Correlation between urinary activity of N-acetyl-β-d-glucosaminidase (NAG) and albumin excretion rate in type II (non-insulin-dependent) diabetic subjects

Summary Different kidney diseases are often associated with high urinary excretion of N-acetyl-β-D-glucosaminidase (NAG), a lysosomal enzyme involved in the breakdown of glycoproteins, whose activity is also increased in diabetic patients with poor metabolic control or vascular complications. In order to evaluate the relationship between renal function and urinary NAG levels in diabetes mellitus, 30 type II diabetic patients without evidence of kidney disease and 18 control subjects were studied. In each subject 24-h urinary excretion rates of NAG (fluorimetric method), albumin and β₂-microglobulin (radioimmunoassay), together with⁵¹Cr-EDTA clearance were performed. In diabetic patients urinary levels of NAG (356±25vs 162±9.2 nmol/h/mg creatinine, p<0.0001) and albumin (21±2.5vs 4.3±0.5 mg/24h, p<0.0001) were significantly higher than in the controls, while β₂-microglobulin levels and⁵¹Cr-EDTA clearance did not differ in the two groups. Moreover in diabetic patients NAG and albumin levels were positively and significantly correlated (r=0.63, p<0.001). These results suggest that urinary NAG excretion rate may be altered early in diabetic patients with apparently normal renal function; its diagnostic value seems to be similar to that of the albumin excretion rate.     

Fucosylation of serum α<Subscript>1</Subscript>-acid glycoprotein in rheumatoid arthritis patients treated with infliximab

To analyze fucosylation of α₁-acid glycoprotein (AGP) and to identify relations between AGP fucosylation and clinical and biochemical indices of disease activity in patients with rheumatoid arthritis (RA) treated with monoclonal antitumor necrosis factor (TNF) antibody infliximab, we examined 22 patients with RA who underwent a 54-week treatment with infliximab according to ATTRACT protocol. Blood samples were collected at baseline and before every infusion of infliximab. AGP fucosylation was measured using lectin-binding enzyme-linked immunosorbent assay utilizing fucose-specific lectin Aleuria aurantia (AAL). Moreover, the clinical status/activity, erythrocyte sedimentation rate, serum C-reactive protein (CRP), antitrypsin, α₁-antichymotrypsin, AGP reactivity with concanavalin A, serum C3 and C4 complement components, and serum concentrations of TNF and soluble TNF type 1 and type 2 receptors were determined. In most patients, the fucosylation of AGP decreased rapidly after first infusion of infliximab and remained low during the 54-week therapy (p < 0.001). The decrease in AGP affinity to AAL closely followed changes in clinical and laboratory activity of RA and correlated with pretreatment concentrations of CRP (r = 0.4986, p < 0.05) and TNF (r = 0.5181, p < 0.05). The fucosylation of AGP can be a part of a negative feedback loop regulating migration of inflammatory cells and collagenase-3 activity in RA. The decrease in AGP fucosylation accompanied by improvement in clinical and biochemical parameters of RA could possibly reflect reduced migration of inflammatory cells to inflamed joints and AGP-mediated inhibition of collagenase-3 as a response to infliximab treatment.     

Further evidence for tubular dysfunction in insulin dependent diabetes

There is evidence that increased excretion of urinary enzymes and low-molecular mass proteins indicate impaired tubular function. The excretion of N-acetyl-beta-d-glucosaminidase (NAG), lysozyme, and ribonuclease in Type I diabetic patients with (n = 19) and without (n = 17) persistent proteinuria (urinary protein excretion > 0.5 g/day) was investigated and compared with this exretion in 30 weight- and gender-matched nondiabetic subjects without renal disease. Urinary NAG excretion was significantly higher in diabetic patients with and without persistent proteinuria (1.16 ± 0.09 and 3.19 ± 1.2 Umol/L creatinine, respectively) compared to controls (0.37 ± 0.03 Umol/L creatinine p < 0.01). In addition, the urinary excretion of lysozyme and ribonuclease was significantly increased in diabetic patients. Urinary NAG was found to correlate positively with albuminuria and proteinuria (r = 0.95 and 0.93, respectively), as well as with ribonuclease and lysozyme (r = 0.93 and 0.60; p < 0.01) in patients with persistent proteinuria. Furthermore, NAG excretion was significantly related to the duration of diabetes (r = 0.36; p < 0.05). No relationship existed between urinary NAG and serum creatinine, beta-2-microglobulin, and degree of metabolic control (HbA₇). The lysozyme excretion, but not NAG excretion, was significantly related to hypertension in patients with clinical proteinuria. In conclusion, our results suggest a relationship between the development of tubular dysfunction and the impairment of glomerular function in diabetic nephropathy. An increased excretion of NAG and low-moecular mass proteins may indicate early nephropathy.     

Urinary proteins in multiple myeloma: correlation with clinical parameters and diagnostic implications

Renal failure is one of the worst complications occurring in multiple myeloma (MM) patients. It does not affect survival if reverted by a prompt chemotherapy before the damage becomes irreversible; therefore, the early diagnosis of renal dysfunction is crucial. High and low molecular weight urinary proteins have proved to be helpful in diagnosing initial renal damage since they are more sensitive than urea and creatinine serum levels or creatinine clearance. We studied the renal function of 111 MM patients through serum creatinine, urea, urinary IgG, ₁-microglobulin (₁-M), and albumin (Alb). Two successive controls were made in a subset of 30 patients, categorized in three groups (improved, stable, worsened) according to the behavior of tumor burden markers (bone marrow plasmacytosis, monoclonal component, and ₂-microglobulin). In every group, we evaluated the behavior of urinary proteins. Renal dysfunction evaluated with serum parameters was present in 19 patients (17%), while if studied with urinary proteins was revealed in 71 patients (64.5%). Urinary proteins statistically correlated with each other. They correlated with creatinine, IgG, and ₁-M also with urea. By contrast, they showed a variable correlation with clinical parameters: ₁-M correlated with bone marrow plasmacytosis (BMPC) (p=0.02) and ₂-M (p=0.000001), IgG with all three disease parameters (MC p=0.0005, BMPC p=0.009, ₂-M p=0.007), and Alb only with ₂-M (p=0.0004). In the subset of 30 patients followed with two successive controls, urinary proteins showed a parallel behavior with the indices of tumor burden. In conclusion, IgG, ₁-microglobulin, and albumin are reliable and sensitive to precociously reveal renal damage, and we recommend their routine use for the definition and monitoring of renal function in multiple myeloma patients, mainly those in early stage, to better identify initial signs of progression.     

Urinary vasodilator and vasoconstrictor angiotensins during menstrual cycle, pregnancy, and lactation

Since normal human pregnancy is characterized by normotension in the face of an increased renin-angiotensin-aldosterone system (RAAS), we evaluated the temporal pattern of urinary excretion of a novel vasodilator within this system, angiotensin-(1–7) (Ang-[1–7]), during the menstrual cycle, pregnancy, and lactation. The urinary profiles of Ang I, Ang II, human chorionic gonadotropin, 17β-estradiol, and progesterone were also determined. During the menstrual cycle, urinary Ang-(1–7) and Ang II remained stable (mean cycle value: 94.6±11.3 and 11.4±1.1 pmol/g of creatinine, respectively) in nine females. In 10 normal pregnant women, urinary Ang-(1–7) and Ang II increased throughout gestation, averaging 1499.8±310 and 224.4±58 pmol/g of creatinine, respectively (p<0.05) at wk 35 and falling during lactation to 394.0±95 and 65.7±20 pmol/g of creatinine (p<0.05), respectively. The Ang-(1–7)/Ang II ratio was unchanged in the different reproductive periods. During the menstrual cycle, Ang II and Ang-(1–7) correlated with 17β-estradiol and progesterone using multivariate analysis (r=0.31, p<0.001) and r=0.28, p<0.02, respectively). During gestation, 17β-estradiol and progesterone correlated with urinary Ang-(1–7) (r=0.48, p<0.001 and r=0.47, p<0.001, respectively) and Ang II (r=0.24, p<0.03 and r=0.25, p<0.03, respectively); by multiple regression, only Ang-(1–7) correlated with both steroids (r=0.49, p<0.001). The progressive rise of Ang-(1–7) throughout gestation, probably modulated by estrogen and progesterone, suggests a physiologic counterregulation within the RAAS.     

尿微量蛋白联合尿酶诊断高血压早期肾损害

目的　探讨高血压早期肾损害诊断标准。方法　对 5 0例健康者 (对照组 )和 5 0例高血压患者采用 EL ISA方法检测尿转铁蛋白 ( TRF)、微量白蛋白 ( m AL B)和尿视黄醇结合蛋白 ( RBP) ,终点法测尿 N-乙酰 - β- D-氨基葡萄糖苷酶 ( NAG) ,比色法测尿肌酐。结果　正常对照组尿 TRF/ Cr为 0 .0 5± 0 .0 3 mg/ mmol,m AL B为 3 .61± 2 .46m g/L,RBP/ Cr为 7.46± 5 .0 2 μg/ mm ol,NAG/ Cr为 0 .5 2± 0 .46U/ m mol,尿蛋白定性阴性的高血压患者 TRF/ Cr、m AL B、RBP/ Cr及 NAG/ Gr值较正常对照组增高 ( P<0 .0 1) ;两项指标联合检测其阳性率分别为 :TRF+ m AL B为 62 % ,TRF+ NAG为 5 4% ,m AL B+ NAG为 44 % ,将这三项指标联合检测可使阳性率提高到 78% ,大大提高了阳性检出率。结论　联合检测尿 TRF、m AL B及 NAG是诊断高血压早期肾损害的灵敏、可靠的实验室指标     

Efficacy of urinary N-acetyl-β-D-glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus: a cross-sectional study

We assessed the prognostic accuracy of urinary N-acetyl-β-D-glucosaminidase (NAG), an early proximal tubular damage marker for the onset of diabetic nephropathy. The study included 491 eligible participants with 76 healthy controls, 194 type 2 diabetes mellitus (T2DM) patients with 0–5, 5–10, 10–15, and 15–20 years of T2DM duration, 71 microalbuminuric patients, 100 diabetic nephropathy patients, and 50 non-diabetic nephropathy patients. Fasting glucose, serum fructosamine, HbA1C, urinary microalbumin, serum creatinine, estimated glomerular filtration rate (eGFR), serum NAG, and urinary NAG were estimated. We compared urinary NAG activity with other well-established markers of diabetic nephropathy like microalbuminuria, eGFR, and serum creatinine. Urinary NAG excretion was increased by 8 and 12 folds in T2DM patients of 10–15 and 15–20 years of diabetes duration (p < 0.0001), respectively, without the appearance of microalbuminuria. The urinary NAG activity increased 16 and 18 fold in moderately increased albuminuria and diabetic nephropathy patients, respectively (p < 0.0001), without any change in non-diabetic nephropathy patients. A cutoff value of 3 U/L of urinary NAG has demonstrated a sensitivity of 96.1 % and a specificity of 100 % discriminating healthy controls from patients with T2DM duration of 10–15 years (AUC 1.000) and 15–20 years (AUC 0.999); microalbuminuria (AUC 0.999), and diabetic nephropathy (AUC 1.000). Urinary NAG excretion gradually increases with the increase in duration of diabetes and appeared much before the microalbuminuria, decreased eGFR, and increased serum creatinine. Thus, the urinary NAG may be considered as a potential site-specific early tubular damage marker leading to diabetic nephropathy.

     

Carboplatin pharmacokinetics in patients receiving carboplatin and paclitaxel/docetaxel for advanced lung cancers: impact of age and renal function on area under the curve

Purpose: To further define the most appropriate way of choosing the dose of carboplatin. Patients and methods: The pharmacokinetics of carboplatin were analyzed in 30 patients with advanced lung cancer receiving a total of 48 cycles of carboplatin plus paclitaxel/docetaxel combination chemotherapy. Platin concentrations of ultrafiltrated plasma and urine samples were determined by flameless atomic absorption spectrometry. A multiple regression analysis was performed for interactions between pharmacokinetic parameters and pretreatment characteristics. Results: Using a two-compartment-model, the following parameters were obtained (mean, coefficient of variation): initial half-life, 0.903 h (48%); terminal half-life, 13.6 h (116%); maximum plasma concentration (C_max), 38.5 μM (86%); AUC, 111.9 μM/h (86%); volume of distribution, 411 l (130%); total clearance (C_t), 579 ml/min (75%); renal clearance (C_r), 453 ml/min (80%); renal elimination, 76% of dose (17%). In the univariate analysis, age was significantly related to C_max (P=0.0303), AUC (P=0.0050), C_t (P=0.0020), C_r (P=0.0092). Plasma creatinine (Cr_p) was related to C_max (P=0.0228), and 1/[Cr_p] was related to C_max (P=0.0015) and AUC (P=0.0054), while body weight was related to C_max (P=0.0365). No interaction with the schedule of application of the two drugs was observed. In the multivariate analysis, factors significantly related to AUC were 1/[Cr_p] (P < 0.01) and age (P < 0.01). Cr_p (P < 0.05) and 1/[Cr_p] (P < 0.01) were significantly associated with C_max. Conclusions: These data stress the importance of dosing carboplatin according to renal function and age and warrant further analyses to validate this concept prospectively. Received: 15 December 1999 / Accepted: 18 May 2000     

Altered adhesion molecules expression on peripheral blood mononuclear cells from patients with systemic sclerosis and clinical correlations

The aim of the study was to evaluate the expressions of adhesion molecules (AM) on peripheral blood mononuclear cells (PBMNC) from systemic sclerosis (SSc) patients. Thirty-one SSc patients (ACR) and 20 normal subjects were selected for the study. PBMNC were analyzed for LFA-1α, LFA-1β, ICAM-3, ICAM-1, and l-selectin expressions. ICAM-3 expression was decreased while ICAM-1 was increased on SSc PBMNC, compared to controls (p = 0.04 and 0.003, respectively). A positive association was found between LFA-1α (r = 0.37, p = 0.03), LFA-1β (r = 0.38, p = 0.002), ICAM-3 (r = 0.42, p = 0.01), and l-selectin (r = 0.38, p = 0.03) expressions and greater number of immunosuppressive drugs taken by SSc patients. Also, anti-centromeric positive SSc patients had lower expressions of LFA-1α, LFA-1β, ICAM-3, and l-selectin. Lower expression of ICAM-3 and higher expression of ICAM-1 suggest that AMs may be involved in the pathogenesis of scleroderma.     

Variations in renal threshold for glucose in Type 1 (insulin-dependent) diabetes mellitus

Summary The blood glucose/urinary glucose relationship was studied in 23 patients with Type 1 (insulin-dependent) diabetes. Glucose was infused intravenously in order to increase blood glucose concentration slowly and gradually. The renal threshold was recorded at the slightest trace of glycosuria and varied by a factor of 2 (from 6.0 to 14.3 mmol/l). The rise in blood glucose required to change the urinary output (0–1.1 mmol glucose/20 min) varied by a factor of 7 (1.1–7.6 mmol/l). The maximal rate of tubular glucose reabsorption varied by a factor of 2 (0.93–1.98 mmol/min). The renal threshold was negatively correlated with the creatinine clearance (r=-0.52, p<0.05), but was not correlated with diabetic control, age or duration of diabetes. The maximal rate of glucose reabsorption was negatively correlated with age (r=-0.47, p<0.05) and duration of diabetes (r=-0.54, p< 0.05). In conclusion, urinary glucose excretion is dependent on both renal threshold and the splay and the slope of the blood glucose/urinary glucose excretion curve. Thus, the degree of glycosuria is of value as an index of diabetic control only when the blood glucose/urinary glucose relationship is known. The inverse correlation between renal threshold and creatinine clearance limits the usefulness of measuring glycosuria in patients with nephropathy.     

Effects of aging and menopause on serum interleukin-6 levels and peripheral blood mononuclear cell cytokine production in healthy nonobese women

Inappropriate interleukin-6 production is thought to play a role in the development of several age-related conditions including atherosclerosis. This study aimed to determine whether aging affects circulating interleukin-6 (IL-6) levels. Healthy, nonobese women (n = 208, 44.5 ± 0.70 years, 22.4 ± 0.17 kg/m²) were categorized into four age groups (22–31, 32–41, 42–51, and 52–63 years; cross-sectional study). Cytokine levels in serum and those produced from peripheral blood mononuclear cell (PBMC) were measured. The oldest group had the highest circulating levels of IL-6 and oxidized low-density lipoprotein (ox-LDL) and higher PBMC production of IL-6, tumor necrosis factor-α (TNF-α), and interleukin-1 alpha (IL-1β). Additionally, significant interactions between age and menopause were found for serum IL-6 (P = 0.024), and TNF-α (P = 0.011) and IL-1β (P < 0.001) produced from PBMCs. Serum IL-6 levels positively correlated with age, waist–hip ratio (WHR), systolic blood pressure, circulating levels of TNF-α, IL-1β, and ox-LDL, and urinary 8-epi-prostaglandin F₂α. Multiple stepwise regression models identified the following factors for contributing to serum IL-6 levels: serum IL-1β, menopause status, WHR, and serum TNF-α in mode I (R ² = 0.302); serum IL-1β, age, serum TNF-α, and WHR (β = 0.197; P = 0.006) in model II (R ² = 0.283). Sub-analysis was performed according to menopausal status. Serum IL-6 levels were positively associated with levels of IL-6, TNF-α, and IL-1β in PBMC supernatants (unstimulated) from postmenopausal women, whereas these were negatively associated in premenopausal women. In conclusion, circulating IL-6 levels may be interactively influenced by age and menopause. Additionally, estrogen deprivation after menopause may enhance PBMC cytokine production in postmenopausal women, resulting in increased IL-6 levels which are closely related to oxidative stress.     

Adipokines and the insulin resistance syndrome in familial partial lipodystrophy caused by a mutation in lamin A/C

Aims/hypothesis Familial partial lipodystrophy (FPLD) and obesity are both associated with increased risks of type 2 diabetes and cardiovascular disease. Although adipokines have been implicated, few data exist in subjects with FPLD; therefore we investigated a family with FPLD due to a lamin A/C mutation in order to determine how abnormalities of the plasma adipokine profile relate to insulin resistance and the metabolic syndrome. Methods Plasma levels of adiponectin, leptin, resistin, IL-1β, IL-6 and TNF-α in 30 subjects (ten patients, 20 controls) were correlated with indices of metabolic syndrome. Results Compared with controls, FPLD patients had significantly lower plasma levels of adiponectin (3.7±1.0 in FDLP cases vs 7.1±0.72 μg/ml in controls, p=0.02), leptin (1.23±0.4 vs 9.0±1.3 ng/ml, p=0.002) and IL-6 (0.59±0.12 vs 1.04±0.17 pg/ml, p=0.047) and elevated TNF-α (34.8±8.1 vs 13.7±2.7 pg/ml, p=0.028), whereas IL-1β and resistin were unchanged. In both groups, adiponectin levels were inversely correlated with body fat mass (controls, r=−0.44, p=0.036; FDLP, r=−0.67, p=0.025), insulin resistance (controls, r=−0.62, p=0.003; FDLP, r=−0.70, p=0.025) and other features of the metabolic syndrome. TNF-α concentrations were positively related to fat mass (controls, r=0.68, p=0.001; FDLP, r=0.64, p=0.048) and insulin resistance (controls, r=0.86, p=0.001; FDLP, r=0.75, p=0.013). IL-6, IL-1β and resistin did not demonstrate any correlations with the metabolic syndrome in either group. Conclusions/interpretation Low adiponectin and leptin and high TNF-α were identified as the major plasma adipokine abnormalities in FPLD, consistent with the hypothesis that low adiponectin and high TNF-α production may be mechanistically related, and perhaps responsible for the development of insulin resistance and cardiovascular disease in FPLD.     

Antiphospholipid antibodies and kidney involvement in patients with systemic sclerosis

Antiphospholipid (aPL) antibodies are often detected in systemic autoimmune diseases. The aim of the study was to examine the correlation between the presence of aPL and certain markers of renal function in systemic sclerosis (SSc). Fifty patients (pts) with SSc were examined for the presence of antibodies to cardiolipin (aCL) and to anti-beta 2 glycoprotein I (a-B2GPI) in immunoglobulin M (IgM) and IgG class. Moreover, serum levels of creatinine, cystatin C, and glomerular filtration rate (GFR) were determined in all patients. In all studied pts together, three multiple-regression analyses were performed with one set cystatin C as a dependent variable, in the second GFR according to the Cockcroft–Gault formula and in the third creatinine clearance by Modification of Diet in Renal Disease (MDRD) formula. As independent variables, aPL of either type were inserted in addition to disease duration and age. IgG aCL was significantly positively associated with serum cystatin C (p = 0.002), significantly negatively associated with creatinine clearance according to the Cockcroft–Gault and MDRD formula (p = 0.01 and 0.02, respectively). IgG a-B2GPI was significantly negatively associated with creatinine clearance according to the Cockcroft–Gault (p = 0.03) and MDRD (p = 0.01) formula. IgM aCL and IgM a-B2GPI were not associated with any markers of the renal function. Our study suggests the relationship between kidney involvement and the positivity for some aPL in patients with SSc. Positivity for IgG aCL and IgG a-B2GPI in patients with SSc without secondary antiphospholipid syndrome seems to be connected with decrease of glomerular filtration.     

Exercise-induced renal tubular injury in intermittent claudication

While, exercise in intermittent claudication (IC) may improve symptoms and exercise tolerance, it has been shown to produce an ischemia-reperfusion injury. This study aimed to assess the impact of this on renal function, by measuring the changes in activity of the urinary enzyme N-acetyl--D-glucosaminidase (NAG), a sensitive marker of renal tubular damage. 15 patients with IC and 15 controls underwent a standardized exercise treadmill test. Changes in Ankle/Brachial Pressure Index (ABPI) were measured as was the urinary activity of NAG at rest, and following exercise. While a marked change was seen in ABPI's of the IC group, no change was apparent in the controls. Urinary NAG activity rose significantly in the IC group following exercise (mean 51.25 µmol/h/mmol creatinine) compared with both resting levels (30.4) and with the post-exercise NAG of controls (26.4),P<0.05. There was no significant difference in NAG levels within the control group (23.5 vs 26.4). Exercise in intermittent claudication is associated with a renal tubular cell injury, which may be related to an ischemia-reperfusion injury.     

Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats

Summary Changes in nitric oxide (NO) levels were determined in ischaemic acute renal failure in streptozotocin-induced diabetes mellitus rats. Two weeks after streptozotocin administration and immediately after right nephrectomy, the left renal artery was occluded for 60 min. Similar procedures were carried out in non-diabetic rats. The nitrite (NO₂) + nitrate (NO₃) levels were measured in plasma and urine. The effects of chronic oral supplementation with l-arginine and an NO synthase inhibitor (N-omega-nitro-l-arginine) were also studied in both diabetic and non-diabetic rats before and after renal artery clamping. The rats with diabetic acute renal failure had a much lower creatinine clearance (90±22 l · min^–1 · 100 g body weight^–1, p<0.005), and higher fractional excretion of sodium (FENa)% (10.90±4.2, p<0.001) and protein excretion (2078±69 g/ml creatinine clearance, p<0.001) compared with the respective values in the non-diabetic groups (163±30; 1.46±86; 453.3±31). The plasma and urine NO₂ + NO₃ levels were significantly higher in the untreated diabetic rats compared with the untreated normal rats before ischaemia (p<0.001). The ischaemic acute renal failure in non-diabetic rats increased the plasma and urinary NO₂ + NO₃ excretion after ischaemia. The urinary excretion of these metabolites decreased significantly and their plasma levels remained unchanged in the ischaemic diabetic rats. The l-arginine administration resulted in a small but significantly higher creatinine clearance after clamping in the non-diabetic rats. The NO synthase inhibitor caused deterioration in renal function in all ischaemic and non-ischaemic groups. In summary, the greater vulnerability to ischaemia of the diabetic kidney seems to be associated with both impaired response to and impaired production of NO.Abbreviations IARF Ischaemic acute renal failure - STZ streptozotocin - NOSi nitric oxide synthase inhibitor - ARF acute renal failure - Ccr creatinine clearance - FENa% fractional excretion of sodium     

The relationship between adipocyte fatty acid binding protein-4, retinol binding protein-4 levels and early diabetic nephropathy in patients with type 2 diabetes

Adipocyte fatty acid binding protein-4 (A-FABP4) and retinol binding protein-4 (RBP4) have recently been linked to type 2 diabetes mellitus (DM). Serum A-FABP4 and RBP4 levels and their relationships with early diabetic nephropathy were examined in 87 type 2 diabetic patients. The patients with diabetic nephropathy showed high A-FABP4 levels compared to the patients without diabetic nephropathy (p = 0.0001). Log A-FABP4 correlated positively with age (p = 0.02), log duration of diabetes (p = 0.04), log body mass index (BMI) (p = 0.0001), log creatinine (p = 0.007), log C-reactive protein (CRP) (p = 0.01), log albumin excretion rate (AER) (p = 0.001), and negatively with MDRD-GFR (p = 0.0001). Serum RBP4 levels were similar between the patients with and without diabetic nephropathy. RBP4 correlated positively with triglycerides (p = 0.001), log creatinine (p = 0.009), and negatively with MDRD-GFR (p = 0.04). In regression analysis, log A-FABP4 was associated with age, sex, log BMI, and log AER (r² = 0.43) and RBP4 was associated with triglycerides and log creatinine (r² = 0.22). In conclusion, we found high serum A-FABP4 but unchanged RBP4 concentrations and their associations with renal function and early diabetic nephropathy in type 2 DM.     

Retinol-binding protein 4 is associated with impaired glucose regulation and microalbuminuria in a Chinese population

Aims/hypothesis  Increased retinol-binding protein 4 (RBP4) has been reported in association with insulin resistance and type 2 diabetes. We aimed to investigate the association of serum RBP4 with impaired glucose regulation and microalbuminuria in Chinese adults aged 40 years or older. Methods  Serum RBP4 was measured in 763 individuals with normal glucose regulation, 508 with impaired glucose regulation and 524 newly diagnosed diabetic patients. Serum RBP4 was measured using ELISA and urine albumin/creatinine ratio was used to determine the urinary albumin excretion. Results  Serum RBP4 concentrations were significantly higher in participants with isolated impaired fasting glucose, isolated impaired glucose tolerance, combined impaired fasting glucose/impaired glucose tolerance and diabetes than in those with normal glucose regulation, whereas serum RBP4 levels were not different in the four groups with dysregulation of glucose metabolism. RBP4 was associated with a higher risk for impaired glucose regulation (OR 1.011 for each 1 μg/ml increase in RBP4, 95% CI 1.000–1.022, p = 0.04) after adjustment for sex, age, BMI, current smoking and alcohol intake, family history of diabetes, insulin resistance, triacylglycerol, total cholesterol, and HDL- and LDL-cholesterol; the corresponding OR of combined impaired glucose regulation and type 2 diabetes was 1.022 (95% CI 1.009–1.035, p = 0.0009). RBP4 was associated with the risk of microalbuminuria (OR 1.023, 95% CI 1.004–1.042, p = 0.01) after adjustment for sex, age, smoking habit and alcohol intake, BMI, waist/hip ratio, homeostasis model assessment of insulin resistance, GFR, triacylglycerol, total cholesterol, and HDL- and LDL-cholesterol. Conclusions/interpretation  Serum RBP4 level is closely associated with impaired glucose regulation and is an independent risk factor for microalbuminuria. M. Xu and X. Y. Li contributed equally to this study.     

Pro-inflammatory cytokines are associated with podocyte damage and proximal tubular dysfunction in the early stage of diabetic kidney disease in type 2 diabetes mellitus patients

AimsTo evaluate if there is a link between inflammation (expressed by inflammatory cytokines) and the early stage of diabetic kidney disease (DKD), as shown by markers of podocyte damage and proximal tubular (PT) dysfunction.MethodsIn this study were enrolled 117 type 2 DM patients (36-normoalbuminuria, 42-microalbuminuria, 39- macroalbuminuria), and 11 healthy subjects. Serum and urinary IL-1 alpha, IL-8, IL-18, urinary albumin:creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (podocalyxin, synaptopodin, nephrin) and of PT dysfunction (KIM-1, NAG) were assessed.ResultsIn multivariable regression urinary Il-1 alpha correlated positively with podocalyxin and NAG (p < 0.0001, R²= 0.57); urinary IL-8 correlated directly with synaptopodin, NAG, nephrin, and KIM-1 (p < 0.0001, R² = 0.67); urinary IL-18 correlated directly with synaptopodin, NAG, and nephrin (p < 0.0001, R² = 0.59). Serum IL-1 alpha correlated positively with nephrin, synaptopodin, NAG (P < 0.0001, R² = 0.68); serum IL-8 correlated directly with synaptopodin and NAG (p < 0.0001, R² = 0.66); serum IL-18 correlated directly with NAG, KIM-1, and podocalyxin (p < 0.0001, R²=0.647).ConclusionsPro-inflammatory interleukins are associated with podocyte injury and PT dysfunction in early DKD. These could exert a key role in the pathogenesis of early DKD, before the development of albuminuria.     

Interleukin-1α, interleukin-1β and tumor necrosis factor-α genetic variants and risk of dementia in the very old: evidence from the “Monzino 80-plus” prospective study

The association among single nucleotide polymorphisms in inflammatory genes as interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β) or tumor necrosis factor alpha (TNF-α) and dementia has been explored mostly in Alzheimer’s disease, while few data addressing their association with dementia in very old people are available. We performed a prospective, door-to-door population-based study of 80 years or older residents in eight municipalities of Varese province, Italy (the Monzino 80-plus study). No difference was found by a cross-sectional approach comparing IL-1α rs1800587, IL-1β rs3087258 and TNF-α rs1799724 genotypic and allelic frequencies between those affected and not affected by dementia. After a 5-year follow-up, the elderly carriers of T-allele of TNF-α rs1799724 were at an increased risk of dementia (p = 0.03). This association was no more significant adjusting for the apolipoprotein E epsilon-4 allele (APOE-ε4, p = 0.26), which was an independent predictor of dementia onset (p = 0.0002). In short, in this Italian population of oldest olds, dementia was associated to the APOE-ε4 allele only.     

Soluble receptor activator of NFkappa B-ligand and osteoprotegerin in rheumatoid arthritis - relationship with bone mineral density,disease activity and bone turnover

The aim of our study was to investigate determinants of bone mineral density (BMD) measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN) in patients with rheumatoid arthritis (RA) with special respect to bone resorbing proinflammatory cytokines and their physiological antagonists. In 142 RA patients the following parameters were measured in parallel with BMD: serum levels of soluble receptor activator of nuclear factor kappa-B-ligand (sRANKL), osteoprotegerin (OPG), interleukin (IL)-6, soluble glycoprotein 130 (sgp130), 25-hydroxyvitamin D3 (25OHD₃), 1,25-dihydroxyvitamin D3 (1,25[OH]₂D₃), intact parathyroid hormone, osteocalcin, ionized calcium, renal excretion of pyridinolin and deoxypyridinolin, C-reactive protein, and erythrocyte sedimentation rate (ESR). No significant differences of sRANKL, OPG, IL-6, and spg130 were found between patients with osteoporosis (47.9% of patients), osteopenia (36.6%), and normal BMD (15.5%). However, total sRANKL was significantly higher in postmenopausal women with osteoporosis at FN than in those without (p < 0.05) and showed a negative correlation with BMD-LS in patients older than 60 years (p = 0.01). BMD-LS and BMD-FN (p < 0.001) and total sRANKL (p < 0.01) were negatively related with the age of the patients. Only IL-6 (positive correlation, p < 0.001) and 1,25(OH)₂D₃ (negative correlation, p < 0.001) but not sRANKL, OPG, and sgp130 were related to disease activity. Using multiple linear regression analysis, menopause was identified as the crucial negative determinant of BMD-LS (R ² = 0.94, p = 0.001), whereas cumulative glucocorticoid dose (β = −0.80, p = 0.001) and ESR (β = −0.44, p = 0.016) were the negative determinants of BMD-FN (R ² = 0.86, p = 0.001). The results indicate that influences of age and gender must be considered in investigations on the relationship between BMD and sRANKL in RA and that high serum levels of sRANKL seems to be associated with osteoporosis only in subgroups of RA patients.