis with azathioprine: report of three Turkish cases

Secondary amyloidosis is a well-known complication of certain familial Mediterranean fever (FMF). We presented three Turkish patients with FMF and biopsy proven amyloidosis. These patients were treated with colchicine 1.5 mg/day. They have experienced five to six peritonitis attacks with fever within 1 year. On admission, the laboratory test results were as follows: serum creatinine 2.3, 0.6, and 0.5 mg/dl; albumin 4.2, 1.9, and 1.8 g/dl; and urinary protein excretion 4, 15, and 10 g/day, respectively. All the patients were started azathioprine (AZA) 100 mg/day and attacks were completely stopped. Laboratory findings were as follows after 1 year of AZA treatment: serum creatinine 1, 0.8, and 0.6 mg/dl; albumin 4.3, 3, and 3.5 g/dl; and urinary protein excretion 3, 8, and 1.5 g/day, respectively. Treatment with azathioprine in addition to colchicine could ameliorate the nephrotic syndrome and control the attacks very effectively in these cases.     

Effect of proteinase inhibitor Camostat Mesilate on nephrotic syndrome with diabetic nephropathy

The effect of serine protease inhibitor Camostat Mesilate on nephrotic syndrome with diabetic nephropathy was evaluated. Eight patients with nephrotic syndrome associated with diabetic nephropathy were orally administered 600 mg of Camostat Mesilate per day. Three patients showed a reduction of urinary protein excretion promptly at 4 weeks. Serum protein and degree of edema improved significantly at 4 weeks. Camostat Mesilate had no effect on renal function assessed by creatinine clearance. During the observation period there were no significant changes in blood pressure, level of blood sugar, or HbA₁c. Camostat Mesilate would be beneficial for the treatment of diabetic nephropathy.     

Renal handling of glycated albumin in non-insulin-dependent diabetes mellitus with nephropathy

Renal handling of glycated albumin in diabetic nephropathy was examined by studies on renal selectivity for glycated albumin in 23 normal controls and 52 patients with non-insulin-dependent diabetes mellitus (NIDDM) with various degrees of nephropathy. The serum and urinary levels of glycated albumin were measured by enzyme-immunoassay with monoclonal antibody to glucitol-lysine residues in human glycated albumin. The diabetic patients were divided into 3 groups according to the albumin index (AI): patients with normoalbuminuria [AI less than or equal to 30 mg/g creatinine(Cr)], with microalbuminuria (30 less than AI less than or equal to 270 mg/g Cr), and with macroalbuminuria (AI greater than 270 mg/g Cr). The renal selectivity for glycated albumin was calculated from the ratio of the urinary to serum level of glycated albumin. In the controls, the renal selectivity was as high as 4.40 +/- 0.48, and significantly higher than those in patients with normo- (2.87 +/- 0.29), micro- (1.72 +/- 0.20) and macroalbuminuria (1.26 +/- 0.23). The renal selectivity was inversely correlated with the AI in diabetic patients (r = -0.58, P less than 0.01). These data indicate that glycated albumin was selectively excreted in the urine and that the renal selectivity in diabetic patients gradually decreased to a value of 1 with increase in albuminuria. When the patients with normoalbuminuria were divided into two subgroups with high and low albumin excretion, the renal selectivities for glycated albumin in both subgroups were still significantly lower than that in controls. These results suggested that early diabetic nephropathy which cannot be detected clinically by albuminuria can be diagnosed by measurement of renal selectivity for glycated albumin.     

多项检测指标在2 型糖尿病早期肾损伤中的诊断价值

目的 分析尿白蛋白/ 肌酐比值(ACR)、尿α1-微球蛋白(α1-MG)、尿β2-微球蛋白(β2-MG)和血清胱抑素C(CysC)在2 型糖尿病早期肾损害中的诊断价值。方法 选取2019 年5 月至2020 年1 月芜湖市中医医院收治的2 型糖尿病患者108 例,根据尿蛋白排出率(UAER)将患者分为单纯糖尿病组(UAER <30 mg/ 24 h)68 例和糖尿病肾病组(30 mg/ 24 h≤UAER<300 mg/ 24 h)40 例。并选取同期健康体检者30 例为健康对照组。观察各组尿ACR、尿α1-MG、尿β2-MG 和血清CysC 水平并进行统计学比较。绘制受试者工作特征(ROC)曲线预测各指标对早期糖尿病肾损伤的曲线下面积(AUC),并计算各指标的敏感度和特异度。结果 糖尿病肾病组和单纯糖尿病组的尿ACR、尿α1-MG、尿β2-MG 和血清CysC 水平明显高于健康对照组(P 均<0. 05)。糖尿病肾病组的尿ACR、尿α1-MG、尿β2-MG 和血清CysC 水平明显高于单纯糖尿病组(P 均<0. 05)。尿ACR、尿α1-MG、尿β2-MG 和血清CysC的曲线下面积分别为0. 923、0. 851、0. 755 和0. 702,敏感度分别为84. 4%、75. 0%、71. 9%和62. 5%,特异度分别为96. 4%、85. 5%、81. 8%和67. 3%。结论 尿ACR、尿α1-MG、尿β2-MG 和血清CysC 在糖尿病早期肾损伤的进程中有着重要的作用,其测定有助于糖尿病肾病的早期诊断,为临床诊治提供可靠的依据。     

Nephrotic syndrome associated with B-cell chronic lymphocytic leukemia successfully treated with interferon-alpha

A 31-year-old man was admitted for investigation of proteinuria and hematuria. Physical examination on admission revealed systemic lymphoadenopathy, no hepatosplenomegaly, and ankle edema. Hemoglobin was 14.3 g/dl, platelet 21.4 x 10(4)/microliters and WBC 40,800/microliters which contained 86% mature lymphoid cells. Immunological phenotyping of peripheral lymphoid cells gave positive reactions for CD19, and CD20, and negative reaction for smlg. Urinary protein excretion was 8.3 g/dl in 24h. Serum total protein was 4.1 g/dl with albumin of 2.5 g/dl. Serum IgG was 302 mg/dl, IgA 43 mg/dl, and IgM 56 mg/dl. Renal biopsy showed characteristic features of membranoproliferative glomerulonephritis (MPGN). He was diagnosed as having nephrotic syndrome associated with B-cell chronic lymphocytic leukemia (B-CLL), and was treated with prednisolone and cyclophosphamide without effect. Therefore, he was treated with 18 MU of recombinant-alpha-2a-interferon (IFN-alpha)/day. This treatment resulted in almost normal WBC and differential counts, and urinary protein excretion of 3g in 24h 2 months later. After IFN-alpha treatment was discontinued, WBC count and the amount of urinary protein again increased. He was again treated with IFN-alpha at the dose of 9.0 MU/day three times a week, and is now well without any complaints. This is the first case report in which IFN-alpha was effective in a patient with nephrotic syndrome associated with B-CLL. We think that IFN-alpha therapy is worth trying in similar cases.     

Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients

Summary A progressive decline in glomerular function occurs in diabetic nephropathy. The predictive effects of progression promoters were examined in 182 non-insulin-dependent diabetic patients from a baseline serum creatinine concentration of 133 μml/l. During a total of 605 person-years follow-up, 107 patients developed end-stage renal failure requiring dialysis. The rate of decline of renal function was highly variable. Urinary protein excretion was the strongest predictor correlated to the rate of decline, followed by diastolic and systolic blood pressure, total cholesterol and platelet count, while the protective effects were seen in serum albumin and haematocrit. Ajustment for urinary protein excretion revealed that diastolic blood pressure, familial predisposition to hypertension, serum albumin, and smoking were independent significant predictors. Angiotensin converting enzyme inhibitors (ACE-I) significantly retarded the development of end-stage renal failure compared to antihypertensives other than ACE-I (mostly nifedipine), and the effect was evident particularly in patients with proteinuria below the median (2.5 g/24 h) (presumably those who responded to ACE-I). A complex effect of proteinuria in association with blood pressure elevation, familial predisposition to hypertension, hypoalbuminaemia, and smoking may play an important role in the progression of nephropathy. [Diabetologia (1997) 40: 405–411] Received: 29 July 1996 and in final revised form: 10 December 1996     

血、尿NGAL在2型糖尿病肾病进展各阶段的变化及其临床意义

目的:探讨血、尿中性粒细胞明胶酶相关脂质运载蛋白(NGAL)在2型糖尿病肾病(T2DN)进展各阶段中的变化及临床意义。方法:选择2015年5月~2018年1月入院治疗的T2DN患者240例(T2DN组)。根据24h尿微量白蛋白排泄率(UAER)水平,患者被分为尿蛋白正常(NAU)组(88例,<20mg/24h)、微量蛋白尿(MAU)组(80例,30~300mg/24h)和大量蛋白尿(MPU)组(72例,>300mg/24h)。选择同期入院健康体检者100例,设为健康对照组。测量比较各组血、尿NGAL、血清尿素氮(BUN)、血肌酐(Scr)和胱抑素C(CysC)水平,分析血、尿NGAL水平与上述指标的相关性。结果:与健康对照组比较,T2DN组血NGAL[(0.03±0.00)μg/L比(22.32±3.21)μg/L]、尿NGAL[(1.53±0.08)μg/L比(7.35±2.39)μg/L]、血清BUN[(8.32±1.84)mmol/L比(16.46±2.15)mmol/L]、Scr[(138.46±34.09)μmol/L比(290.48±43.41)μmol/L]和CysC[(1.52±0.46)mg/L比(3.97±1.23)mg/L]水平均显著升高,P均=0.001。上述指标水平均符合:NAU组相似文献   

Chronic renal failure in diabetic patients increases lipid risk factors for atherosclerosis

Diabetic patients are at high risk of cardiovascular disease and the risk is amplified in the presence of nephropathy, which may be partially attributed to modifications in lipoproteins. Moreover, lipoprotein profile may be affected by incipient nephropathy, glomerulopathy, and mild or severe renal failure. The aim of our study was to evaluate whether chronic renal failure (CRF) changes lipoprotein profile and apo A-I urinary excretion in diabetic subjects with glomerulopathy in comparison with non-diabetic subjects with glomerulopathy and CRF. Diabetic (n=25) and non-diabetic (n=10) patients with glomerulopathy and CRF showed significantly higher LDL-cholesterol, non-HDL-cholesterol and HDL-triglyceride levels than diabetic individuals without CRF (n=10). Arylesterase and paraoxonase activities did not show any difference between groups. Apo A-I could not be detected in urine samples from diabetic patients without CRF. All diabetic subjects with glomerulopathy and CRF who presented proteinuria above 6.5 g/24 h showed detectable urinary apo A-I (range=13.1-61.0 mg/24 h). Similarly, all non-diabetic patients with glomerulopathy and CRF who had proteinuria above 8.0 g/24 h also evidenced detectable apo A-I in urine (range=25.6-557.3 mg/24 h). Urinary apo A-I showed positive and significant correlations with urea (r=0.73, p<0.05) and proteinuria (r=0.97, p<0.0001), and a negative correlation with albumin plasma levels (r=-0.68, p<0.05). In conclusion, the presence of CRF in diabetic patients was associated with a more atherogenic lipoprotein profile.     

Impact of renal donation. Long-term clinical and biochemical follow-up of living donors in a single center

Forty-six renal donors who responded to a questionnaire and two additional donors with nephrotic syndrome and renal insufficiency were studied. The mean age was 46 +/- 2.0 years (mean +/- SE). Duration of follow-up was 6 +/- 0.5 years. Serum creatinine levels increased from 1.0 +/- 0.03 mg/dl before donation to 1.2 +/- 0.04 mg/dl at follow-up. The incidence of proteinuria (more than 150 mg over 24 hours) was 39 percent. The serum creatinine level was 1.0 +/- 0.08 mg/dl and 1.2 +/- 0.06 mg/dl in the proteinuric and nonproteinuric groups, respectively. The incidence of hypertension was 31 percent with a serum creatinine level of 1.1 +/- 0.11 mg/dl and 1.2 +/- 0.07 mg/dl in the hypertensive and normotensive groups, respectively. One patient with nephrotic syndrome had proliferative glomerulonephritis. It is concluded that renal donation is associated with a minimal but statistically significant increment in serum creatinine levels. The incidence of mild hypertension and proteinuria is increased, but impact on renal function is minimal as assessed by serum creatinine determination.     

Olmesartan reducing incidence of endstage renal disease in diabetic nephropathy trial (ORIENT): rationale and study design.

Diabetic nephropathy (DN) is a leading cause of endstage renal disease (ESRD) in Japan and Hong Kong. Asian patients are known to be more predisposed to DN and ESRD than Caucasians. Strict blood glucose and blood pressure control are key factors in prevention and treatment of DN. In the last decade, inhibition of the renin-angiotensin-aldosterone (RAA) system has been confirmed to reduce the incidence of cardiovascular complications in Caucasian patients with diabetes. Although the RENAAL study has demonstrated the beneficial effects of inhibition of the RAA system on prevention of ESRD and death in type 2 diabetic patients with overt proteinuria, only 17% of patients in this multicenter study were of Asian ethnicity. Given the predilection of Asian diabetic patients for renal complications and the rising burden of ESRD, there is a need to confirm these findings in a homogenous group of Asian patients. The ORIENT (Omesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial) is a randomized, double-blind, placebo-controlled study in Japan and Hong Kong to evaluate the renal protective benefits of olmesartan medoxomil in type 2 diabetic patients with overt proteinuria (urinary albumin to creatinine ratio > or =300 mg/g creatinine) and renal insufficiency (serum creatinine: 1.0-2.5 mg/dl). The study has a targeted enrollment of 400 Japanese and Hong Kong Chinese patients. The primary outcome is the composite endpoint of time to the first occurrence of doubling of serum creatinine, ESRD (serum creatinine more than 5.0 mg/dl, the need for chronic dialysis, or renal transplantation) or death. The average follow-up period is 4 years and the study ends in 2009.     

Urinary excretion of advanced glycation endproducts in patients with type 2 diabetes and various stages of proteinuria

OBJECTIVE: The objective of the study was to detect AGE-immunoreactive proteins in urine, and to evaluate AGE excretion at various stages of diabetic nephropathy in type 2 diabetes assessed by the level of proteinuria. METHODS: AGEs were measured in 24-h urine collection of patients with normoalbuminuria (N) (n=22), microalbuminuria (Mi) (n=31), macroalbuminuria (Ma) (n=28), and overt proteinuria with elevated serum creatinine level (PC) (n=25). A competitive ELISA with polyclonal anti-AGE antibodies was used to monitor AGE excretion. RESULTS: Multiple comparison of urine AGE content among various stages of proteinuria showed significant differences (summary p<0.000). Fifty percent of samples from the group of normoalbuminuric, and only 15% of samples from the group of microalbuminuria patients were AGE negative. However, there was no significant difference in AGE excretion between the patients with persistent proteinuria and elevated serum creatinine, and those with macroalbuminuria (PC vs Ma, p=0.265). None of the samples from these two groups of patients with highest AGE content in 24-h urine was negative for AGE-immunoreactivity. In addition, the ratio between 24-h urinary AGEs and urinary albumin excretion was calculated to determine whether total 24-h urinary AGE content is an index of the toxic form of albumin released in the course of diabetic nephropathy. The ratio values were log-transformed and bivariate comparison showed significant differences between the N vs Mi (p=0.006) and Mi vs Ma (p=0.000) groups. However, there was no significant difference (p=0.407) between values in the Ma and PC groups of patients. Multiple stepwise regression analysis indicated a relationship of urinary AGE-immunoreactivity with creatinine clearance values (r=0.52, p<0.001). CONCLUSION: The study demonstrated the presence of AGE-immunoreactivity in the urine of diabetic patients with various stages of proteinuria. Study results pointed to creatinine clearance as the main predictor of AGE excretion. Therefore, the measurement of urinary AGE appears to offer limited extra information in patients with impaired renal function.     

Variability of albumin excretion in diabetes

The variability of urinary albumin excretion was determined in 3 consecutive overnight urine collections from 152 adult type I diabetic patients (study A) and in two 1-h urine collections from 57 adult type I and type II diabetic patients, obtained at a 10-wk interval (= median, range = 2-30 wk) (study B). In both studies the coefficient of variation (CV) of urinary albumin excretion recorded as urinary albumin concentration (mg/l) was highest (study A: CV 51.1%; study B: CV 61.8%), whereas the CV of the urinary albumin/urinary creatinine ratio (mg/mmol) was lowest (study A: CV 41.9%; study B: CV 50.8%). In study A the CV of urinary albumin excretion rate (microgram/min) (CV 43.5%) did not differ from that of urinary albumin/urinary creatinine ratio. In study B, however, the CV of urinary albumin excretion rate (CV 57.2%) was higher than that of the urinary albumin/urinary creatinine ratio and of fractional albumin clearance (CV 51.0%). The variability of urinary albumin excretion was not related to its magnitude and could not be attributed to variations in plasma glucose, glycosylated haemoglobin or renal tubular glucose reabsorption. This high variability stresses the need to obtain several urine samples before the amount of albumin excreted can be reliably estimated. It is recommended that one does not use urinary albumin concentration but urinary albumin/urinary creatinine ratio or fractional albumin clearance in the assessment of urinary albumin excretion in diabetes management.     

Studies on diurnal blood pressure variation in kidney diseases associated with excessive salt and water retention.

Salt and water retention, a cardinal feature of nephrotic syndrome, was suggested to be an important factor leading to reduced diurnal blood pressure (BP) variation in renoparenchymal disease. Twenty-four hour BP (SpaceLabs SL 90207), 24-h urine excretion of catecholamines, plasma renin activity and plasma aldosterone concentration were therefore determined in 10 nephrotic patients with normal serum creatinine levels (group A, serum creatinine 1.0+/-0.2 mg/dl), in 10 nephrotic patients with increased serum creatinine levels (group B, serum creatinine 2.4+/-0.9 mg/dl) and in 20 controls matched in respect of age and BP. To study the direct influence of fluid volume overload, diurnal BP variation was determined before and after volume depletion by ultrafiltration in 10 patients with end-stage renal failure. Diurnal BP variation was characterised by the difference of mean BP during daytime (10 pm to 8 am) and night-time (8 am to 10 pm). In group A, the systolic and diastolic day-night difference was not changed when compared with the controls (NS). In contrast, in group B the day-night difference was significantly lower than in the controls (P < 0.01). Twenty-four hour urine catecholamine excretion and plasma aldosterone were comparable between the study groups. Plasma renin activity, however, was significantly increased in group A (P < 0.05). Nocturnal BP drop was not related to plasma renin activity in the nephrotic patients. The blunted diurnal blood pressure variation in end-stage renal failure was not influenced by ultrafiltration. The study demonstrates that the blunted diurnal BP variation in kidney disease is unaffected by marked changes in total exchangeable sodium and fluid volume, but is sensitive to changes in glomerular filtration rate.     

Atherogenic lipoprotein changes in diabetic nephropathy

Cardiovascular risk is increased in patients with diabetic nephropathy. The aim of this study was to examine the relative impacts of albuminuria and renal failure, the two important features of diabetic nephropathy, on potentially atherogenic lipoprotein changes in this condition. The subjects were 160 non-diabetic healthy controls and a total of 200 type 2 diabetes patients with various degrees of nephropathy. The diabetic patients were divided into four groups by urinary albumin/creatinine ratio (U-ACR) and serum creatinine (S-Cr) levels: DM-1 (U-ACR< 30 mg/g, N=85), DM-2 (U-ACR=30-300 mg/g, N=48), DM-3 (U-ACR > 300 mg/g, N=29) and DM-4 (S-Cr>177 micromol/l or 2.0mg/dl, N=38). Lipids in very low (VLDL), intermediate (IDL), low (LDL), and high density (HDL) lipoproteins were measured following ultracentrifugation. VLDL-cholesterol (VLDL-C) was elevated (by 73-100%) in diabetic patients and it did not differ among the stages of nephropathy. IDL-C was higher as the nephropathy stage was advanced, and the elevation was significant in the DM-3 (by 75%) and DM-4 (by 131%) groups. LDL-C was not elevated in diabetic patients and was not different among the stages of nephropathy. Reduction of HDL-C was significant in DM-1, DM-2 and DM-3 (by 12-16%) and it was more exaggerated in DM-4 (by 35%). Multiple regression analyses indicated that elevated S-Cr, but not U-ACR, was an independent factor associated with raised IDL-C and lowered HDL-C in diabetic patients. These results indicate that diabetic patients with nephropathy show multiple lipoprotein changes, and that renal failure has greater impact than albuminuria on abnormalities in IDL and HDL. These lipoprotein alterations may contribute to an increased cardiovascular risk in diabetic nephropathy, especially in diabetic renal failure.     

Probucol delays progression of diabetic nephropathy

Probucol has antioxidant and cholesterol-lowering effects. This study examined the effect of probucol on progression of diabetic nephropathy. We performed a randomized, open trial on 102 type 2 diabetes patients with clinical albuminuria (urinary albumin excretion >300 mg/g Cr). Fifty-one patients were assigned to probucol treatment (500 mg/day) and 51 to no probucol treatment. Among all patients, 40 who had serum creatinine >or=2mg/dl at baseline were defined as advanced cases. All patients were followed for a maximum 3 years. HbA1c levels were not different between two groups. High-density lipoprotein cholesterol decreased significantly in probucol group. Increase in urinary protein (g/day/month) was significantly greater in non-probucol than in probucol group. Hemodialysis was initiated in 23 patients (10 in probucol group and 13 in non-probucol group). The mean interval to initiation of hemodialysis was significantly longer in probucol group (20.7+/-8.2 months) than in non-probucol group (11.3+/-7.4 months). In advanced cases, increases of both serum creatinine and urinary protein were significantly suppressed in probucol group. In advanced cases, the hemodialysis-free rate was significantly higher in probucol group than in non-probucol group. These results suggest that probucol may suppress the progression of diabetic nephropathy.     

Transferrinuria in type 2 diabetic patients with early nephropathy and tubulointerstitial injury

BACKGROUND: Transferrinuria is thought to be a marker for early stages of diabetic nephropathy. Transferrin has also been proposed as a mediator of tubular toxicity because the reabsorption of transferrin results in the release of reactive iron in proximal tubular cells, promoting the formation of hydroxyl radicals. We evaluated the role of urinary transferrin excretion in diabetic patients with early nephropathy by comparing tubulointerstitial injury in renal biopsy specimens. PATIENTS AND METHODS: 45 type 2 diabetic patients with normoalbuminuria (urinary albumin excretion <30 mg/24 h) or microalbuminuria (30-300 mg/24 h) were studied. All patients with microalbuminuria underwent renal biopsy, and the severity of the tubulo-interstitial lesions was determined by a semiquantitative estimate of interstitial fibrosis, tubular atrophy, and interstitial inflammatory infiltrates. Subjects were classified into group A (normoalbuminuria, n=25), group B (microalbuminuria without tubulointerstitial changes, n=11) or group C (microalbuminuria with tubulointerstitial changes, n=9). RESULTS: Urinary transferrin excretion (UTf), as well as UTf/creatinine clearance (Ccr), and transferrin clearance (CTf/Ccr), was significantly higher in groups B and C than in group A, and it was significantly higher in group C than in group B. There were no significant differences in urinary albumin excretion or mesangial expansion rate (MR% estimated by quantitative morphometric studies) between groups B and C. Although urinary beta2-microglobulin excretion was significantly higher in group C than in groups A and B, urinary N-acetyl-beta-D-glucosaminidase activity was significantly higher in groups B and C than in group A. CONCLUSIONS: Increased transferrinuria in the microalbuminuric stage may lead to the development of tubulointerstitial injuries in type 2 diabetic patients.     

Elevation of urinary betaig-h3, transforming growth factor-beta-induced protein in patients with type 2 diabetes and nephropathy

Transforming growth factor-beta (TGF-beta) is a pro-sclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. betaig-h3 is an extracellular matrix protein which is induced in many cells by TGF-beta. This study examined urinary betaig-h3 excretion in diabetic patients with elevated urinary albumin excretion and the clinical application of urinary betaig-h3 as a marker of diabetic nephropathy. Urinary and serum betaig-h3 levels were determined by enzyme-linked immunosorbent assay in 163 type 2 diabetic patients and 101 healthy control subjects of comparable age and weight. The ratio of urinary betaig-h3 and TGF-beta to creatinine was analyzed in patients with different degree of nephropathy. The betaig-h3 to creatinine ratio in urine was elevated in all groups of type 2 diabetics with normoalbuminuria (101.6 +/- 9.27), microalbuminuria (120.2 +/- 14.48), and overt proteinuria (146.3 +/- 16.34), when compared with control subjects (64.8 +/- 7.14) (P < 0.01). There was a positive correlation between urinary betaig-h3 and TGF-beta excretion rate and a positive correlation between urinary betaig-h3 and albumin excretion rate (AER). These data show that urinary levels of betaig-h3 are elevated in type 2 diabetic patients with nephropathy and may be used as a marker of diabetic nephropathy.