Angela D'Angelo

Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension

Objectives Advanced glycation end-products (AGE) may cause vascular stiffening by forming crosslinks through the collagen molecule or by interaction with their cellular transductional receptor (RAGE). A secreted isoform of RAGE, termed soluble RAGE (sRAGE), may contribute to the removal/detoxification of AGE by acting as a decoy. Here we studied the plasma sRAGE levels in hypertensive and normotensive human subjects. We also investigated the relationship between blood pressure parameters and plasma sRAGE concentrations. Design A cross-sectional case–control study. Setting and participants The outpatient clinic of a university teaching hospital. Participants were 147 never-treated patients with essential hypertension (87 men and 60 women, aged 50 ± 10 years) and 177 normotensive controls (118 men and 59 women, aged 49 ± 10 years). Main outcome measures Plasma sRAGE levels determined by enzyme-linked immunosorbent assay, systolic blood pressure (SBP), diastolic blood pressure, pulse pressure (PP) and mean arterial pressure. Results The plasma concentration of sRAGE [median (interquartile range)] was 1206 (879–1658) pg/ml in hypertensive subjects and 1359 (999–2198) pg/ml in normotensive controls (P = 0.002). Simple correlation analysis revealed that log-transformed sRAGE levels were inversely correlated with SBP (r = −0.11; P < 0.001) and PP (r = −0.23; P < 0.001). Forward-selection multiple regression analysis revealed that log-transformed sRAGE levels were determined more strongly by PP (F = 3.127, P < 0.001). Conclusions Plasma sRAGE levels are decreased in patients with essential hypertension and are inversely related to PP. Our results raise the possibility that sRAGE may play a role in arterial stiffening and its complications.

Alendronate Prevents Further Bone Loss in Renal Transplant Recipients

The aim of this study was to investigate the effects of alendronate, calcitriol, and calcium in bone loss after kidney transplantation. We enrolled 40 patients (27 men and 13 women, aged 44.2 ± 11.6 years) who had received renal allograft at least 6 months before (time since transplant, 61.2 ± 44.6 months). At baseline, parathyroid hormone (PTH) was elevated in 53% of the patients and the Z scores for bone alkaline phosphatase (b‐ALP) and urinary type I collagen cross‐linked N‐telopeptide (u‐NTX) were higher than expected (p < 0.001). T scores for the lumbar spine (−2.4 ± 1.0), total femur (−2.0 ± 0.7), and femoral neck (−2.2 ± 0.6) were reduced (p < 0.001). After the first observation, patients were advised to adhere to a diet containing 980 mg of calcium daily and their clinical, biochemical, and densitometric parameters were reassessed 1 year later. During this period, bone density decreased at the spine (−2.6 ± 5.7%; p < 0.01), total femur (−1.4 ± 4.2%; p < 0.05), and femoral neck (−2.0 ± 3.0%; p < 0.001). Then, the patients were randomized into two groups: (1) group A—10 mg/day of alendronate, 0.50 μg/day of calcitriol, and 500 mg/day of calcium carbonate; and (2) group B—0.50 μg/day of calcitriol and 500 mg/day of calcium carbonate. A further metabolic and densitometric reevaluation was performed after the 12‐month treatment period. At the randomization time, group A and group B patients did not differ as to the main demographic and clinical variables. After treatment, bone turnover markers showed a nonsignificant fall in group B patients, while both b‐ALP and u‐NTX decreased significantly in alendronate‐treated patients. Bone density of the spine (+5.0 ± 4.4%), femoral neck (+4.5 ± 4.9%), and total femur (+3.9 ± 2.8%) increased significantly only in the alendronate‐treated patients. However, no trend toward further bone loss was noticed in calcitriol and calcium only treated subjects. No drug‐related major adverse effect was recorded in the two groups. We conclude that renal transplanted patients continue to loose bone even in the long‐term after the graft. Alendronate normalizes bone turnover and increases bone density. The association of calcitriol to this therapy seems to be advantageous for better controlling the complex abnormalities of skeletal metabolism encountered in these subjects.

Effects of one-year cyclical treatment with clodronate on postmenopausal bone loss.

We studied 60 women with postmenopausal bone loss randomly allocated to the following treatments: Group 1 (20 patients), no treatment; Group 2 (20 patients), clodronate 400 mg daily by mouth for 30 consecutive days, followed by 60 days of no treatment; Group 3 (20 patients) oral calcitriol 2 mcg by mouth for 5 days and oral clodronate 400 mg daily for additional 25 days, followed by 60 days of no treatment. The therapeutic cycles were repeated four times in the 12-month study period. In the 36 treated patients of Groups 2 and 3 who completed the study period we observed a progressive and significant increase in lumbar bone density both at 6 and 12 months of therapy, without significant differences between the two treatment protocols (+3.88 +/- 0.65%, P < 0.001 and +3.21 +/- 0.89%, P < 0.005 in Groups 2 and 3, respectively, at the end of the study). In contrast, there was a progressive and significant decline of bone mineral density in untreated patients (-2.34 +/- 0.49%, P < 0.001). After 12 months serum calcium values in treated subjects were higher than in untreated patients (P < 0.05). Serum phosphate was raised only in Group 2, mean values being higher after 12 months than before treatment (P < 0.05); parathyroid hormone (PTH) declined in all treated patients, the fall being significant in Group 2 (P < 0.02). No important side effects were observed with treatment and no patient withdrew because of these. We conclude that cyclical low dose clodronate therapy induced a gain in lumbar spine bone mass in patients with postmenopausal osteoporosis.

Telmisartan and Irbesartan Therapy in Type 2 Diabetic Patients Treated with Rosiglitazone: Effects on Insulin-Resistance, Leptin and Tumor Necrosis Factor-α

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56±5, treated with telmisartan; and 45 males and 48 females, aged 55±4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c, fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-α (TNF-α), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbA1c and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-α and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid control and metabolic parameters related to metabolic syndrome compared to irbesartan. These observed metabolic effects of different angiotensin type 1 receptor blockers could be relevant when choosing a therapy to correct metabolic derangement of patients affected by metabolic syndrome and diabetes.

Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study.

Vitamin K (vitamin K1 or phylloquinone and vitamin K2, a series of menaquinones [MKs]) is involved in the production of bone and matrix amino acid γ‐carboxy‐glutamic acid (Gla) proteins, regulating bone and vascular calcification. Low vitamin K concentrations are associated with increased risks of fractures and vascular calcification, and frequent complications in hemodialysis patients. We carried out an observational study to establish the prevalence of vitamin K deficiency and to assess the relationship between vitamin K status, vertebral fractures, vascular calcification, and survival in 387 patients on hemodialysis for ≥1 year. We determined plasma levels of vitamin K compound, bone‐Gla‐protein, matrix‐Gla‐protein, and routine biochemistry. Vertebral fractures (reduction in vertebral body height by ≥20%) and aortic and iliac calcifications were also investigated in a spine (D5–L4) radiograph. Three‐year patient survival was analyzed. Important proportions of patients had deficiency of MK7 (35.4%), vitamin K1 (23.5%), and MK4 (14.5%). A total of 55.3% of patients had vertebral fractures, 80.6% had abdominal aorta calcification, and 56.1% had iliac calcification. Vitamin K1 deficiency was the strongest predictor of vertebral fractures (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.38–6.26). MK4 deficiency was a predictor of aortic calcification (OR, 2.82; 95% CI, 1.14–7.01), whereas MK5 deficiency actually protected against it (OR, 0.38; 95% CI, 0.15–0.95). MK7 deficiency was a predictor of iliac calcification (OR, 1.64; 95% CI, 1.03–2.60). The presence of vertebral fractures was also a predictor of vascular calcifications (OR, 1.76; 95% CI, 1.00–3.08). Increased alkaline phosphatase and C reactive protein (CRP), age, and cerebrovascular events were predictors of mortality. Our study suggests that the vitamin K system may be important for preserving bone mass and avoiding vascular calcification in hemodialysis patients, pointing out a possible role of vitamin K in bone and vascular health. Based on our results, we suggest that the general population should also be studied for vitamin K deficiency as a possible cause of both vertebral fractures and vascular calcification.

In search of adult renal stem cells.

The therapeutic potential of adult stem cells in the treatment of chronic degenerative diseases has becoming increasingly evident over the last few years. Significant attention is currently being paid to the development of novel treatments for acute and chronic kidney diseases too. To date, promising sources of stem cells for renal therapies include adult bone marrow stem cells and the kidney precursors present in the early embryo. Both cells have clearly demonstrated their ability to differentiate into the kidneys specialized structures. Adult renal stem cells have yet to be identified, but the papilla is where the stem cell niche is probably located. Now we need to isolate and characterize the fraction of papillary cells that constitute the putative renal stem cells. Our growing understanding of the cellular and molecular mechanisms behind kidney regeneration and repair processes ‐ together with a knowledge of the embryonic origin of renal cells ‐ should induce us, however, to bear in mind that in the kidney, as in other mesenchymal tissues, the need for a real stem cell compartment might be less important than the phenotypic flexibility of tubular cells. Thus, by displaying their plasticity during kidney maintenance and repair, terminally differentiated cells may well function as multipotent stem cells despite being at a later stage of maturation than adult stem cells. One of the major tasks of Regenerative Medicine will be to disclose the molecular mechanisms underlying renal tubular plasticity and to exploit its biological and therapeutic potential.

High levels of soluble receptor for advanced glycation end products may be a marker of extreme longevity in humans

at hospital discharge remained unchanged (3%). Patients admitted between 2003 and 2005, although slightly more functionally and cognitively impaired, had fewer comorbid conditions than those hospitalized between 1998 and 2000 (data not shown). In the last few years, some important changes have begun in the care of older people in Italy, the country in Europe with the most older people. First, the mean age of older people hospitalized for acute diseases has increased, reflecting not only the aging of the population, but also the need for intensive medical care for the oldestold. Second, the length of hospitalization has decreased, mainly due to national policy requirements (reduction of the number of admissions and the length of stay to control expenditure). Third, the proportion of cases needing a fulltime caregiver increased, and there were changes in caregiver profile. The aging of the population has led to a greater number of widowed patients and a larger number of people needing a caregiver and thus a greater burden for relatives. Apart from social services (such as nursing home admission), families also sought alternative solutions for the provision of care to their elderly relatives, generating private financial commitments. Descriptive studies of older persons’ perceptions and views about their providers of care are needed.

Prevalence of CKD in Northeastern Italy: Results of the INCIPE Study and Comparison with NHANES

BACKGROUND AND OBJECTIVES Sufficiently powered studies to investigate the CKD prevalence are few and do not cover southern Europe. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS For the INCIPE study, 6200 Caucasian patients ≥40 years old were randomly selected in northeastern Italy in 2006. Laboratory determinations were centralized. The albumin to creatinine ratio in urine and estimated GFR from calibrated creatinine (SCr) were determined. A comparison with 2001 through 2006 NHANES surveys was performed. RESULTS Prevalence of CKD was 13.2% in northeastern (NE) Italy (age and gender standardized to the U.S. 2007 Caucasian population). Prevalence of CKD in U.S. Caucasians is higher (20.3%), the major difference being in CKD 3. Risk factors for CKD are more prevalent in the United States than in Italy. With use of CKD 3a and 3b stages, CKD prevalence decreased in NE Italy (8.5%) and in the United States (12.8%). CONCLUSIONS The prevalence of CKD is high in NE Italy, but lower than that in the United States. A large part of the difference in CKD prevalence in NE Italy versus that in the United States is due to the different prevalence of CKD 3. The higher prevalence of a number of renal risk factors in persons from the United States explains in part the different dimensions of the CKD problem in the two populations.

TGFβ1 induces epithelial–mesenchymal transition, but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture

The origin and fate of renal interstitial myofibroblasts (MFs), the effector cells of renal fibrosis, are still debated. Experimental evidence suggests that renal MFs derive from tubular epithelial cells throughout the epithelial–mesenchymal transition (EMT) process. Primary human tubular epithelial cells (HUTECs) were cultured for 4 and 6 days on plastic or type I collagen‐coated plates with 1, 5, 10 and 50 ng/ml of transforming growth factor β1 (TGFβ1). The EMT process was monitored by morphology and immunophenotyping for αSMA, cytokeratin 8–18, E‐cadherin, vimentin and collagen III. Quantitative comparative RT/PCR and real‐time PCR were used to evaluate the expression of collagen III and IV, fibronectin, tenascin, MMP‐2, CTGF, E‐cadherin and cadherin 11 genes, as well as those of the Smad signalling pathway. TGFβ1 was found capable of reactivating the mesenchymal programme switched off during tubulogenesis, but it induced no de novo expression of αSMA gene or myofibroblast phenotype. We demonstrate that the EMT process is conditioned by the extracellular matrix and characterized by TGFβ1‐driven Smad3 downregulation. Our study results suggest that TGFβ1 could function as a classic embryonal inducer, initiating a cascade of de‐differentiating events that might be further controlled by other factors in the cellular environment.

Renal Handling Of Sodium and Water in Early Chronic Liver Disease: Evidence for a Reduced Natriuretic Activity of the Cirrhotic Urinary Extracts in Rats

Acute expansion of extracellular fluid volume during maximal water diuresis was induced in 8 chronic liver disease patients without clinical evidence of fluid retention, and in 8 controls. Fractional reabsorption of sodium was inferred in the proximal tubule, in the ascending limb of Henles loop, and in the more distal site of the tubule. The results indicate that the significantly reduced increment of sodium excretion in cirrhotic patients was due to its augmented reabsorption in the proximal tubule. To establish whether there was a reduced activity of a natriuretic factor, a biologic assay was performed in 16 albino Wistar rats by using urine samples collected immediately after completion of a saline load and processed with gel filtration. The infusion of this fraction resulted in a significant lowering of the increment of urine output, and absolute and fractional sodium excretion only in the rats infused with urine extracts from cirrhotic patients. The results of this study raise the possibility that a reduced production of a natriuretic factor may play some role in the pathogenesis of sodium retention, which is observed in patients with cirrhosis of the liver.