Sympathetic blockade prevents the decrease in cardiac VEGF expression and capillary supply in experimental renal failure.

Uremic cardiomyopathy of men and rodents is characterized by lower myocardial capillary supply that in rats could be prevented by central and peripheral blockade of the sympathetic nervous system. The underlying pathomechanisms remain largely unknown. We investigated whether alterations of cardiac vascular endothelial growth factor (VEGF) gene and protein expression were involved. In our long-term experiment, we analyzed whether VEGF gene and protein expression was altered in the heart of male Sprague-Dawley rats with either sham operation (sham, n=10) or subtotal nephrectomy (SNX, n=10). In our short-term experiment (17 sham, 24 SNX), the effect of a putative downregulation of sympathetic nervous activity by surgical renal denervation (interruption of renal afferent pathways) on cardiac gene expression of VEGF, flt-1, and flk-1 and on myocardial capillary supply was analyzed. In the long-term study, cardiac capillary supply and vascular endothelial growth factor gene and protein expression were significantly lower in SNX than in sham. In the short-term experiment, cardiac VEGF mRNA expression was significantly lower in untreated SNX (4,258±2,078 units) than in both sham groups (11,709±4,169 and 8,998±4,823 units); this decrease was significantly prevented by renal denervation (8,190±3,889, P<0.05). We conclude that cardiac VEGF gene and protein expression is reduced in experimental renal failure, and this may be considered as one potential reason for impaired myocardial adaptation under the situation of cardiac hypertrophy. The beneficial effect of sympathetic downregulation on cardiac structure and function in renal failure may be at least in part explained by increased cardiac VEGF gene expression.

H5N1 influenza virus and the safety of plasma products.

BACKGROUND: The ever-increasing number of human H5N1 influenza virus infections may enable these viruses to acquire the ability to spread effectively among humans and potentially to cause a pandemic. Recently, more systemic virus dissemination was reported during H5N1 virus infection of humans, resulting in significant virus concentrations also in the blood. The observation has raised concerns about the safety of labile blood products for transfusion and consequentially also for plasma derivatives. To confirm the safety margins of plasma products, dedicated virus inactivation processes used during their production were investigated for their effectiveness in inactivating this virus of recent concern. STUDY DESIGN AND METHODS: Virus inactivation by steps commonly used during the manufacture of plasma derivatives, such as pasteurization for human albumin, solvent/detergent treatment for intravenous immunoglobulin (IVIG), vapor heating for factor VIII inhibitor bypassing activity, and incubation at low pH for IVIG, were investigated with a reassortant strain of H5N1 influenza virus. RESULTS: The results show that H5N1 influenza behaves as expected for lipid-enveloped viruses; that is, the virus is effectively inactivated by all the commonly used virus inactivation procedures tested. CONCLUSION: The safety margins of plasma derivatives against the theoretical transmission of H5N1 influenza virus are very substantial.

[Adverse renal effects of legal and illicit drugs]. / Nierenschädigung durch legale und illegale Drogen.

The most important task of clinical and experimental nephrology is to identify risk factors for progression of renal failure with the ultimate goal to counteract the dramatic increase of patients reaching end-stage renal disease. Recently, cigarette smoking has been recognized to be one of the most important remediable renal risk factors. The adverse renal effects of smoking seem to be independent of the underlying renal disease and the current evidence suggests a near doubling of the rate of progression in smokers vs. non-smokers. Cessation of smoking slows the rate of progression. Besides smoking, alcohol abuse has also been implicated as a renal risk factor. The present article reviews the current knowledge about the adverse renal effects of these legal drugs. Furthermore, the acute and chronic renal complications due to illegal recreational drugs is discussed. The impact of these drugs on the risk to reach end-stage renal failure is difficult to assess, which is mainly due to the fact that it is difficult to perform controlled prospective studies in substance abusers. According to estimates, 5-6% of new patients starting end-stage renal disease therapy may have opiate-use-related renal diseases in the USA--a figure which documents the magnitude of the problem. Thus, in any case of unexplained renal functional impairment substance abuse should be considered by the physician.

Cigarette smoking: an important renal risk factor - far beyond carcinogenesis.

In recent years, it has become apparent that smoking has a negative impact on renal function, being one of the most important remediable renal risk factors. It has been clearly shown that the risk for high-normal urinary albumin excretion and microalbuminuria is increased in smoking compared to non-smoking subjects of the general population. Data from the Multiple Risk Factor Intervention Trial (MRFIT) indicate that at least in males, smoking increases the risk to reach end-stage renal failure. Smoking is particularly "nephrotoxic" in older subjects, subjects with essential hypertension and patients with preexisting renal disease. Of interest, the magnitude of the adverse renal effect of smoking seems to be independent of the underlying renal disease. Death-censored renal graft survival is decreased in smokers, indicating that smoking also damages the renal transplant. Cessation of smoking has been show to reduce the rate of progression of renal failure both in patients with renal disease or a renal transplant. The mechanisms of smoking-induced renal damage are only partly understood and comprise acute hemodynamic (e.g., increase in blood pressure and presumably intraglomerular pressure) and chronic effects (e.g., endothelial cell dysfunction). Renal failure per se leads to an increased cardiovascular risk. The latter is further aggravated by smoking. Particularly survival of smokers with diabetes mellitus on hemodialysis is abysmal. In the present review article the current state of knowledge about the renal risks of smoking is reviewed. It is the aim of the article to point out that smoking not only increases the risk of renal cell carcinoma or uroepithelial cell carcinoma, but also the risk of a faster decline of renal function. The latter is a relatively new negative aspect which has not been widely recognized.

Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers.

BACKGROUND: Uremia is characterized by inadequately increased sympathetic activity. Sympathetic overactivity is involved in the genesis of hypertension in uremia, but its potential role on progression has not been well investigated. To address this issue, the effect of subantihypertensive doses of an alpha blocker and a beta blocker, and their combination on renal morphology and on albuminuria were investigated in the model of the subtotally nephrectomized rat. METHODS: Male Sprague-Dawley rats were subjected to surgical ablation (SNX) or sham operation (sham). Three days after surgery groups were treated either with phenoxybenzamine (PBZ, 5 mg/kg body weight/day), metoprolol (MET, 150 mg/kg body weight/day) or their combination (PBZ 2.5 mg/kg body weight/day + MET, 50 mg/kg body weight/day). Renal morphology was evaluated after 12 weeks by quantitative histology, immunohistochemistry, and electron microscopy. Urine albumin excretion and kidney endothelin-1 (ET-1), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta) mRNA expression were assessed. RESULTS: Systolic blood pressure was significantly higher in all SNX groups compared with sham-operated controls with no difference in the SNX groups. The number of glomeruli per left kidney was reduced from 30,904 +/- 3212 to 17,480 +/- 2341 by SNX (-43.5%). Mean glomerular volume increased from 2.63 +/- 0.7 in untreated sham operated to 4.11 +/- 0.48 microm 3 x 10(6) in untreated SNX (56.3%). The glomerulosclerosis index did not change in SNX + PBZ rats, but was significantly lower in SNX + MET (0.56 +/- 0.14) and particularly SNX + PBZ + MET rats (0.49 +/- 0.11) than in untreated SNX (0.74 +/- 0.24). Glomerular capillary length density (LV) as a sensitive index of capillary obliteration was significantly lower in SNX and almost normalized in the three intervention groups. The same was true for the mean podocyte number per glomerulus. Glomerular ultrastructure in SNX was largely preserved by all treatments. The albumin excretion rate was significantly higher in untreated SNX than in sham; it was significantly lower in all treated SNX groups. CONCLUSION: The beneficial effect of non-hypotensive doses of alpha and beta blockers and their combination on renal morphology and albuminuria in the model of renal ablation argue for a blood pressure-independent role of sympathetic overactivity in the genesis of progression. In addition, the beneficial effect of adrenergic receptor blockade indicates that a substantial part is not mediated by sympathetic cotransmitters such as adenosine 5'-triphosphate (ATP) and neuropeptide Y (NPY).

Adverse effects of smoking in the renal patient.

Smoking is a known risk factor for cardiovascular diseases, cancer, and several other health problems. It is the number one preventable cause of death in modern countries. The first evidence that smoking may be a renal risk factor was published in 1978. Since then, several studies documented that smoking is nephrotoxic in patients with diabetic and non-diabetic renal disease. Data from the Multiple Risk Factor Intervention Trial indicate that smoking even increases the renal risk in the general male population: an increased relative risk for end-stage renal failure (ESRF) was found for smokers as compared to non-smokers (up to 1.69 for heavy smokers). Several potential mechanisms of smoking-induced renal damage have been discussed, e.g. increase in blood pressure, alteration of intrarenal hemodynamics, as well as activation of the sympathetic nerve, the reninangiotensin and the endothelin systems. The pathomechanisms are, however, only partly understood. Once ESRF has become established, the failure to discontinue smoking adversely affects the prognosis of patients on renal replacement therapy, mainly by increasing the risk of cardiovascular complications. Discontinuation of smoking has been shown to improve both renal and cardiovascular prognosis in the renal patient and is probably the single most effective measure to retard progression of renal failure.

Endothelin in renal diseases and cardiovascular remodeling in renal failure.

The pathogenetic mechanisms leading to progression of renal failure are only partly understood. Several studies in immune- and non-immune-mediated models of renal damage have recently implicated the endothelin (ET) system as a major player in these processes. In animal models, ET receptor antagonists have been shown to be highly effective in abrogating the progression of renal failure. Furthermore, cardiac structural alterations seen in hypertension and/or renal insufficiency, e.g. left ventricular hypertrophy, thickening of intramyocardial arterioles, and the increase in non-vascular interstitial tissue, are largely prevented by ET receptor antagonists. In this context it is of interest that these beneficial renal and cardiac effects are, at least in most studies, independent of systemic blood pressure. In addition to the specific pharmacological blockade of the renin-angiotensin system [ACE inhibitors, angiotensin II receptor (AT1) antagonists], blockade of ET receptors or ET converting enzyme (ECE) may be a new tool to interfere with progression of renal failure and cardiovascular remodeling in humans.

Sympathetic overactivity and arterial hypertension in renal failure.

In the past, it had been presumed that hypertension in chronic renal disease can be explained by the dual effects of sodium retention and inappropriate activity of the renin-angiotensin system. Recent experimental and clinical data provide strong evidence that the increase in blood pressure is to a large part due to sympathetic overactivity which is triggered by afferent signals emanating from the kidney and resetting sympathetic tone by stimulation of hypothalamic centres. The sequelae of sympathetic overactivity extend beyond their effects on blood pressure and include accelerated progression of renal failure and presumably increased cardiac arrhythmia.

Adult human mesangial cells (HMCs) express endothelin-B-receptors which mediate endothelin-1-induced cell growth.

Endothelin (ET) receptor antagonists are nephroprotective in renal damage models of the rat. It is unknown whether ET receptor antagonists are also beneficial in human renal diseases. Major differences exist between the ET systems in rats and humans, therefore this study was designed to characterize the ET receptors expressed on human adult mesangial cells (HMCs). HMCs cultures are a surrogate model for the development of glomerulosclerosis. Binding experiments with [125I]ET-1 in the presence or the absence of the test compounds [endothelin-1, -3 (ET-1, ET-3), sarafotoxin 6c (S6c), or BQ123] revealed an affinity (IC50 values) of 10.5 nm for ET-1 and 87.6 nm for ET-3. The affinities of the ET(B) agonist S6c and the ET(A) antagonist BQ123 were 85.9 nm and > 10 microm, respectively. Thus, the ET receptor on HMCs shows an ET(B)-like pharmacology, but in contrast to the classical ET(B)-receptor the affinities are low. No affinity for BQ123 up to > 10 microm excludes the presence of ET(A)-receptors. Functional studies using microfluorimetry (fura-2 method) showed comparable biphasic calcium signals induced by 10 nm ET-1, ET-3 and S6c. This effect could not be inhibited by BQ123, but by the ET(B) antagonist BQ788. Reverse transcriptase polymerase chain reaction (RT-PCR) studies under different culture conditions showed that both ET(A)- and ET(B)-receptor mRNAs are expressed in HMCs. The amount of ET(A)-receptor mRNA increased 2.7-fold and that of the ET(B)-receptor mRNA 7.1-fold after stimulation with 10% fetal calf serum (FCS). ET-1, ET-3 and S6c stimulated HMCs growth (ET-1 > S6c > ET-3), but the magnitude of the effect of ET-1 is lower than reported in rat mesangial cells (rat MCs). The effect on HMCs growth could be inhibited by BQ788, but not by BQ123. Our data provide evidence for the expression of ET(B)-receptors on HMCs that are functionally active. This finding differs from the ET receptor expression in rat MCs as reported by others.

Smoking--a renal risk factor.

One of the most important tasks of clinical and experimental nephrology is to identify the risk factors of progression of renal failure. A major renal risk factor which has not been sufficiently acknowledged despite increasing evidence is cigarette smoking. Diabetologists were the first to recognize the adverse effects of smoking on the kidney: both in type 1 and in type 2 diabetes smoking (i) increases the risk of development of nephropathy and (ii) nearly doubles the rate of progression to end-stage renal failure. Until recently it was not known whether smoking also increases the risk to progress to end-stage renal failure in patients with primary renal disease. A retrospective multicenter European case-control study showed that smoking is an independent risk factor for end-stage renal failure in patients with inflammatory and noninflammatory renal disease, i.e. IgA glomerulonephritis and polycystic kidney disease. The pathogenesis of the smoking-related renal damage is largely unknown. The intermittent increase in blood pressure during smoking seems to play a major role in causing renal damage, but further potential pathomechanisms are presumably also operative. Smoking as a renal risk factor is of great interest to diabetologists as well as nephrologists, but unfortunately so far this information has had little impact on patient management. The present article reviews the current knowledge about the renal risks of smoking and discusses the potential mechanisms of smoking-mediated renal injury.

Smoking: a factor promoting onset and progression of diabetic nephropathy.

Although smoking was identified two decades ago as a factor promoting the onset and progression of nephropathy in Type 1 and then in Type 2 diabetes, its role has been largely neglected. More recently, it has been shown that smoking adversely affects renal haemodynamics and protein excretion even in subjects without renal disease. In addition, it impairs the prognosis for renal function in patients with non-diabetic renal disease. Recent studies have suggested the involvement of sympathetic activation, increased endothelin production, and impaired endothelial cell-dependent vasodilatation in the genesis of smoking-induced renal function impairement. Cessation of smoking apparently slows progression to renal failure, but the decision to stop smoking is difficult because of the high addictive potential of the habit. The challenge remains for diabetologists and nephrologists to motivate patients to stop smoking.

Effects of ACE inhibition and bradykinin antagonism on cardiovascular changes in uremic rats.

BACKGROUND: Cardiovascular death continues to be a major problem in renal failure. Structural abnormalities of the heart and the vasculature contribute to the increased cardiovascular risk. They are ameliorated by angiotensin-converting enzyme (ACE) inhibitors, but because of the nonspecifity of ACE inhibition, it is uncertain whether the beneficial effect is mediated by interfering with angiotensin II (Ang II) or by modulating other effector systems, for example, bradykinin. METHODS: To assess a potential role of bradykinin, subtotally nephrectomized Sprague-Dawley rats (SNX) received either the ACE inhibitor Ramipril (Rami, 0.2 mg/kg body weight p.o.), the specific B2 bradykinin receptor antagonist Hoe140 (0.2 mg/kg body weight, s.c.), or a combination of both, and were compared to sham-operated controls. To separately assess the effect of Ramipril on development and reversal of structural abnormalities, animals were either treated from the third day after SNX or from the fourth week after SNX onward (0.01 mg/kg body weight, p.o.). RESULTS: Heart and aorta were evaluated by morphometric and stereologic techniques. The weight of the perfused left ventricle, as an index of cardiac hypertrophy, was significantly higher in untreated SNX. While it was significantly lower in animals with early and late Ramipril treatment, the beneficial effect was completely antagonized by Hoe140. The wall-to-lumen ratio of intramyocardial arterioles was significantly higher in untreated SNX compared with controls, but failed to be modified by administration of either Ramipril or Hoe140. In the heart, the intercapillary distance was significantly higher in SNX, but it was not lowered by either early or late Ramipril or Hoe140 treatment. Treatment of SNX with Hoe140 alone, however, resulted in a marked further increase in intercapillary distance. The wall thickness of the aorta was significantly higher in SNX than in controls; early and late Ramipril treatment prevented such increase, and this effect was antagonized by Hoe140. CONCLUSION: These findings illustrate that bradykinin plays an important role for the beneficial effect of Ramipril in preventing (and potentially reversing) abnormal cardiovascular structure in uremic hypertensive rats.