[Sympathetic nerve activity in chronic renal failure - what are the therapeutic options?]. / Sympathikusaktivität bei Niereninsuffizienz - Therapieoptionen.

Patients with chronic renal failure are characterized by a tonic elevation of sympathetic tone. This factor largely contributes to their increased cardiovascular risk. The increased sympathetic drive is caused by activiation of renal afferent fibers in the diseased kidneys. Therapeutic options for hypertensive patients with chronic renal failure with respect to their sympathetic overactivity are inhibitors of the renin-angiotensin-system and central sympatholytic drugs. The role of catheter-based renal denervation in these patients is currently under investigation.

The impact of "high-producer" interleukin-6 haplotypes on cardiovascular morbidity and mortality in a kidney transplant population.

BACKGROUND: At present, inflammation is considered to be one of the key players in the development and maintenance of atherosclerosis, with ample impact on renal transplant outcomes. Interleukin-6 (IL-6) levels and the underlying genetically determined "high-producer" status impact cardiovascular morbidity and mortality. In end-stage renal disease (ESRD) patients, the role of genetically determined IL-6 differences in cardiovascular and renal outcomes of kidney transplantation is controversial. In this study, we sought to clarify the influence of IL-6 haplotypes on cardiovascular and renal outcomes among kidney transplant recipients. METHODS: Three hundred fifty-two first kidney transplant patients were genotyped for the two "clade" IL-6 polymorphisms ((-174)G/C and (1888)G/T) and two missense polymorphisms (Pro32Ser, Asp162Val), which are known to influence IL-6 levels and outcome. RESULTS: We observed four IL-6 haplotypes among our population: CCAG: 57.0%, CCAT: 2.8%, GCAT: 39.2%, GCTT: 1.0%. After stratifying the haplotypes into diplotypes in three different models, we failed to observe associations with early or late graft outcomes, or with all-cause or cardiovascular mortality. These findings were also confirmed when we separately analyzed each polymorphism. CONCLUSION: Despite evidence of associations in other transplant and ESRD cohorts, we could not confirm any association between IL-6 haplotypes/diplotypes and cardiovascular or graft-related outcomes among our population at high risk for inflammatory diseases.

Early onset of a decreased intracellular magnesium and phosphate concentration in smooth muscle cell of SHR.

A decrease in total magnesium content is not a direct proof of a decreased magnesium ion concentration. It could reflect a phosphate alteration or an ATP metabolism disorder. Plasma phosphate levels are lower in spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto rats (WKYs), and defects in membrane regulation or mitochondrial ATP synthase occur. Only sparse data exist concerning cellular magnesium and phosphate concentrations in hypertensive cells. In aortic smooth muscle cells from 10 SHRs of the Münster strain and 10 age-matched normotensive WKY rats, the intracellular phosphate and magnesium content was measured by electron probe X-ray microanalysis (Camscan CS 24 apparatus, Cambridge, U.K.). The Mg++ content was 0.09 +/- 0.15 g/kg dry weight in SHRs versus 1.15 +/- 0.10 g/kg dry weight in WKY rats (p < 0.01). Vascular smooth muscle phosphate content was 23.6 +/- 0.79 g/kg dry weight in WKY rats versus 15.81 +/- 1.22 g/kg dry weight in SHRs (p < 0.01). In aortic smooth muscle cells of one month old SHRs intracellular magnesium was measured as 1.05 +/- 0.08 versus 1.09 +/- 0.09 g/kg dry weight in WKYs. Intracellular phosphate concentration in one month old SHRs was 18.71 +/- 2.41 versus 21.36 +/- 1.25 g/kg dry weight in WKYs (eight animals in each group). Aortic smooth muscle cells of SHRs are caracterized by markedly lowered intracellular phosphate and magnesium concentrations, resulting in an altered ATP-metabolism, as described earlier. Possibly a membrane defect or a magnesium deficiency or disturbed magnesium channels are responsible for the early onset in the pathogenesis of primary hypertension.

Early-onset increased calcium and decreased magnesium concentrations and an increased calcium/magnesium ratio in SHR versus WKY.

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 decreased magnesium and an 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 mmHg) and 13 normotensive rats (NT, systolic blood pressure 118.5+/-7.2 mmHg) 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 (Means+/-SD, p < 0.01), the magnesium content was 35.5+/-3.9* in SHR versus 50.1+/-4.9 mmol/kg dry weight in NT /p < 0.01). The calcium/magnesium ratio was significantly increased in SHR versus NT (3.56+/-0.39* versus 2.23+/-0.27, p < 0.01). In hypertensive one month old animals the increase in the calcium/magnesium ratio was not as pronounced as in 9 month old animals. The calcium/magnesium ratio was measured 3.3+/-0.42 in SHR (n = 8) as compared to 2.51+/-0.39 in normotensive animals (n = 8, p < 0.01). Aortic smooth muscle cells from SHR are characterized by markedly elevated intracellular calcium and decreased intracellular magnesium contents compared with normotensive cells. The increased calcium/magnesium ratio in hypertensive cells may be a pathogenetic factor for the development of arteriosclerosis and hypertension.

Lowered Total Intracellular Magnesium Status in a Subgroup of Hypertensives.

A new method to determine total Mg++ content in lymphocytes was developed, offering advantages for routine measurements as compared to fluorescence methods. Intracellular total Mg++ measurements were performed in lymphocytes of 18 healthy subjects and 19 untreated essential hypertensive patients. Mg++ content was referred to lymphocytic and membrane protein, which was determined according to Bradford's method. Mg++ measurements were performed by atomic absorption spectroscopy using a Video 12 apparatus of Thermo Electron Instrumentation Laboratory, Andover, USA. The results show that in patients with essential hypertension total intralymphocytic Mg++ content is significantly lower (0.07 +/- 0.05 mmol/g lymphocytic protein, mean +/- s.d.) as compared to controls (0.11 +/- 0.04 mmol/g lymphocytic protein, mean +/- s.d., p < 0.05). Free intracellular Mg++ content was measured in lymphocytes by the fluorescent indicator mag-fura-II, showing no significant differences in normotensives and hypertensives (0.30 +/- 0.16 versus 0.38 +/- 0.17 mmol/l). Additionally, in platelets free intracellular Mg++ concentrations were not found of significant difference in normotensives and hypertensives (0.52 +/- 0.23 versus 0.47 +/- 0.27 mmol/l) using mag-fura-II. In plasma Mg++ concentrations there was no significant difference in the normotensive and hypertensive group (0.92 +/- 0.07 versus 0.88 +/- 0.07 mmol/l). There was no correlation between plasma or free or total cellular magnesium concentrations in both groups. Furthermore this method seems also suitable for routine measurements of total intracellular Mg++ concentrations in even larger measurements like mag-fur-II. Lowered total intracellular Mg++ concentrations in a subgroup of primary hypertensives may contribute to the development of this disorder, perhaps due to different buffering systems.http://link.springer-ny.com/link/service/journals/00547/bibs/8n3p154.html

Decreased membrane Mg2+ concentrations in a subgroup of hypertensives: membrane model for the pathogenesis of primary hypertension.

Intracellular Mg2+ measurements were performed in erythrocyte membranes of 18 untreated normotensive and 19 untreated essential hypertensive patients. Mg2+ concentrations were determined by atomic absorption spectroscopy using a Video 12 apparatus. The results show that in patients with essential hypertension total Mg2+ content in erythrocyte membranes was significantly decreased as compared with the control group (0.28 +/-0.05 v 0.52+/-0.15 mmol/g membrane protein; mean+/-SD, P < .001). Additionally, plasma and free intracellular Mg2+ content of lymphocytes and platelets showed no significant difference in normotensives and hypertensives. Lowered total membrane Mg2+ concentrations in a subgroup of primary hypertensives may contribute to the development of this disorder, perhaps due to different buffering or membrane transport systems.

Sodium-dependent Cl-/HCO3- exchange in patients with chronic renal failure: correlation with renal function.

To investigate the effects of uremia on cellular function the activity of the sodium-dependent chloride-bicarbonate exchanger (sodium-dependent Cl-/HCO3- exchanger) and the sodium-independent chloride-bicarbonate exchanger (sodium-independent Cl-/HCO3- exchanger) were examined in lymphocytes from 25 patients with mild chronic renal failure, 9 patients with end-stage chronic renal failure on regular hemodialysis, and from 25 age-matched healthy control subjects. Cytosolic pH (pHi) and the activity of the sodium-dependent Cl-/HCO3- exchanger and the sodium-independent Cl-/HCO3- exchanger were measured spectrophotometrically using the pH-sensitive fluorescent dye 2'7'-bis-carboxyethyl-5 [6]-carboxyfluorescein acetoxy-methylester (BCECF-AM). The activation of the sodium-dependent Cl-/HCO3- exchanger by removal of extracellular chloride was prevented in the presence of 500 micromol/liter 4,4' diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) or in the absence of extracellular sodium, but was not affected by the specific inhibitor of the sodium/proton exchanger, ethyl isopropyl amiloride (EIPA). The sodium-dependent Cl-/HCO3- exchangers were significantly different in lymphocytes from healthy control subjects, patients with mild chronic renal failure, and patients with end-stage chronic renal failure (X2 = 6.43, P = 0.040 by Kruskal-Wallis-test). The sodium-dependent Cl-/HCO3- exchanger was significantly lower in patients with end-stage chronic renal failure compared to patients with mild chronic renal failure or compared to healthy control subjects (each P < 0.05). In patients with chronic renal failure a significantly negative correlation between sodium-dependent Cl-/HCO3- exchanger and the serum creatinine concentration (r = -0.507; P = 0.0022) could be observed. On the other hand, resting pHi in lymphocytes and sodium-independent Cl-/HCO3- exchanger were not significantly different in lymphocytes from healthy control subjects, patients with mild chronic renal failure or patients with end-stage chronic renal failure. The present study suggests that the activity of the sodium-dependent Cl-/HCO3- exchanger is progressively impaired in chronic renal failure.