Influence of erythropoietin on arterial stiffness and endothelial function in renal transplant recipients.

BACKGROUND/AIMS: Recent retrospective studies suggest an association of therapy with erythropoiesis-stimulating agents (ESAs) and increased mortality in renal transplant recipients (RTR). Large artery structure and function are significantly impaired in RTR which contributes to their high cardiovascular morbidity and could be altered by erythropoietin. We aimed to examine the influence of ESA therapy on large artery stiffness and endothelial function in RTR. METHODS: 63 RTR with chronic allograft dysfunction and renal anemia were randomized to a group receiving darbepoetin alfa (Dar) and a control group (Co). At baseline and after 8 months of treatment (cumulative Dar dose 11.1 µg/kg b.w.) brachial and common carotid artery distensibility coefficients, aortic pulse wave velocity, brachial artery flow-mediated and nitroglycerin-mediated vasodilation were measured as well as the following biomarkers of vascular function: vWF, sVCAM, sICAM, E-selectin, t-PA and PAI-1. RESULTS: 23 patients in the Dar group and 17 patients in the Co group were available for per-protocol analysis. Hemoglobin increased significantly from 10.9 to 12.6 g/dl after 8 months in the Dar group, whereas it remained stable at 11.3 g/dl in the Co group. Effects on large artery stiffness, endothelial function and biomarkers of vascular function did not differ significantly between the two groups. CONCLUSION: Therapy with Dar during 8 months did not significantly impact parameters of large artery stiffness and endothelial function in RTR. These data suggest that therapy with erythropoietin does not deteriorate arterial stiffness and endothelial function in RTR.

A randomized, double-blind study of valsartan versus metoprolol on arterial distensibility and endothelial function in essential hypertension.

BACKGROUND: Antihypertensive drugs may have differential, pressure-independent effects on hypertension-associated alterations of arterial function. We compared the effects of a 12-week therapy with the AT(1)-receptor antagonist valsartan (Val) versus the beta-blocker metoprolol (Met) on arterial stiffness and endothelial function in mildly hypertensive patients at rest and during generalized sympathetic stimulation. METHODS: Sixty-eight patients (37 male, 31 female, 46 +/- 6 years) were randomized to Val (80-160 mg/d) or Met (50-100 mg/d). Effects of therapy on endothelial function, brachial and carotid artery distensibility coefficients, pulse wave velocity, carotid intima-media thickness and elastic modulus were assessed at rest and during the cold pressor test. RESULTS: Fifty-two patients were available for per protocol analysis. Blood pressure was comparably reduced in both treatment groups. Effects on endothelial function and large artery elastic wall properties did not differ significantly between the two antihypertensive treatment regimens. Trends did not differ significantly between groups for any parameter including carotid intima-media thickness and elastic modulus. CONCLUSION: Short-term treatment with Val and Met had similar effects on large artery functional vessel wall properties in a population of mildly hypertensive patients.

Sympathetic nerve activity in renal transplant patients before and after withdrawal of cyclosporine.

BACKGROUND: It has been suggested that the increase in blood pressure observed in transplant patients treated with cyclosporine is mediated by cyclosporine-induced sympathoexcitation. However, the chronic effects of cyclosporine on sympathetic outflow in renal transplant patients have not been investigated. Therefore we studied sympathetic nerve activity and blood pressure before and 6 months after the withdrawal of cyclosporine in renal transplant patients. METHODS: Twenty-four renal transplant patients with histologically confirmed chronic allograft nephropathy (age 48 +/- 3 years, 60 +/- 10 months after transplantation) were included in the prospective study and randomly assigned to either withdrawal (n = 12) or continuation (n = 12) of cyclosporine. Both groups received mycophenolate mofetil and prednisolone as additional immunosuppressants. At entry and 6 months later blood pressure, muscle sympathetic nerve activity (MSNA), and plasma norepinephrine were measured. To assess the potential influence of the diseased native kidneys, three renal transplant patients who had their native kidneys removed were studied before and after cyclosporine withdrawal. RESULTS: Mean arterial pressure decreased significantly in the cyclosporine-withdrawal group (95 +/- 4 versus 105 +/- 4 mmHg 6 versus 0 months, P < 0.05) but not in the cyclosporine-continuation group (103 +/- 3 versus 105 +/- 4 mmHg, NS). However, plasma norepinephrine and MSNA did not change significantly in either group (MSNA 43 +/- 4 versus 44 +/- 3 and 38 +/- 5 versus 39 +/- 4 bursts/min in the cyclosporine-withdrawal and cyclosporine-continuation groups, NS). Graft function remained stable in both groups and in transplant patients who had their native kidneys removed MSNA did not decrease after cyclosporine withdrawal. CONCLUSION: The withdrawal of cyclosporine in renal transplant patients, receiving relatively low doses of cyclosporine, resulted in a substantial decrease in blood pressure. However, MSNA and norepinephrine did not change. This suggests that cyclosporine treatment does not cause chronic sympathetic activation that could explain the cyclosporine-induced blood pressure elevation in renal transplant patients.

Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082).

PURPOSE: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter. EXPERIMENTAL DESIGN: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed. RESULTS: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2-82.2] in the temozolomide arm and 69.6% (95% CI, 55.8-79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77-1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04-0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus. CONCLUSIONS: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797-806. ©2016 AACR.

Sympathetic nerve activity in end-stage renal disease.

BACKGROUND: Uremia is proposed to increase sympathetic nerve activity (SNA) in hemodialysis patients. The aims of the present study were to determine whether reversal of uremia by successful kidney transplantation (RTX) eliminates the increased SNA and whether signals arising in the diseased kidneys contribute to the increased SNA in renal failure. METHODS AND RESULTS: We compared muscle sympathetic nerve activity (MSNA) in 13 hemodialysis patients wait-listed for RTX and in renal transplantation patients with excellent graft function treated with cyclosporine (RTX-CSA, n=13), tacrolimus (RTX-FK, n=13), or without calcineurin inhibitors (RTX-Phi, n=6), as well as in healthy volunteers (CON, n=15). In addition to the above patients with present diseased native kidneys, we studied 16 RTX patients who had undergone bilateral nephrectomy (RTX-NE). Data are mean+/-SEM. MSNA was significantly elevated in hemodialysis patients (43+/-4 bursts/min), RTX-CSA (44+/-5 bursts/min), RTX-FK (34+/-3 bursts/min), and RTX-Phi (44+/-5 bursts/min) as compared with CON (21+/-3 bursts/min), despite excellent graft function after RTX. RTX-NE had significantly reduced MSNA (20+/-3 bursts/min) when compared with RTX patients. MSNA did not change significantly with RTX in 4 hemodialysis patients studied before and after RTX (44+/-6 versus 43+/-5 bursts/min, P=NS). In contrast, nephrectomy resulted in reduced MSNA in all 6 RTX patients studied before and after removal of the second native kidney. CONCLUSIONS: Despite correction of uremia, increased SNA is observed in renal transplant recipients with diseased native kidneys at a level not significantly different from chronic hemodialysis patients. The increased SNA seems to be mediated by signals arising in the native kidneys that are independent of circulating uremia related toxins.

Relationship between muscle sympathetic nerve activity and large artery mechanical vessel wall properties in renal transplant patients.

OBJECTIVES: Renal transplant recipients (RTX) show a major impairment of large artery elastic wall properties. Sympathetic overactivity present in patients with renal disease has been shown to alter large artery elasticity; however, in RTX, this issue has not been addressed. The present study therefore investigated a possible relationship between sympathetic activity and large artery distensibility in RTX. METHODS: In 32 patients treated with calcineurin inhibitors (RTX-CI, cyclosporine n = 16, tacrolimus n = 16) mean arterial pressure (MAP, automatic sphygmomanometer), muscle sympathetic nerve activity (MSNA, microneurography) and distensibility coefficients of the brachial and carotid arteries (pulsed Doppler) were measured. Sixteen healthy volunteers (CTR), six patients with calcinneurin inhibitor-free immunosuppression (RTX-AZA) and 12 transplant patients after native kidney nephrectomy (RTX-NC) served as control groups. RESULTS: RTX-CI significantly increased MSNA compared to CTR (36 +/- 3 versus 16 +/- 2 bursts/min, P < 0.05, mean +/- SEM). Both brachial and carotid artery distensibility were decreased in RTX-CI compared to CTR (7 +/- 1 versus 13 +/- 1 +/- 10(-3) /kPa and 17 +/- 1 versus 25 +/- 2 x 10(-3) /kPa, respectively, both P < 0.05). In RTX-CI, a significant inverse correlation between brachial, but not carotid artery distensibility and MSNA (r = -0.46, P < 0.01, r = -0.12, not significant, respectively) was found. Correlation between brachial artery distensibility and MSNA remained statistically significant on separate analysis of cyclosporine- or tacrolimus-treated RTX and after correction for arterial diameter, blood pressure, graft function, age and sex by stepwise multiple regression analysis. Results in RTX-AZA were similar to those in RTX-CI. In contrast, in RTX-NC with MSNA not significantly different from CON (16.6 +/- 2.0 bursts/min), brachial artery distensibility was significantly higher compared to RTX-CI and RTX-AZA (14.2 +/- 2.0 x 10(-3) /kPa, P < 0.05, respectively). CONCLUSIONS: Increased sympathetic nerve activity in renal transplant patients is related to decreased distensibility of the muscular type brachial artery, but not the elastic type carotid artery.

Reduced arterial distensibility is a predictor of cardiovascular disease in patients after renal transplantation.

OBJECTIVE: Arterial distensibility is reduced in end-stage renal failure and also after renal transplantation. The aim of the present study was to test the hypothesis that reduced carotid artery distensibility is a predictor of cardiovascular disease in patients after renal transplantation. SUBJECTS AND METHODS: Sixty-eight asymptomatic renal transplant recipients were studied between March 1990 and December 1992, 3-6 months after transplantation. The mean duration of follow-up was 95 +/- 2 months (mean +/- SEM). At entry, vessel wall movements of the common carotid artery were recorded using a pulsed multigate Doppler system; blood pressure was measured by sphygmomanometry. RESULTS: Nineteen cardiovascular events (CVE) occurred during follow-up, leading to death in six cases. The distensibility coefficient of the common carotid artery was significantly lower in patients with CVE than in those without CVE (12.2 +/- 1.0 10-3/kPa versus 16.8 +/- 0.7 10-3/kPa, P < 0.005). Logistic regression analysis showed that the occurrence of cardiovascular disease during follow-up was related to carotid artery distensibility (P < 0.05), independent of sex, age, smoking habits, carotid artery end-diastolic diameter, systolic and diastolic blood pressure levels, heart rate, serum creatinine, cholesterol and haemoglobin levels. Patients with a distensibility coefficient above the age-adjusted mean had a significantly longer interval free of cardiovascular disease than patients with a distensibility coefficient below the age-adjusted mean (P < 0.01). CONCLUSIONS: The distensibility of the common carotid artery is an independent predictor of cardiovascular disease in renal transplant recipients.

Studies on effects of calcineurin inhibitor withdrawal on arterial distensibility and endothelial function in renal transplant recipients.

Whether withdrawal of calcineurin inhibitors has a beneficial effect on disturbed endothelial function and large artery distensibility in renal transplant recipients is not clear. We studied the effects of cyclosporine A (CsA) withdrawal on arterial compliance and endothelium-dependent flow-mediated vasodilatation (FMD) in a prospective, randomized trial; 24 renal transplant recipients receiving mycophenolate mofetil were randomized to withdrawal (n=12) or continuation of CsA (n=12). At baseline and after 6 months, carotid and brachial artery distensibility coefficients and brachial FMD were measured. Brachial distensibility coefficients increased in both groups (withdrawal: 11.1+/-1-14.9+/-2 10(-3)/kPa, continuation: 10.7+/-1-15.2+/-3 10(-3)/kPa, P<0.05, respectively). However, there was no significant effect of treatment on carotid artery distensibility coefficients, FMD, or graft function. Withdrawal of CsA failed to improve carotid artery distensibility or brachial FMD in patients after renal transplantation. Our data indicate that CsA treatment does not contribute significantly to endothelial dysfunction observed in renal transplant recipients.

Impact of renal transplantation on small vessel reactivity.

BACKGROUND: The function of large arteries is altered after renal transplantation. Whether transplantation also induces agonist-dependent functional changes in small arterial renal and extrarenal vessels has not yet been studied. METHODS: Chronic rejection was induced by grafting Lewis rats with kidneys from Fischer rats (FL). Rats that underwent transplantation were bilaterally nephrectomized. Rats that underwent syngeneic transplantation, uninephrectomized rats, uninephrectomized rats with denervated kidneys or with kidneys made ischemic, and native rats served as controls. All animals were treated with cyclosporine for 10 days. Eighteen weeks after surgery, the reactivity of small arteries (220-270 microm) was tested by myography. RESULTS: Weight gain, glomerular filtration rate, and arterial pressure were similar in all groups, whereas proteinuria was elevated in FL. Only kidneys from FL showed glomerular lesions, tubular atrophy, and vasculopathy. Responsiveness of coronary, mesenteric, and femoral resistance vessels to both constrictor and dilator agonists was similar in transplanted and nontransplanted animals. Resistance vessels obtained from both allogeneically and syngeneically transplanted kidneys were more sensitive to norepinephrine, phenylephrine, angiotensin II, and vasopressin than renal vessels from weight-matched controls. Vasodilation in response to acetylcholine and sodium nitroprusside was mitigated in transplanted versus nontransplanted kidneys. CONCLUSIONS: In rat renal transplantation, renal resistance vessel responsiveness to constrictor or dilator stimuli is altered. Extrarenal small vessel function is not affected. The changes in function of renal resistance vessels are not explained by reduction of nephron mass, denervation, ischemia, or chronic rejection.

Effect of a 3-year therapy with the 3-hydroxy-3-methylglutaryl coenzyme a reductase-inhibitor fluvastatin on endothelial function and distensibility of large arteries in hypercholesterolemic renal transplant recipient.

BACKGROUND: In patients after renal transplantation functional arterial vessel wall properties are impaired. Whether 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have a sustained effect on endothelial function and arterial distensibility in patients after renal transplantation is not clear. The authors studied the effects of a long-term therapy with fluvastatin on large artery distensibility and flow-mediated vasodilation (FMD) in hypercholesterolemic patients after renal transplantation in a prospective, blinded, and randomized trial. METHODS: Twenty-six patients who had undergone renal transplantation were assigned randomly to either fluvastatin, 40 mg/d (n = 13) or placebo (n = 13) and underwent follow-up for 3 years. At baseline and after 6, 12, and 36 months of treatment, carotid and brachial artery distensibility, endothelium-dependent FMD, and nitroglycerine-induced vasodilation (NMD) of the brachial artery were measured by a echo-tracking device. RESULTS: A significant decrease in total and low-density cholesterol was observed after 6, 12, and 36 months in patients treated with fluvastatin but not in the placebo group. FMD increased with fluvastatin from 4.6 +/- 2% to 12.4 +/- 2% after 12 months; this improvement was sustained with 13.4 +/- 3% after 36 months (P < 0.05). However, placebo did not alter FMD (P < 0.001 for trend difference between groups by analysis of covariance). Endothelium-independent NMD was similar in both groups at baseline and during therapy. Neither carotid nor brachial artery distensibility coefficients were altered by either treatment. CONCLUSION: HMG-CoA reductase inhibitor therapy over 3 years results in a significant and sustained improvement of endothelial function in hypercholesterolemic patients after renal transplantation. However, this is not accompanied by a beneficial effect on impaired large artery distensibility even after long-term therapy with fluvastatin.

Increased calcium and decreased magnesium concentrations and an increased calcium/magnesium ratio in spontaneously hypertensive rats versus Wistar-Kyoto rats: relation to arteriosclerosis.

Alterations in the metabolism of calcium and magnesium have been implicated in the pathogenesis of primary hypertension. Calcium influx across the external cellular membrane in smooth muscle cells and cardiomyocytes plays a crucial role in the control of cellular excitation contraction and impulse propagation. Intracellular calcium and magnesium concentrations are controlled by reversible binding to specific calcium-binding proteins. The calcium and magnesium flux across the external membrane is regulated by a calcium pump (calcium-magnesium-ATPase), calcium channels, and binding to the membrane. In cell membranes and in lymphocytes of essential hypertensives our group showed increased calcium and a decreased magnesium and increased calcium/magnesium ratio in hypertensive cells. In this context, in aortic smooth muscle cells from 13 spontaneously hypertensive rats (SHR) of the Münster strain (systolic blood pressure 188.4 +/- 9.8 mm Hg) and 13 normotensive rats (NT, systolic blood pressure 118.5 +/- 7.2 mm Hg) aged 9 months, the intracellular calcium and magnesium contents were measured under nearly in vivo conditions by electron probe microanalysis. Measurements were performed in aortic cryosections 3 microm thick; the calcium content was 124.7 +/- 4.5 mmol/kg dry weight in SHR versus 110.3 +/- 4.1 mmol/kg dry weight in NT (mean +/- SD, P <.01 for both), the magnesium content was 35.5 +/- 3.9 in SHR versus 50.1 +/- 4.9 mmol/kg dry weight in NT (P <.01 for both). The calcium/magnesium ratio was significantly increased in SHR versus NT (3.56 +/- 3.9 versus 2.23 +/- 0.27 [P <.01 for both]). Thus, aortic smooth muscle cells from SHR are characterized by a markedly elevated intracellular calcium and decreased intracellular magnesium contents compared with normotensive cells. Cellular calcium and magnesium handling is disturbed in SHR aortic smooth muscle cells as it is in hypertensive blood cells. The increased calcium/magnesium ratio in hypertensive cells is a pathogenetic factor for the development of arteriosclerosis and hypertension.

[Indications and practical management of parenteral iron therapy]. / Indikation und praktische Durchführung der parenteralen Eisentherapie.

Absolute or functional iron deficiency is a common problem in chronic disease which may lead to iron-deficient erythropoesis. Moreover, lack of available iron is the most common reason for unresponsiveness to epoetin in patients on chronic dialysis. Measurements of serum ferritin, transferrin saturation and percentage of hypochromic red blood cells allow the assessment of iron status. Lack of iron resorption and dose-dependent side-effects limit oral supplementation in a number of patients. Several iron preparations are available for intravenous substitution, especially the newly registered iron-saccharose offers safe and reliable iron supplementation and reduces the risk of anaphylaxis and iron toxicity. This review discusses new guidelines concerning diagnosis of iron status, indication for therapy and application of intravenous iron preparation.