Markus Kosch

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-Ø, 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-Ø (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.

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.

Impaired flow-mediated vasodilation of the brachial artery in patients with primary hyperparathyroidism improves after parathyroidectomy

OBJECTIVE The endothelium is a newly recognised target tissue of parathyroid hormone (PTH). It is not clear whether hyperparathyroidism affects endothelial function and whether parathyroidectomy (Ptx) has an influence on arterial vessel wall properties. We studied brachial flow-mediated vasodilation (FMD) and brachial and carotid intima-media thickness (IMT) in patients with primary hyperparathyroidism (pHPT) before and after Ptx and in healthy controls. METHODS 19 patients with pHPT (mean+SEM, age 45+/-4.7 years, PTH 238+/-52 ng/l) were studied. Diabetes, hypertension and vascular disease were excluded. Twenty healthy volunteers matched for age, sex and blood pressure served as controls. Enddiastolic diameter, FMD and nitroglycerine-induced (NMD) dilation of the brachial artery were measured by a multigate pulsed doppler system (echo-tracking), IMT was determined using automatic analysis of the M-line signal. Healthy volunteers where studied on one occasion, patients were studied at baseline and 6 months after Ptx. RESULTS Six months after Ptx PTH had decreased to normal, blood pressure levels remained unchanged. Endothelium dependent FMD at baseline was impaired in patients compared to controls (4.7+/-1.2 vs. 18.2+/-3.7%, P<0.01), however, FMD improved significantly after Ptx (16.7+/-3.0%, P<0.01). Nitroglycerine-induced dilation, IMT and artery diameter were not different between groups and did not change after Ptx. CONCLUSIONS Impaired endothelium dependent vasodilation in patients with primary hyperparathyroidism improves after successful parathyroidectomy. Endothelial dysfunction associated with primary hyperparathyroidism occurs without detectable structural wall alterations of the brachial artery and appears therefore to be an early and reversible arterial alteration.

Membrane, intracellular, and plasma magnesium and calcium concentrations in preeclampsia

Changes in intracellular calcium and magnesium concentrations seem to be involved in the pathogenesis of preeclampsia, whereas the role of cell membranes has not been studied in detail yet. To investigate the changes in calcium and magnesium metabolism in normal pregnancy and preeclampsia, plasma, intracellular, and membrane calcium and magnesium concentrations were determined in a clinical study. Twenty-five control, 18 untreated healthy pregnant, and 16 nulliparas preeclamptic women were investigated. Plasma, cellular, and membrane (erythrocytes) calcium and magnesium contents were measured by atomic absorption spectroscopy. Plasma and intracellular magnesium concentrations were significantly lower in the healthy pregnant group and the preeclamptic group as compared to controls (P < .01). In erythrocyte membranes magnesium content was found significantly decreased in the preeclamptic women as compared to healthy subjects (P < .001). There was a significant decrease in the plasma calcium concentration in the preeclamptic group compared to controls or healthy pregnant women (P < .05). Membranous calcium content was significantly increased in the preeclamptic group versus controls or healthy pregnant women (P < .001) and an inverse correlation with membranous magnesium content was found (r = -0.79,P < .01). Lowered plasma, intracellular, and membrane magnesium concentrations in preeclampsia may contribute to the development in hypertension in pregnancy. In addition, a disturbed calcium homeostasis is observed in preeclampsia.

Studies on flow-mediated vasodilation and intima-media thickness of the brachial artery in patients with primary hyperparathyroidism

The endothelium is a newly recognized target organ of parathyroid hormone (PTH) and may contribute to its effects on vascular tone and blood pressure regulation. Flow-mediated vasodilation (FMD), brachial and carotid intima-media thickness (IMT) were studied in patients with primary hyperparathyroidism (pHPT) and controls to evaluate endothelial function and structural arterial vessel wall alterations. Sixteen patients with pHPT (mean +/- SEM, age 44 +/- 5 years; PTH 229 +/- 72 ng/L; serum calcium 3.0 +/- 0.06 mmol/L; serum phosphate 2.0 +/- 0.2 mg/L) and 16 normocalcemic control subjects matched for age, sex, and blood pressure were included. Diabetes, hypertension, and vascular disease were excluded in both groups. End-diastolic diameter, flow-mediated (FMD) and nitroglycerin-mediated (NMD) dilation of the brachial artery were measured by a multigate pulsed Doppler system (echo-tracking). IMT was determined using automatic analysis of the M-line signal. Endothelium-dependent FMD was impaired in patients compared to controls (4.6 +/- 1.6% v 19.2 +/- 3.9%, P < .001). NMD (23.8 +/- 3.1% v. 22.4 +/- 2.8%, P = NS), carotid and brachial IMT (0.60 +/- 0.04 mm v 0.64 +/- 0.06 mm, P = NS, and 0.46 +/- 0.04 mm v 0.47 +/- 0.08 mm, P = NS, respectively) and artery diameters were not different. Endothelium-dependent vasodilation is impaired in patients with primary hyperparathyroidism despite normal IMT. Endothelial dysfunction may contribute to increased cardiovascular morbidity and mortality in pHPT.

Flow-mediated vasodilation and distensibility in relation to intima-media thickness of large arteries in mild essential hypertension☆

Whether endothelial dysfunction in essential hypertension is a cause or a consequence of structural vessel wall alterations is not known. The purpose of the present study was to compare flow-mediated vasodilation and mechanical vessel wall properties of large arteries between never treated mild essential hypertensive patients with normal intima-media thickness (IMT) and those exhibiting intima-media thickening. We measured brachial and carotid artery diameter and distension by Doppler frequency analysis of vessel wall movements in M-mode in ten essential hypertensive patients with normal carotid artery IMT (HYP1), in ten patients with increased IMT (HYP2), and in 13 normotensive control subjects (CON). Thereafter, we measured changes in brachial artery (BA) diameters during distal reactive hyperemia after 4 min of forearm occlusion. Nitroglycerin-mediated vasodilation was measured to assess endothelium-independent vasodilation, and BA blood flow was estimated using a pulsed Doppler system. Intima-media thickness of the carotid arteries was examined by high resolution B-mode ultrasound. IMT was 0.66 +/- 0.02 mm in the HYP1 group, 0.84 +/- 0.03 mm in the HYP2 group (P < .01 v HYP1, P < .01 v CON), and 0.71 +/- 0.04 mm in the CON group. Forearm occlusion was reduced in both the HYP1 group (3.4% +/- 3.6%, P < .01 v CON) and the HYP2 group (6.4% +/- 1.5%, P < .05 v CON) when compared with the CON group (16.5% +/- 2.8%). Nitroglycerin-mediated vasodilation and BA blood flow were not different between study groups. BA distension (as well as carotid artery distension) was significantly lower in the HYP1 group (52 +/- 6 microm, P < .05 v CON), but not in the HYP2 group (72 +/- 10 microm) when compared with the CON group (88 +/- 13 microm). The data suggest that endothelial dysfunction and reduced distensibility of large arteries in patients with essential hypertension occur in the absence of structural vessel wall alterations.

Folate metabolism in renal failure

In most patients with chronic kidney disease, provision of sufficient human recombinant erythropoietin (rHuEPO) and iron replacement therapy will effectively correct renal anaemia. Folate deficiency has been implicated as a contributory factor in renal anaemia and hyporesponsiveness to rHuEPO treatment. As such, the necessity of regular folate supplementation has been debated over the last decade. Although folate loss through dialysis is greater than by urinary excretion, these losses are easily balanced by a normal mixed diet containing 60 g protein/day. Thus, unless patients show significant folate depletion, additional supplementation of folic acid does not appear to have a beneficial effect on erythropoiesis or on responsiveness to rHuEPO therapy. However, a diagnosis of folate deficiency should be considered in patients with chronic renal insufficiency and significant elevation in mean cell volume or hypersegmented polymorphonuclear leucocytes; in patients with malnutrition or a history of alcohol abuse, or in patients hyporesponsive to rHuEPO treatment, especially when accompanied by macrocytosis. Measurements of serum folate are not necessarily indicative of tissue folate stores and red blood cell (RBC) folate measures provide a more accurate picture. Low RBC folate concentrations in these patients indicate the need for folate supplementation. Folate supplementation can also reduce elevated levels of homocysteine in dialysis patients, which may contribute to the high cardiovascular morbidity prevalent in these individuals. High-dose folate therapy (5-15 mg/day) has been shown to reduce plasma homocysteine levels by 25-30% and appears to be well tolerated provided the patient has adequate vitamin B(12) stores. Although long-term benefits of this intervention for cardiovascular protection and patient survival have yet to be established, folic acid is considered a relatively non-toxic and well-tolerated vitamin.

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.

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 × 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 × 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.

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.