Peritoneal dialysis in diabetic patients.
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Biological Availability↗
Biomedical subjects
A D'Angelo
Publications and source records attributed to A D'Angelo.
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 microg/day of calcitriol, and 500 mg/day of calcium carbonate; and (2) group B-0.50 microg/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.
Adult↗
Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes.
Cardiovascular disease and the development of coronary artery disease play a pivotal role in increasing mortality in patients with type 1 diabetes. The aim of our study was to evaluate the effects of pancreas transplantation on atherosclerotic risk factors, endothelial-dependent dilation (EDD), and progression of intima media thickness (IMT) in patients with uremia and type 1 diabetes after kidney-alone (KA) or kidney-pancreas (KP) transplantation. A cross-sectional study comparing two groups of patients with type 1 diabetes was performed. Sixty patients underwent KP transplantation and 30 patients underwent KA transplantation. Age and cardiovascular risk profile were comparable in patients before transplantation. In all patients, atherosclerotic risks factors (lipid profile, fasting and post-methionine load plasma homocysteine, von Willebrand factor levels, D-dimer fragments, and fibrinogen) were assessed and Doppler echographic evaluation of IMT and endothelial function with flow-mediated and nitrate dilation of the brachial artery was performed. Twenty healthy subjects were chosen as controls (C) for EDD. Compared with patients undergoing KA transplantation, patients undergoing KP transplantation showed lower values for HbA1c (KP = 6.2 +/- 0.1% vs. KA = 8.4 +/- 0.5%; P < 0.01), fasting homocysteine (KP = 14.0 +/- 0.7 mcromol/l vs. KA = 19.0 +/- 2.0 micromol/l; P = 0.02), von Willebrand factor levels (KP = 157.9 +/- 8.6% vs. KA = 212.5 +/- 16.2%; P < 0.01), D-dimer fragments (KP = 0.29 +/- 0.02 microg/ml vs. KA = 0.73 +/- 0.11 microg/ml;P < 0.01), fibrinogen (KP = 363.0 +/- 11.1 mg/dl vs. KA = 397.6 +/- 19.4 mg/dl; NS), triglycerides (KP = 122.7 +/- 8.6 mg/dl vs. KA = 187.0 +/- 30.1 mg/dl; P = 0.01), and urinary albumin excretion rate (KP = 13.5 +/- 1.9 mg/24 h vs. KA = 57.3 +/- 26.3 mg/24 h; P < 0.01). Patients undergoing KP transplantation showed a normal EDD (KP = 6.21 +/- 2.42%, KA = 0.65 +/- 2.74%, C = 8.1 +/- 2.1%; P < 0.01), whereas no differences were observed in nitrate-dependent dilation. Moreover, IMT was lower in patients undergoing KP transplantation than in patients undergoing KA transplantation (KP = 0.74 +/- 0.03 mm vs. KA = 0.86 +/- 0.09 mm; P = 0.04). Our study showed that patients with type 1 diabetes have a lower atherosclerotic risk profile after KP transplantation than after KA transplantation. These differences are tightly correlated with metabolic control, fasting homocysteine levels, lower D-dimer fragments, and lower von Willebrand factor levels. Normal endothelial function and reduction of IMT was observed only in patients undergoing KP transplantation.
Adult↗
Urinary excretion of vasoactive substances in chronic renal failure.
To investigate the pathophysiological role of vasoactive substances in the progression of chronic renal disease, we measured the 24-hour urinary excretion of prostaglandin 6-keto F1alpha, thromboxane B2, NOx, cGMP and ET-1 in 26 patients with chronic renal failure under conservative treatment and in 40 control subjects. Urinary 6-keto PgF1alpha, TxB2 and cyclic GMP were evaluated by RIA, and ET-1 was assayed by EIA. NOx were evaluated using a colorimetric assay as nitrate/nitrite. Urinary excretion of prostaglandin 6-keto F1alpha averaged 18.1 +/- 20.9 ng/g Ucreat in patients vs. 240.9 +/- 257.3 in controls (p < 0.0001), thromboxane B2 422 +/- 374 ng/g Ucreat in patients vs. 967 +/- 589 in controls (p < 2x 10(-5)), NOx 7.07 +/- 5.54 mg/g Ucreat in patients vs. 9.79 +/- 3.77 in controls (p < 0.01), cGMP 310 +/- 200 pg/g Ucreat in patients vs. 488 +/- 241 in controls (p < 0.001). In contrast, ET-1 urinary excretion was almost doubled in patients (13.45 +/- 5.84 ng/g of Ucreat) in comparison with controls (6.84 +/- 2.81 p < 1x10(-5)). While in control subjects significant correlations between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.69, p < 0.001) or NOx and ET-1 (r = 0.54, p < 0.001) were present, in patients only the relationship between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.53, p < 0.01) was retained. Our data suggest that in the normal kidney a balance between prostaglandin I2 and thromboxane A2, or nitric oxide and endothelin-1 is present, which contributes to hemodynamic regulation and protects this organ from ischemic damage. This balance is abolished in CRF, where a large increment of vasopressor agent endothelin is present, which, joined to a prevalent decrease of prostaglandin I2 synthesis, could contribute to the ischemic and fibrogenetic damage of the kidney, leading to progression of renal disease.
6-Ketoprostaglandin F1 alpha↗
Persistently increased bone turnover and low bone density in long-term survivors to kidney transplantation.
AIMS: There are few data on the long-term outcome of bone health in renal transplant recipients. We wanted to evaluate the prevalence of osteoporosis and related clinical fractures in long-term survivals to kidney transplantation. METHODS: We carried out a cross-sectional study of 80 males and 44 females, aged 45 +/- 1 years, who had undergone kidney transplantation (KTx) 55.6 +/- 4.6 months earlier. Patients were treated according to standard immunosuppressive protocols. RESULTS: High parathyroid hormone levels were observed in 55 out of the 124 patients (44.6%) and the prevalence of secondary hyperparathyroidism (SHPT) remained similar even when subjects were grouped according to the time elapsed since transplant. The Z scores for bone alkaline phosphatase, osteocalcin, urinary N telopeptide and galactosyl-hydroxylysine were increased as compared to normal controls, both in males and females (p < 0.05). Bone formation markers normalized, while bone resorption markers remained elevated in these patients even ten years after transplant. Vertebral and femoral osteoporosis were present in 37% and 56% of the patients, respectively, and no tendency toward a recovery in bone mass was seen even in those patients who had survived the longest time since KTx. Clinical fracture rate was 0.006 and 0.031 patient years, before and after KTx, respectively. The number of fractures was lower in patients taking lower mean daily doses of corticosteroids (p < 0.025). PTH levels positively correlated with bone alkaline phosphatase, osteocalcin and N telopeptide. CONCLUSION: In conclusion, bone density is decreased and bone turnover increased even many years after KTx, with persistent SHPT and corticosteroid use being the main pathogenetic factors.
Adult↗
Mild hyperhomocysteinemia and fibrinolytic factors in patients with history of venous thromboembolism.
Mild hyperhomocysteinemia is recognized as a risk factor for venous thromboembolism (VTE), though its role in the thrombogenic processes is not understood. Its possible association with impaired fibrinolysis was investigated in 157 patients (61 women, 96 men) below the age of 60 years (43+/-11, mean+/-SD) with a history of objectively confirmed VTE. Patients had significantly higher fasting total plasma homocysteine (tHcy) levels than 138 apparently healthy subjects (8.0, 6.6-9.9 micromol/L vs. 7.2, 5.9-8.6 micromol/L, P=0. 001; median, range between first and third quartile). In 17 of 157 patients (12%) hyperhomocysteinemia (tHcy>11.4 micromol/L for women and tHcy>12.6 micromol/L for men) was established. The adjusted odds ratio as an estimate of relative risk for VTE was 2.3 (0.8-7.0; 95% confidence interval). When patients with hyperhomocysteinemia were compared to patients without hyperhomocysteinemia, no significant differences in t-PA (antigen 9.2+/-5.5 microg/L and 9.7+/-4.7 microg/L, respectively; activity 1.3+/-0.5 IU/mL and 1.3+/-0.7 IU/mL, respectively) and PAI-1 (antigen 19.3+/-17.5 microg/L and 22.6+/-20. 4 microg/L, respectively; activity 15.0+/-12.6 and 15.8+/-13.3 IU/mL, respectively) were observed. In conclusion, this study showed an association between mild hyperhomocysteinemia and VTE, but provided no evidence for an independent association between hyperhomocysteinemia and alterations in fibrinolytic proteins.
Adult↗
Oral anticoagulation treatment in the elderly: a nested, prospective, case-control study.
BACKGROUND: Whether elderly patients are at increased risk of complications during oral anticoagulant treatment (OAT) is still a matter of debate. METHOD: Bleeding and thrombotic events occurring during OAT in 461 patients, aged 75 years or older when they started OAT, and in 461 patients younger than 70 years, matched for sex, OAT indication, and treating center, were examined in a prospective, multicenter, inception-cohort study. RESULTS: Bleeding rate was 9.9% and 6.6% patient-years in elderly and young patients, respectively (P = .07), and 2.1% and 1.1% for major bleeding (P = .19); 6 and 1 events, respectively, were fatal (all intracranial, relative risk, 6.4; P = .05). In the elderly, bleeding rate was lower (4.5%) for international normalized ratios (INRs) between 2.0 and 2.9; it was higher during the first 90 treatment days (P = .05) and when arterial vascular disease was the indication for OAT (P = .03). Thrombosis rate was 4.2% and 2.5% patient-years in elderly and young patients, respectively (P = .10); however, 13 and 5 events were fatal (relative risk, 2.8; P = .04). Thrombosis rate was lower (1.5%) for INRs between 2.0 and 2.9; it was higher during the first 90 treatment days (P<.001) and 6 of 7 venous events occurred at lower than 2.0 INRs. CONCLUSIONS: A nonsignificant trend was noted toward a higher rate of both bleeding and thrombotic complications in elderly vs matched younger patients. Intracranial bleeding and fatal thrombotic events were significantly more frequent in the elderly. Our results also indicate that lower than 2.0 INRs do not preclude bleeding in the elderly nor offer adequate protection from thrombotic events. Moderate anticoagulation (2.0-3.0 INRs) in elderly patients seems the safest and most effective.
Administration, Oral↗
Association studies of genetic polymorphisms and complex disease.
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Alleles↗
Idiopathic hypercalciuria: O2(-)NO relationship and altered bone metabolism.
The pathogenesis of idiopathic hypercalciuria (IH) has not been elucidated yet, but a correlation between IH and altered bone metabolism has been proposed. Since nitric oxide (NO) regulates osteoclasts' bone resorption, a possible role for NO can be suggested. In this study we evaluated iNOS gene expression by reverse transcription of mRNA from monocytes, followed by polymerase chain reaction in patients with IH subdivided into fasting (FH) and absorptive (AH) hypercalciuria. Since superoxide (O2-), which metabolizes NO, is overproduced by osteoclasts during bone resorption, peroxynitrite plasma level was evaluated as index of O2-. Vertebral BMD in IH as a whole group was lower vs controls (C) (Z score=-1.78+/-0.2 vs 0.51+/-0.25, p<0.001), but only FH patients showed a reduced bone density (2.13+/-0.18 vs 0.51+/-0.25, p<0.0001). PTH and calcitriol were not different. FH showed an increase in b-ALP vs AH and C (41.1+/-2.6 vs 30.1+/-3.9 vs 26.6+/-3.6 U/l p<0.02), and higher uHP, either on NCD (17.7+/-1.6 vs 11.4+/-1.3 mg/g uCr, p<0.04) or after LCD (26.7+/-2.5 vs 16.7+/-1.9, p<0.01). Cells from FH patients, but not from both AH patients and C, expressed iNOS. Peroxynitrite plasma level was elevated in FH (0.30+/-0.07) pmol/l while not detectable in AH and C. This study confirms an altered bone metabolism only in FH which shows an abnormal NO system. The increased iNOS gene expression in FH, in fact, points toward an altered NO system's activity downstream the generation of NO. A possible interaction of NO with O2-, which breaks down NO, and the role of this interaction in the pathophysiology of IH is discussed.
Adult↗
Role of insulin-like growth factor-I in primary osteoporosis: a correlative study.
Osteoporosis is characterized by impairment of bone mass and deterioration of bone microscopic structure, resulting in increased bone fragility and susceptibility to fracture. Recent reports have indicated that reduced plasma levels of IGF-I are associated with osteoporosis in both males and females. Moreover, there is accumulating clinical evidence that treatment with GH or IGF-I has beneficial effects on bone mass and bone remodeling in men with idiopathic osteoporosis, in the elderly and in hypopituitary patients. As correlative studies on IGF-I, IGF-BP3 and bone mass in the elderly are lacking, we studied the relationships between serum IGF-I, IGF-BP3, bone mineral density (BMD), body mass index (BMI), calciotropic hormones and age in 102 premenopausal and postmenopausal women. Our study indicates that the reduction of the anabolic processes mediated by IGF-I may account for the slow and progressive loss of bone mass that take place after the age of 40-50 years. In addition, nutritional caloric or proteic deficit may add to the effects of GH, age and other factors in decreasing IGF-I synthesis and therefore further contribute to the development of primary osteoporosis.
Adult↗
Cyclosporin-induced endothelial dysfunction and hypertension: are nitric oxide system abnormality and oxidative stress involved?
Hypertension is a major side effect of cyclosporin (CsA). While the mechanism(s) responsible are unclear, CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to the CsA effect on the endothelial-derived factors controlling vasomotor tone. Endothelial nitric oxide (NO) is crucial in the maintenance of a state of basal vasodilation, and recent studies have suggested an NO-mediated counterregulatory mechanism protective from CsA-induced vasoconstriction. Our study evaluates endothelial nitric oxide synthase (ecNOS) gene status (PCR analysis) and plasma levels of NO metabolites (ELISA) in kidney and heart transplant patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolises NO, plasma hydroperoxides from cholesterol esters and from triglycerides and peroxynitrite were also evaluated (HPLC) as an index of the presence of superoxides and of "oxidative stress". Quantification of monocyte ecNOS mRNA and NO metabolites plasma levels from patients and controls (C) demonstrated NO system upregulation in patients notwithstanding the hypertension. The mean ecNOS to beta-actin ratio was 1.80 +/- 0.85 in patients vs 0.40 +/- 0.09 in C (P < 0.04). NO metabolites were 34.03 +/- 14.32 microM in patients vs 11.53 +/- 5.64 microM in C (P < 0.001). Hydroperoxides from cholesterol esters and from triglycerides were also increased in patients, 3.4 +/- 1.4 vs 1.3 +/- 0.6 integrated area units (i. a. u.), P < 0.007 and 10.6 +/- 6.4 vs 1.3 +/- 0.8 i. a. u., P < 0.008, respectively, as well as the peroxynitrite plasma level, 0.32 +/- 0.11 microM/l vs undetectable in C. This study confirms a CsA-induced NO system upregulation in transplanted patients. However, the NO-mediated counterregulatory system to CsA-induced vasoconstriction, present in normals, could be canceled in patients by CsA-induced superoxide (O2-) and free radical production which, by increasing NO metabolism, could contribute to CsA-induced vasoconstriction and hypertension and predispose to atherosclerosis.
Adult↗
Effect of in vivo administration of naloxone on ATP-ase's enzyme systems of synaptic plasma membranes from rat cerebral cortex.
Naloxone is a specific competitive antagonist of morphine, acting on opiate receptors, located on neuronal membranes. The effects of in vivo administration of naloxone on energy-consuming non-mitochondrial ATP-ases were studied in two different types of synaptic plasma membranes from rat cerebral cortex, known to contain a high density of opiate receptors. The enzyme activities of Na+, K(+)-ATP-ase, Ca(2+), Mg(2+)-ATP-ase and Mg(2+)-ATP-ase and of acetylcholinesterase (AChE) were evaluated on synaptic plasma membranes obtained from control and treated animals with effective dose of naloxone (12microg x kg(-1) i.m. 30 minutes). In control (vehicle-treated) animals specific enzyme activities assayed on these two types of synaptic plasma membranes are different, being higher on synaptic plasma membranes of II type than of I type, because the first fraction is more enriched in synaptic plasma membranes. The acute treatment with naloxone produced a significant decrease in Ca(2+),Mg(2+)-ATP-ase activity and an increase in AChE activity, only in synaptic plasma membranes of II type. The decrease of Ca(2+), Mg(2+)-ATP-ase enzymatic activity and the increased AChE activity are related to the interference of the drug on Ca(2+) homeostasis in synaptosoplasm, that leads to the activation of calcium-dependent processes, i.e. the extrusion of neurotransmitter. These findings give further evidence that pharmacodynamic characteristics of naloxone are also related to increase [Ca(2+)]i, interfering with enzyme systems (Ca(2+), Mg(2+)-ATP-ase) and that this drug increases acetylcholine catabolism in synaptic plasma membranes of cerebral cortex.
Acetylcholinesterase↗
GLUT-1 and TGF-beta: the link between hyperglycaemia and diabetic nephropathy.
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Diabetic Nephropathies↗
Angiotensin-converting enzyme gene deletion polymorphism determines an increase in frequency of migraine attacks in patients suffering from migraine without aura.
Many authors have reported an association between the angiotensin-converting enzyme (ACE)-D allele and coronary heart disease and other cardiovascular diseases. The mechanism underlying the positive associations between the ACE-D alleles and diseases are not yet clear. Previous reports showed an association between migraine without aura and ACE-D allele polymorphism. The study is aimed to evaluate if the DD genotype could also be associated with the frequency and duration of migraine without aura. In 302 patients suffering from migraine without aura (at least for 1 year), with no history of cardiovascular diseases and major risk factors for ischemic events, the genotypes of the ACE gene, plasma ACE activity, and the frequency (weekly) and duration of migraine attacks were evaluated. No drugs were given before (4 weeks) and during the study. The same evaluations were performed in 201 subjects without migraine. The molecular biologist and the physician evaluating the patient data were blinded to the clinical history and ACE-DD gene determination. Genotypes were determined by polymerase chain reaction amplification. Plasma ACE activity was performed by the HPLC method. The groups were similar for sex, age and smoking habit (migraines: 302 patients (200 F/102 M), mean age 37.8 +/- 8.2 years; control: 201 subjects (127 F/74 M), mean age 37.5 +/- 9.3 years). Patients with migraine without aura showed higher incidence of the ACE-DD gene (48.34%) than control subjects (37.32%), p < 0.05. The frequency of migraine (average attacks per week) was higher in patients with DD (2.11 +/- 1.9) than in patients with ID (1.54 +/- 1. 44), p < 0.05. No difference in duration of migraine attacks (hours per week) was observed. Plasma ACE activity was increased in patients with the ACE-DD gene. Our data suggest that ACE-DD gene polymorphism could have an important role in determining migraine attacks and the frequency of these attacks. Further data are needed through further studies, especially on the biomolecular level.
Adult↗
The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events.
Total fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 +/- 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 +/- 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 microM in men and >15 microM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous thrombosis: 3.25, 1.78-5.91). The 677TT MTHFR genotype was not significantly more prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42: 0.84-2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for case/control status: 8.29, 4.61-14.9). The 2756GG MS genotype, observed in 4 patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was negatively correlated to folate and vitamin B12 levels, with better correlation found in subjects with the 677TT mutation (r = -0.42 and -0.25) than with the 677CC or CT MTHFR genotype (r = 0).37 and -0.11). However, folate was similar in patients and controls and vitamin B12 was higher in patients (460 +/- 206 vs. 408 +/-185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p < or =0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p < or =0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B,2 levels (p = 0.023). Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12 requirements irrespective of the A2756G polymorphism of the MS gene. Yet unidentified abnormalities of MS or of any of the enzymes participating in the synthesis of methylated vitamin B12 may play an important role in the phenotypic expression of moderate hyperhomocysteinemia.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Oxidative stress and nitric oxide system in post-transplant hypertension.
BACKGROUND: CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to CsA effects on the endothelial-derived factors controlling vasomotor tone, but the mechanisms responsible are unclear. Endothelial nitric oxide (NO) is known to maintain a state of basal vasodilation and recently a NO mediated counterregulatory mechanism protective from CsA-induced vasoconstriction has been suggested. PATIENTS AND METHODS: Our study evaluates ecNOS gene status and NO metabolites in kidney transplanted patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolizes NO, plasma hydroperoxides and peroxynitrite were also evaluated as index of the presence of "oxidative stress". RESULTS: Quantification of monocyte ecNOS mRNA and NO metabolites plasma level from patients and control subjects (C) demonstrated NO system up regulation in patients notwithstanding hypertension. The mean ecNOS to beta-actin ratio was 2.00 +/- 0.87 vs 0.29 +/- 0.08 in C, p < 0.04. NO metabolite plasma level was 30.03 +/- 9.62 mM vs 9.37 +/- 3.86, p < 0.001. Hydroperoxides were also increased in patients: 3.6 +/- 1.6 i.a.u. vs 1.4 +/- 0.8, p < 0.007 (from cholesterol esters) and 10.8 +/- 6.6 vs 1.5 +/- 0.9, p < 0.008 (from triglycerides) as well as peroxynitrite plasma level: 0.36+/- 0.14 mM/L vs undetectable in C. CONCLUSIONS: This study confirms a NO system up-regulation in transplanted patients. However, the counterregolatory system to CsA-induced vasoconstriction, could be cancelled by CsA induced superoxide and free radicals production which, increasing NO metabolism could contribute to CsA induced vasoconstriction and hypertension.
Humans↗
Direct effect of chronic cyclosporine treatment on collagen III mRNA expression and deposition in rat kidneys.
BACKGROUND: It is hypothesized that in acute and chronic CsA nephrotoxicity, in vivo models CsA side-effects are mediated by Renin-Angiotensin II (RAS)-TGF-beta-1 pathway. However, to induce chronic nephrotoxicity, CsA administration has to be combined with a low salt diet, which causes hemodynamic changes and RAS up-regulation. MATERIALS AND METHODS: In order to define any direct correlation between CsA and nephrotoxicity, we studied in normal sodium fed rats, the chronic effects of CsA administration (group-1 treated with 12.5 mg/Kg/day of CsA subcutaneously; group 2 received daily placebo; group 3 interrupted CsA injection after 60 days), on renal TGF-beta-1 and collagen III expression, and on TGF-beta-1, collagen III and IV deposition. Sacrifices were performed after 2, 4, 8 and 12 weeks (wks) and kidneys were harvested for immunohistological studies and RT/PCR analysis. RESULTS: No difference of TGF-beta-1 expression and deposition was found among groups. Starting from the 2nd week of treatment, an increased collagen III deposition was evident in vessels and in outer medulla with subsequent extension at the 4th week to medullary rays and to cortex interstitium. The deposition paralleled the renal collagen III mRNA up-regulation: it was significantly higher in group 1 than in group 2 (p < 0.009 at 2nd wk; p < 0.016 at 4th wk). Collagen IV deposition did not differ between groups at any point. CONCLUSIONS: Our results suggest that chronic CsA administration can induce, in normal fed rats, the process of interstitial fibrogenesis through TGF-beta non-related mechanisms.
Animals↗
Parathyroid hormone and bone metabolism in kidney-transplanted patients.
BACKGROUND: Decreases in bone mass and increased susceptibility to fractures are well-recognized complications in organ transplants. SUBJECTS AND METHODS: We performed a cross-sectional study on 60 patients (40 males, 20 females, mean age 43.2 +/- 1.06, SE range 22 - 70) who underwent kidney transplantation (KTX) 55.6 +/- 4.5 months before. Blood and 24-hour urine samples were analyzed for the main parameters of mineral metabolism, and also for osteocalcin (BGP), bone alkaline phosphatase (b-ALP, urine N-telopeptid (u-NTx) and urine galactosyl-hydroxylysine (u-Ghyl). DEXA scan of the lumbar spine (LS) and proximal femur (PF) and ultrasound determination of the heel (stiffness) was also performed. RESULTS: T-score values for bone density (BD) were 2.14 +/- 0.11 SD's for LS, -2.56 +/- 0.09 for PF and 2.49 +/- 0.15 for stiffness. There were 29 peripheral fractures in 16 patients. The rate of fractures before KTX were 0.0011 per patient/year and 0.0005 after transplantation (p < 0.02). When expressed as number of SD's with respect to normal controls, BGP (1.48 +/- 0.23), b-ALP (0.95 +/- 0.19), u-NTx excretion correlated negatively with BD at the femoral neck (p < 0.02) and trochanter (p < 0.03). Cumulative steroids intake were negatively correlated with b-ALP positively (p < 0.05). Current CsA was positively correlated with b-ALP (p < 0.001). Both cumulative steroid (p < 0.02) and CSA (p < 0.01) intakes were negatively correlated with BD at Wards triangle. CONCLUSIONS: Our data demonstrate an important bone depletion at each stage KTX. PTH plays a major role in the observed increase in bone turnover, exacerbating the negative effects on the bone on immunosuppressive treatment. Glucocorticosteroid therapy is an important risk factor for osteoporosis in this setting also.
Adult↗