Activation of transforming growth factor-beta1 in diabetic kidney disease

Recent data have suggested that certain growth factors and cytokines are involved in the development of diabetic nephropathy. The aim of this study was to investigate whether circulating transforming growth factor beta 1 (TGF-beta1) and tumor necrosis factor alpha (TNF-alpha) are associated with diabetic kidney disease. Serum levels of active and total TGF-beta1 and TNF-alpha were measured in type 2 diabetic patients with nephropathy (n = 23) or without (n = 35) and normoglycemic controls (n = 12). Serum levels of circulating active TGF-beta1 were significantly higher in patients with diabetic nephropathy (0.43 +/- 0.06 ng x mL(-1)) compared with diabetic patients without renal involvement (0.23 +/- 0.03 ng x mL(-1), P = .002) and healthy controls (0.24 +/- 0.03 ng x mL(-1), P= .001), whereas the levels of total (active + latent) TGF-beta1 were not different between the subgroups. Active TGF-beta1 concentrations were correlated with urinary albumin excretion (r = .49, P < .003) and serum creatinine (r= .55, P < .01). Sera from patients with type 2 diabetes contained significantly more TNF-alpha than sera from normoglycemic controls (3.07 +/- 0.24 v 1.65 +/- 0.20 pg x mL(-1), P = .001). However, the comparison of serum TNF-alpha concentrations between microalbuminuric and normoalbuminuric diabetic patients showed no significant difference (3.21 +/- 0.28 v 2.97 +/- 0.34 pg x mL(-1), P = .12). In conclusion, type 2 diabetic patients with diabetic nephropathy exhibit increased activation of TGF-beta1, in serum, suggesting an association between circulating TGF-beta1 activity and the development of renal disease.     

Plasma and urinary vascular endothelial growth factor and diabetic nephropathy in Type 2 diabetes mellitus.

AIMS: Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of diabetes mellitus. We determined whether alterations of plasma and urinary VEGF levels are related to diabetic nephropathy in Type 2 diabetic patients. METHODS: One hundred and seven patients and 47 healthy controls were studied. Study subjects were divided into four groups using urinary albumin-to-creatinine ratio (ACR): a non-diabetic healthy control group (n = 47), a normoalbuminuric diabetic group (n = 37), a microalbuminuric diabetic group (n = 37) and an overt proteinuric diabetic group (n = 33). VEGF levels were measured by enzyme-linked immunosorbent assay. RESULTS: (i) Urinary VEGF concentrations were significantly higher in the diabetic groups, even at the normoalbuminuric stage (log VEGF/Cr, normoalbuminuria; 4.33 +/- 1.06 vs. control; 3.53 +/- 0.79, P = 0.009). Urinary VEGF excretions increased as diabetic nephropathy advanced. (ii) Plasma and urinary VEGF levels were higher in hypertensive diabetic patients than in the normotensive individuals with diabetes. (iii) In those with diabetes, plasma VEGF levels were found to be positively correlated with plasma urea (r = 0.398, P = 0.039) and urinary ACR (r = 0.251, P = 0.044), and urinary VEGF to be positively correlated with urinary ACR (r = 0.645, P < 0.001), and creatinine (r = 0.336, P = 0.009), and to be negatively correlated with serum albumin (r = -0.557, P < 0.001). Urinary VEGF and serum creatinine were independently correlated with urinary ACR. CONCLUSIONS: Urinary excretion of VEGF increased during the earlier stage of diabetic nephropathy and was significantly correlated with urinary albumin excretion. This suggests that urinary VEGF might be used as a sensitive marker of diabetic nephropathy and for predicting disease progression.     

URINARY EXCRETION OF HUMAN EPIDERMAL GROWTH FACTOR IN THE VARIOUS STAGES OF DIABETIC NEPHROPATHY

Epidermal growth factor (EGF) is a polypeptide mitogen first isolated from mouse submaxillary glands and later from human urine. We have examined the pattern of urinary excretion of human EGF (hEGF) in normal subjects and in diabetic patients with varying degrees of nephropathy. hEGF was measured by homologous radioimmunoassay and expressed in terms of urinary creatinine excretion. On the basis of their albumin excretion rate, the diabetic patients were divided into those with normoalbuminuria (albumin excretion rate 3.5 (1.4-9.8) micrograms/min; mean (range)), microalbuminuria (albumin excretion rate 75 (30-128) micrograms/min) and macroalbuminuria (289 (169-879) micrograms/min). The albumin excretion rate for the normal subjects was 3.7 (1.6-9.7) micrograms/min. The mean (range) hEGF excretion (nmol hEGF/mmol creatinine) was 0.69 (0.47-1.29) for 19 healthy subjects, 0.60 (0.16-1.36) for the normoalbuminuric group (n = 18; NS), 0.47 (0.10-0.83) for the microalbuminuric patients (n = 19; P less than 0.001 vs controls and normoalbuminuric diabetics) and 0.38 (0.10-0.63) for the macroalbuminuric group (n = 18; P less than 0.001 vs controls and normoalbuminuric diabetics). There was an inverse correlation between albumin excretion rate and hEGF: creatinine ratio (r = -0.49; P = 0.02). These results show a progressive decline in hEGF excretion in diabetic patients with varying degrees of nephropathy and do not support the hypothesis that increased kidney size seen in early nephropathy is due to excessive amounts of EGF in the urine.     

Urinary transferrin excretion in type 1 (insulin-dependent) diabetes mellitus.

Urinary excretion of transferrin and albumin was studied by radioimmunoassay in 47 adult patients with Type 1 diabetes and 28 control subjects. Median (range) urinary transferrin excretion rate was significantly elevated in the diabetic group 0.58 (0.02-2663.3) micrograms min-1 compared with the control group 0.04 (0.01-0.28) micrograms min-1, p less than 0.001. Urinary transferrin:creatinine ratios (x 10(2)) were different in diabetic 47 (0.6-958.0) micrograms mmol-1 and control groups 0.7 (0.06-2.3) micrograms mmol-1, p less than 0.001). There were correlations between urinary transferrin and albumin excretion rates in diabetic (r = 0.78, p less than 0.001) and control groups (r = 0.81, p less than 0.05). Forty (85%) diabetic patients had elevated transferrin excretion rates, 18 (38.3%) had elevated albumin excretion rates. All diabetic patients with elevated albumin excretion rates had elevated transferrin excretion rates. Twenty-one (77.8%) of the patients with normal albumin excretion rates had elevated transferrin excretion rates. Urinary excretion of N-acetyl-beta-D-glucosaminidase was greater in diabetic patients than control subjects (142 vs 58 mumol h-1 l-1, p less than 0.001). There were correlation between transferrin and N-acetyl-beta-D-glucosaminidase excretion (r = 0.67, p less than 0.01) and albumin and N-acetyl-beta-D-glucosaminidase excretion (r = 0.63, p less than 0.01) in the diabetic group. Elevated urinary transferrin excretion rate may be a marker for renal dysfunction in diabetes mellitus.     

Association between genetic variation in transforming growth factors beta1 and beta3 and renal dysfunction in non-diabetic Chinese

Genetic variants of transforming growth factor (TGF) beta1 have been reported to be associated with diabetic nephropathy. Few studies investigated polymorphisms in the TGF-beta1 and TGF-beta3 genes in relation to renal dysfunction in non-diabetic subjects. In all, 601 non-diabetic Chinese were genotyped for the TGF-beta1 T869C and TGF-beta3 IVS3-98G>A polymorphisms by PCR-restriction fragment length polymorphism and real-time allele-specific PCR, respectively. Renal dysfunction was defined as a predicted glomerular filtration rate (GFR) of 60mL/min/1.73m(2) or less. 24-hour urinary albumin excretion was measured by an immunonephelometric assay in 352 hypertensive subjects. Our study sample included 184 (30.6%) women, 396 (65.9%) hypertensive patients (65.9%), and 94 (15.6%) patients with renal dysfunction. In men but not women, the TGF-beta1 TC genotype was significantly (p = 0.0005) overrepresented in patients with renal dysfunction (52.2% vs 36.8% in subjects with normal renal function). Accordingly, in men, with adjustment for age, body mass index, and systolic and diastolic blood pressure, serum creatinine concentration was significantly (p < or = 0.03) higher in the TC heterozygotes than TT and CC homozygotes. Furthermore, in 231 male hypertensive patients, with similar adjustments applied, 24-hour urinary albumin excretion was significantly (p = 0.02) higher in the IVS3-98 AA homozygotes than G allele carriers. In further multivariate regression analysis, only in men, TGF-beta1 and TGF-beta3 genotypes as independent predictors had statistically significant effect on serum creatinine (p = 0.007) and urinary albumin excretion (p = 0.022), respectively. Our study demonstrated the associations of genetic variants in the TGF-beta genes with renal dysfunction and albuminuria in non-diabetic Han Chinese men but not women.     

Effect of long-term near-normoglycemia on the progression of diabetic nephropathy

The effect of prolonged restoration of near-normoglycemia on the progression of diabetic nephropathy was evaluated in a controlled study in which 10 insulin-dependent (type 1) diabetic patients with clinical proteinuria were randomized to continue with conventional insulin treatment (CIT) or to undertake more intensive diabetic therapy using continuous subcutaneous insulin infusion (CSII). The patients, mean age 33 +/- 8 yr, mean duration of diabetes 15 +/- 4 yr, were studied before and during 12 months of either CIT or CSII therapy. Glycemic control was assessed by means of mean blood glucose (MBG) +/- Standard deviation (SD), urinary glucose excretion and glycosylated hemoglobin, while renal function was assessed by albumin, IgG and beta-2-microglobulin urinary excretion rates, serum creatinine and creatinine clearance. Blood glucose level, urinary glucose excretion and glycosylated hemoglobin fell significantly in the CSII group, while no differences were found in the CIT group after the 12 months observation period. Both groups showed a deterioration in all indices of renal function, as illustrated by an increase of protein excretion rates and of serum creatinine, and by a decline in creatinine clearance. Comparison of the rate of increase of urinary albumin and IgG excretion and of serum creatinine and of the rate of fall in creatinine clearance between CIT and CSII groups demonstrated that the rate of progression of diabetic nephropathy may be slowed by correction of hyperglycemia. Our study, with due reservations because of the small number of examined patients and differences in kidney function at the beginning of the trial shows that intensive diabetic care may play a role in the proteinuric stage of diabetes in slowing further destruction of residual glomerular structure and in delaying end stage renal failure.     

Coronary arterial calcification is associated with albuminuria in type 2 diabetic patient

AIM: Although microalbuminuria has been suggested as an independent risk factor for ischemic heart disease, the relationship between diabetic nephropathy and macroangiopathy remains unclear. Previously, we reported that coronary artery calcification detected by electron beam computed tomography (EBCT) could indicate the degree of coronary atherosclerosis in type 2 diabetic patients. In this study, we examine the association between coronary arterial calcification and microalbuminuria and aortic calcification and microalbuminuria. METHODS: Two hundred and fifty-six patients, including 177 type 2 diabetic patients (106 patients with normoalbuminuria, 71 with microalbuminuria) and 79 non-diabetic patients were evaluated by assessing the urinary albumin excretion rate and using EBCT to determine a coronary calcification score (CCS) and an aortic calcification score (ACS). RESULTS: No differences were observed regarding age, smoking index or BMI. Diabetic patients exhibited a greater CCS than non-diabetic subjects (non-diabetes 33 +/- 75 vs. diabetes 203 +/- 467, p < 0.05). Diabetic patients with microalbuminuria exhibited the most advanced CCS (253 +/- 491, p < 0.05). In contrast, no difference was observed in ACS among three groups. Multiple regression analysis showed that CCS is significantly associated with urinary albumin excretion rate as well as age, duration of diabetes and serum creatinine (R(2) = 0.31), while ACS is strongly associated with age, smoking, serum creatinine, systolic blood pressure and low-density lipoprotein cholesterol level (R(2) = 0.29). CONCLUSION: Increased urinary albumin excretion is associated with coronary arterial calcification in diabetic patients.     

The course of incipient diabetic nephropathy: studies of albumin excretion and blood pressure

With the aim of defining the transitional phase from normal or near normal albumin excretion to overt diabetic nephropathy, 23 male diabetics of more than 7 years' duration, below 40 years of age and a baseline urinary albumin excretion above 15 micrograms/min but without clinical proteinuria (incipient diabetic nephropathy) were studied. For comparison 18 normals, 23 diabetics with normal albumin excretion and 10 patients with overt nephropathy were also examined. Diastolic blood pressure (DBP) was elevated to 88 +/- 9 mmHg (mean +/- S.D.) compared to patients with normal urinary albumin excretion: 80 +/- 7 (S.D.) (2p = 0.13%) but was below pressures in patients with overt diabetic nephropathy 109 +/- 15 (2p = 0.002%). Glomerular filtration rate (GFR) was elevated to 142 +/- 21 ml/min (mean +/- S.D.) compared to 132 +/- 9 in patients with normal urinary albumin excretion (2p = 4.3%). Renal plasma flow (RPF) was not altered. Renal vascular resistance (RVR) was increased (0.200 +/- 0.035) compared to that of patients with normal urinary albumin excretion (0.180 +/- 0.025) (2p = 3.8%). In a longitudinal study of 10 of the patients with incipient nephropathy, followed for 4.9 (Mean) years, urinary albumin excretion increased significantly during the observation period, the yearly increase rate being 19 +/- 22% (mean +/- S.D.). DBP increased from 84 +/- 9 to 93 +/- 13 (2p = 3.8%) in 6 patients followed for more than 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma brain natriuretic peptide levels in normotensive noninsulin-dependent diabetic patients with microalbuminuria.

Brain natriuretic peptide (BNP), a member of the natriuretic peptide family, is produced and released from cardiac ventricles. BNP regulates the body fluid volume, blood pressure, and vascular tones through the A-type guanylate cyclase-coupled receptor. The presence of renal dysfunction in patients with diabetes affects the plasma levels of atrial natriuretic peptide (ANP). In the present study, we investigated the plasma levels of BNP and ANP and their relationship in normotensive diabetic patients with normoalbuminuria and microalbuminuria. Forty-seven normotensive lean noninsulin-dependent diabetic patients (31 with normoalbuminuria, 16 with microalbuminuria), with normal cardiac function, and 30 age-matched control subjects were enrolled in this study. The plasma levels of BNP in diabetic patients with microalbuminuria were significantly higher than those in diabetic patients with normoalbuminuria (16.7+/-2.4 vs. 9.6+/-1.3 pg/mL, P<0.01) or normal subjects (16.7+/-2.4 vs. 7.0+/-0.6 pg/mL, P<0.01). There was a significant positive correlation between plasma BNP levels and urinary albumin excretion rate in all diabetic patients (r = 0.58, P<0.0001). There was also a significantly positive correlation between plasma BNP and ANP levels in diabetic patients (r = 0.62, P<0.0001). The increased plasma level of BNP in patients with microalbuminuria and its significant correlation with urinary albumin excretion rate suggest that the elevated circulating levels of BNP are caused by the presence of diabetic nephropathy. Down-regulation of A-type guanylate cyclase-coupled receptor of renal tubules may explain the increased plasma levels of both BNP and ANP in normotensive diabetic patients with microalbuminuria.     

Increased plasma thrombin-activatable fibrinolysis inhibitor levels in normotensive type 2 diabetic patients with microalbuminuria

Hypofibrinolysis is a common finding in patients with diabetes mellitus and a risk factor for diabetic nephropathy. Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI), has been isolated from human plasma. The possibility that TAFI also participates in the mechanism of hypofibrinolysis has not been appraised in diabetic patients with microalbuminuria. In the present study, we investigated the plasma levels of TAFI and its relation to urinary albumin excretion in normotensive diabetic patients with normo- and microalbuminuria. Thirty-nine normotensive nonobese type 2 diabetic patients (27 with normoalbuminuria, 12 with microalbuminuria) and 20 age-matched normal subjects were enrolled in this study. The plasma level of thrombin-antithrombin complex was significantly increased (22.1 +/- 2.6 vs. 8.3 +/- 1.0 nmol/liter; P < 0.05), whereas the D-dimer/thrombin-antithrombin complex ratio was significantly decreased (15.7 +/- 1.4 vs. 26.5 +/- 2.2; P < 0.05), showing the occurrence of hypercoagulability and hypofibrinolysis in diabetic patients. The plasma level of TAFI in diabetic patients was significantly elevated, compared with normal subjects (147.4 +/- 11.6 vs. 99.5 +/- 4.9%; P < 0.05). The plasma level of TAFI in diabetic patients with microalbuminuria was significantly higher than the level in diabetic patients with normoalbuminuria (194.1 +/- 24.5 vs. 128.8 +/- 12.3%; P < 0.02) or normal subjects (194.1 +/- 24.5 vs. 99.5 +/- 4.9%; P < 0.005). Univariate analysis showed that the plasma TAFI levels are significantly and proportionally correlated with urinary albumin excretion rate (r = 0.58; P < 0.005) and with plasma soluble thrombomodulin level, a marker of endothelial cell damage, in all diabetic patients (r = 0.42; P < 0.01). These data suggest that increased plasma level of TAFI may be involved in the mechanism of vascular endothelial damage in patients with type 2 diabetes mellitus.     

Elevated urinary prostaglandin excretion and the effect of indomethacin on renal function in incipient diabetic nephropathy

We investigated whether the glomerular synthesis of prostaglandins modulates the glomerular filtration rate and urinary albumin excretion in incipient diabetic nephropathy (defined as urinary albumin excretion between 30 and 300 mg/24 h (microalbuminuria) in two out of three sterile ketone-free 24-h urine collections in patients having insulin-dependent diabetes mellitus (IDDM) without hypertension or other kidney disease). The urinary excretion of prostaglandin E2 was significantly elevated in 8 insulin-dependent diabetic patients with incipient nephropathy as compared with 9 normoalbuminuric IDDM patients and 11 healthy controls: 317 (182-1273); 95 (67-225); 132 (54-263) pg/min, respectively (2p less than 0.01). Glomerular filtration rate (single bolus 51Cr-EDTA technique) and albuminuria (radioimmunoassay) were measured twice within 2 weeks in 8 females having IDDM with incipient nephropathy. The study design was a randomized double-blind trial with the patients receiving either indomethacin (150 mg/day) or placebo for 3 days prior to the kidney function studies. Indomethacin treatment induced a significant reduction in urinary prostaglandin E2 excretion (73%) (2p less than 0.01), urinary albumin excretion rate diminished from 207 (63-253) to 87 (49-147) mg/24 h (2p less than 0.01), fractional clearance of albumin declined (70%) (2p less than 0.01). Glomerular filtration rate remained stable (108 (88-133) versus 110 (95-142) ml/min). Blood glucose and blood pressure were comparable during the placebo and indomethacin treatment (12.6 +/- 3 versus 13.4 +/- 5 mmol/l and 122/79 +/- 3/9 versus 122/82 +/- 4/10 mmHg, respectively). Our results suggest that enhanced glomerular synthesis of vasodilating prostaglandins may accelerate microalbuminuria in incipient diabetic nephropathy.     

糖尿病患者尿液中期因子与糖尿病肾病的关系

目的探讨尿液中期因子（MK）与糖尿病肾病的关系。方法96例糖尿病患者,根据尿白蛋白排泄率分为正常白蛋白尿组（NUAlb组）,微量白蛋白尿组（MUAlb组）,大量白蛋白尿组（CUAlb组）,设对照组（NC组）。用酶联免疫吸附法测定尿液MK水平。结果CUAlb组尿液MK水平高于NC组、NUAlb组及MuAlb组（P〈0．01）,MUAlb组高于NC组及NUAlb组（P〈0．05）,NUAlb组与NC组差异无统计学意义（P〉O．05）。相关分析显示,尿液MK与尿白蛋白排泄率（r=0．40,P〈O．05）及病程（r=0．23,P〈0．05）呈正相关,与内生肌酐清除率（CCr）呈负相关（r=-0．20,P=〈0．05）。结论尿液MK可能参与临床糖尿病肾病的发生。     

Kidney injury molecule-1 (Kim-1): an early biomarker for nephropathy in type II diabetic patients

Renal damage is a serious major microvascular diabetic complication implicated in the death of diabetic patients, which would necessitate the need for new biomarkers to detect early stage of diabetic nephropathy (DN). Kidney injury molecule-1 (Kim-1), a type I transmembrane protein, is undetectable in normal kidneys but markedly induced in proximal tubules after ischemic and toxic injury. So, the present study was conducted to estimate and evaluate Kim-1 as a biomarker for DN. This cross-sectional study was carried out on 60 male and female type II diabetic patients (whose serum creatinine level was less than 2 mg/dL). Diabetic patients were classified as microalbuminuric with nephropathy (urinary albumin was 30–300 mg/dL) and normoalbuminuric without nephropathy (urinary albumin was <30 mg/dL). Twenty matched apparently healthy subjects were included as control group. Patients and controls were assessed for fasting blood glucose, glycosylated hemoglobin (HbA1c), serum creatinine, blood urea nitrogen (BUN), microalbuminuria, and urinary Kim-1. Urinary Kim-1 levels were elevated significantly tenfold in type II diabetic microalbuminuric patients as compared to the control group and normoalbuminuric diabetic patient. Urinary Kim-1 levels were positively correlated with microalbuminuria, serum creatinine, BUN, duration of diabetes, and BMI. Higher urinary Kim-1 level in T2D particularly in those with nephropathy and its correlation with urinary microalbumin, serum creatinine, blood urea, and BUN may reflect the role of Kim-1 as a biomarker for diagnosis and prognosis of diabetic nephropathy among T2D patients taking into account other risk factors.

     

The relationship between the development and progression of microalbuminuria and arterial blood pressure in type 1 (insulin-dependent) diabetes mellitus.

OBJECTIVE: to investigate the association between urinary albumin excretion and arterial blood pressure in type 1 (insulin-dependent) diabetes. RESEARCH DESIGN AND METHODS: urinary albumin excretion and blood pressures were followed prospectively for a mean period of 26 months (range 18-29 months) in 46 young type 1 (insulin-dependent) diabetic subjects without overt nephropathy. Supine blood pressures (BP) were measured by a single observer using a random zero sphygmomanometer. Albumin excretion was assessed at baseline by a timed clinic excretion rate (AER; microalbuminuria = AER greater than 33 micrograms/min), and at follow-up in at least two urine specimens by the albumin/creatinine (A/Cr) ratio (micro-albuminuria = A/Cr greater than 3.7 mg/mmol). RESULTS: 39 subjects initially had normal AERs. Seven had developed microalbuminuria at follow-up: their mean BP rose from 114 +/- 13/62 +/- 13 to 119 +/- 7/77 +/- 5 mmHg (for diastolic BP, P less than 0.05), while there was no change in the mean BP in the remaining 32 patients. A rise in diastolic BP of greater than 10 mmHg occurred in five of the seven subjects who developed microalbuminuria, and in only seven of 32 who did not (P = 0.02). In the seven patients in whom microalbuminuria persisted (n = 3) or progressed to overt proteinuria (n = 4), BP increased from 123 +/- 12/70 +/- 14 to 139 +/- 12/88 +/- 10 mmHg (P less than 0.02 for both). CONCLUSIONS: this study has shown that BP is normal before the onset of microalbuminuria, and that a rise in diastolic BP accompanies the development or progression of microalbuminuria. The rate of rise in BP may be more important than the absolute level in defining 'hypertension' in young diabetic patients with microalbuminuria.     

Urinary cystatin C as a biomarker of early renal dysfunction in type 2 diabetic patients

AimsWe aimed to evaluate urinary CysC (cystanin c) as an early marker of diabetic nephropathy in patients with type 2 diabetes and investigate the correlation of urinary CysC with albuminuria and GFR.MethodologyThis case-controlled study was conducted on 66 type 2 diabetic patients who were classified according to albuminuria into 3 groups and consisting of 20 healthy subjects as the control group. We assessed urinary CysC, urinary albumin excretion rate (UACR).ResultsUrinary CysC levels were significantly higher in normoalbuminuric diabetic compared with healthy control and there was a progressive linear increase in urinary CysC levels with increasing albuminuria in the diabetic patients. Despite insignificant deference in creatinine between participants groups, we observed significant differences between these groups as regard eGFR, urinary CysC, and UACR. Urinary CysC did not have significant correlations with any clinical or biochemical parameters. Moreover, urinary CysC had a statistically significant association with albuminuria and eGFR.ConclusionUrinary CysC levels correlated with UACR and GFR. It is linked to subclinical tubular injury and can be an earlier marker of kidney involvement, even before albuminuria and it is less influenced by non-renal factors. Therefore, Urinary CysC is useful biomarker for early diagnosis of diabetic nephropathy.     

The relationship between obesity and transforming growth factor beta on renal damage in essential hypertension

The aim of this study was to evaluate the effect of obesity on renal functions and the possible relationship between TGF-beta1 and obesity in hypertensive patients. Seventy newly diagnosed, hypertensive patients (male/female 36/34, aged 45.0 +/- 8.0 years) and 30 (male/female 17/13, aged 41.8 +/- 7.7 years) normotensive controls were included. Patients in both groups were analyzed for serum levels of glucose, creatinine, uric acid, lipids, and TGF-beta1. A 24-hour urine sample was also obtained; creatinine clearance rate and urinary albumin excretion (UEA) were investigated. TGF-beta1 levels were significantly higher (40.7 +/- 13.6 versus 34.2 +/- 12.1 pg/mL, P = 0.02), and creatinine clearance was significantly lower in patients compared with controls (98.9 +/- 25.5 versus 124.5 +/- 23.1 mL/min. per. 1.73 m(2), P = 0.001). Serum TGF-beta1 levels (45.2 +/- 14 versis 38.0 +/- 12.8 pg/mL, P = 0.03), creatinine clearance rates (109.8 29.9 versus 93.0 +/- 20.8 mL/min. per. 1.73 m(2), P = 0.001), and urinary albumin excretion (55.7 +/- 62.0 versus 12.7 +/- 12.6 mg/24 h, P = 0.002) were higher in obese hypertensive patients than in nonobese patients. In hypertensive patients, TGF-beta1 levels correlated with body mass index (r = 0.296, P = 0.01) and creatinine clearance (r = 0.238, P = 0.04). The results suggest that increased body mass index is associated with increased creatinine clearance, urinary albumin excretion, and TGF-beta1 levels in essential hypertension. In addition, TGF-beta1 is positively correlated with body mass index and creatinine clearance in patients with essential hypertension.     

Prospective follow-up study of renal function in type 2 diabetes

Type 2 diabetes mellitus is the main cause of increase in patients suffering from end-stage renal failure in France. We performed an observational study of the change in renal function of type 2 diabetic patients, attending our diabetology clinic. Clinical and biological data were regularly entered in an informatic database (Pénélope, Poitiers University Hospital). We prospectively followed 351 type 2 diabetic patients (age at diagnosis: 40 to 75 years), for 32 months (extremes: 1-120). Renal function was graded in 4 stages according to plasma creatinine and urinary albumin excretion (UAE) determined by nephelometry on random urinary sample: absent (UAE < 20 mg/L et creatinine < 150 mumol/L), incipiens (UAE 20 to 200 mg/L and creatinine < 150 mumol/L), established (UAE = 200 mg/L et creatinine < 150 mumol/L) advanced (creatinine = 150 mumol/L). Glycated haemoglobin (HbA1c) was determined by HPLC. Systolic/Diastolic Blood Pressure (SBP/DBP) was measured with a mercury sphygmomanometer. We defined renal events as the change from one stage of nephropathy to a higher one. A total of 351 type 2 diabetic subjects were studied: 194 men/157 women mean age 63 +/- 11 years, mean diabetes duration 10 +/- 9 yr. At baseline, 206 patients had no nephropathy, 98 incipient nephropathy, 28 established nephropathy and 19-advanced nephropathy. Baseline stage of nephropathy was related to SBP (p < 0.0001), DBP (p = 0.0002), diabetes duration (p = 0.0064) but not HbA1c (p = 0.2182) or sex (p = 0.4794). Among those 332 subjects without baseline advanced nephropathy, 134 progressed in nephropathy. Progression of nephropathy was not related to the presence of hypertension (SBP/DBP > or = 160/95 mmHg) (log-rank = 0.22; p = 0.6377). Conversely, patients with a poor glycaemic control (HbA1c > or = 10%) had a worse renal-event free survival (log-rank = 4.89; p = 0.0269). Glycaemic control is a risk factor for the progression in nephropathy of type 2 diabetic patients.     

Transforming growth factor-beta 1 in diabetic nephropathy

In diabetic nephropathy the extent of matrix accumulation in both glomeruli and the interstitium correlates strongly with the degree of renal insufficiency and proteinuria. Factors responsible for the deposition and accumulation of extra cellular matrix material within the kidney are therefore of considerable interest. Such factors include the potent fibrotic cytokine TGF-beta. We measured serum TGF-beta1 in patients with various stages of diabetic nephropathy, and correlated its level with different biochemical parameters. The study was conducted on: Group I: 30 patients with diabetic nephropathy (Subgroup IA: 20 patients with microalbuminuria; Subgroup IB: 10 patients with overt nephropathy), Group II: 19 diabetic patients without nephropathy (positive control), Group III: 20 healthy volunteers (negative control). Serum creatinine, Fasting and postprandial blood glucose, Fasting serum cholesterol, Glycated haemoglobin (HbA1c), Microalbumin estimation in urine, Serum TGF-beta1 estimation were done for all the studied groups. Our results showed a statistically significantly higher serum TGF-beta1 level in patients with diabetic nephropathy versus diabetic patients without nephropathy (mean +/- SD, 47.66 +/- 21.92 and 27.07 +/- 15.46 respectively) (P<0.001). Also in patients with diabetic nephropathy versus healthy controls (mean +/- SD, 47.66 +/- 21.29 and 27.05 +/- 8.95 respectively) (P<0.001). While serum TGF-beta1 concentrations were almost similar in diabetic patients without nephropathy and in healthy controls. Serum TGF-beta1 was statistically significantly higher in patients with overt nephropathy versus patients with microalbuminuria (mean+/-SD, 73.5 +/- 2.41 and 34.9 +/- 12.41) (P<0.001). Serum TGF-beta1 was significantly positively correlated with albumin excretion rate, fasting and postprandial blood glucose levels, serum cholesterol and HbA1c, these correlations were only found in diabetic patients with nephropathy but not in those without nephropathy or the control group. (r=0.86, P<0.001, r=0.444, P<0.05, r=0.375, P<0.05, r=0.532, P <0.01, r=0.696, P<0.001 respectively. HbA1c was found to be predictor of 68% of changes of serum TGF-beta1 (P<0.001) and serum cholesterol was predictor of 73% of changes of serum TGF-beta1 concentration (P<0.01). In conclusion, our results suggest that TGF-beta1 may play a key role in the development and progression of diabetic nephropathy. Accordingly, it may be also directly implicated in the functional deterioration of the kidney functions seen in patients with diabetic nephropathy, therefore beside proper glycemic control, strategies aiming at antagonizing TGF- beta1 for example by the use of specific antibodies or a specific inhibitor of TGF-beta1 may help to prevent the development or attenuate the progression of nephropathy in diabetic patients.     

Association of serum levels of IGF-I and IGFBP-1 with renal function in patients with type 2 diabetes mellitus.

OBJECTIVE: Our aim was to determine whether serum Insulin-like growth factor-I (IGF-I) and Insulin-like growth factor binding protein-1 (IGFBP-1) levels were different between type 2 diabetic patients and non-diabetic control group. We also aimed to establish any relationship that might exist between the serum IGF-I and IGFBP-1 levels with the urinary albumin excretion (UAE), creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion (as a marker of renal tubular dysfunction) and other parameters (such as age, duration of diabetes, treatment, etc.) in patients with type 2 diabetes mellitus (DM). DESIGN: Fifty-nine type 2 diabetic patients and thirty-one non-diabetic controls were included in this study. RESULTS: Mean serum IGF-I levels in diabetic patients were lower than the non-diabetic controls (158+/-12 vs. 287+/-26microg/l), (p<0.001). Serum IGFBP-1 levels were also higher in type 2 diabetic patients compared to the control group (67+/-5 vs. 35+/-4microg/l), (p<0.001). No relationship was obtained between IGF-I and IGFBP-1 levels with neither UAE nor urinary NAG excretion. A significant negative relationship was observed between creatinine clearance and serum IGFBP-1 level (r=-0.39, p=0.004). In multiple regression analysis IGF-I was independently and negatively associated with age and insulin treatment. On the other hand, IGFBP-1 was negatively related with creatinine clearance and positively related with the duration of diabetes. CONCLUSION: These results suggest that type 2 DM leads to a decrease in the IGF-I while elevating the IGFBP-1 levels. Further studies are needed to clarify a potential role of increased levels of IGFBP-1 in decreased creatinine clearance in type 2 DM.     

Urinary neutrophil gelatinase-associated lipocalin in type 2 diabetes: Relation to nephropathy and retinopathy

Background

Diabetes mellitus is the leading cause of end stage renal disease worldwide. Early identification of diabetic nephropathy even before appearance of microalbuminuria is a challenge for early prevention of occurrence and progression of this complication. Neutrophil gelatinase-associated lipocalin is a small protein that belongs to the lipocalin protein. Urinary neutrophil gelatinase-associated lipocalin is a promising early marker in different renal problems.