Stephan R. Orth

Smoking: A Risk Factor for Progression of Chronic Kidney Disease and for Cardiovascular Morbidity and Mortality in Renal Patients—Absence of Evidence or Evidence of Absence?

Although it is beyond any doubt that smoking is the number one preventable cause of death in most countries, smoking as an independent progression factor in renal disease has been questioned against the background of evidence-based criteria. This is because information from large, randomized, prospective studies that investigate the effects of smoking on renal function in healthy individuals as well as in patients with primary or secondary renal disease are lacking. Since 2003, a substantial number of clinical and experimental data concerning the adverse renal effects of smoking have been published, including large, prospective, population-based, observational studies. These more recent data together with evidence from experimental studies clearly indicate that smoking is a relevant risk factor, conferring a substantial increase in risk for renal function deterioration. This review summarizes the present knowledge about the renal risks of smoking as well as the increased cardiovascular risk caused by smoking in patients with chronic kidney disease. The conclusion is that smoking is an important renal risk factor, and nephrologists have to invest more efforts to motivate patients to stop smoking.

Monocyte Chemoattractant Protein-1 Induces Proliferation and Interleukin-6 Production in Human Smooth Muscle Cells by Differential Activation of Nuclear Factor-κB and Activator Protein-1

Inflammatory response and chemotaxis of vascular wall cells play an important pathogenic role in the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant for monocytes. Besides the induction of monocyte recruitment, it has been suggested that MCP-1 may directly activate smooth muscle cells. We investigated whether MCP-1 affects the proliferation and cytokine production of human vascular smooth muscle cells (VSMCs) and determined the underlying signal transduction pathways. Stimulation of VSMCs with MCP-1 induced proliferation and resulted in a concentration- and time-dependent release of the proinflammatory cytokine interleukin-6 (IL-6). Pretreatment with pertussis toxin, GF109203X, and pyrrolidine dithiocarbamate inhibited MCP-1–dependent IL-6 release, suggesting the involvement of Gi proteins, protein kinase C, and nuclear factor-&kgr;B (NF-&kgr;B). MCP-1 also induced extracellular signal–regulated kinase, which, along with IL-6 release, was inhibited by pertussis toxin. PD98059 prevented MCP-1–induced extracellular signal–regulated kinase activation and cell proliferation. MCP-1 stimulated the binding activity of NF-&kgr;B and of activator protein-1 (AP-1). As demonstrated by cis element double-stranded (decoy) oligodeoxynucleotides, NF-&kgr;B was involved in IL-6 release by MCP-1, whereas proliferation was dependent on AP-1. The results clearly demonstrate that MCP-1 induces differential activation of NF-&kgr;B and AP-1 in VSMCs. Thus, our data propose a new mechanism for the proatherogenic effect of MCP-1.

Smoking and the Kidney

Nephrologists “rediscovered” smoking as a major renal risk factor in 1997 ([1][1]), although investigators in the 19th and 20th centuries had noted an association between smoking and renal damage ([2][2]). In the past few years the knowledge about the renal risks of smoking has expanded rapidly

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

In renal failure, parathyroid hormone (PTH) is not only involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa; it is also a permissive factor in the genesis of hypertension, cardiovascular damage, and dyslipidemia. The allosteric activator of the calcium sensing receptor NPSR-568 (R-568) has been shown to reduce the serum intact PTH (iPTH) concentration in uremic rats. It was the purpose of this study in subtotally nephrectomized (SNX) rats to compare pharmacologic abrogation of secondary hyperparathyroidism by R-568 with parathyroidectomy (PTX). The effects on progression of renal failure, BP, and lipid and structural parameters of kidney and heart were studied. Four groups of male SD-rats were studied: (1) sham-operated + vehicle-treated rats (controls); (2) SNX + vehicle-treated rats (SNX); (3) parathyroidectomized SNX + vehicle-treated rats (SNX+PTX); and (4) SNX + calcimimetic R-568-treated rats (SNX+R-568). R-568 (50 micro mol/kg per d) was administered by gavage. Eight weeks after SNX, serum creatinine concentration, urinary albumin excretion, BP, and serum LDL-cholesterol concentration were significantly lower in both R-568-treated and parathyroidectomized SNX compared with vehicle-treated SNX. In addition, structural abnormalities of the kidney (glomerulosclerosis, tubulointerstitial changes) and the heart (interstitial fibrosis, capillary length density, arteriolar wall thickness) were significantly less pronounced than in vehicle-treated SNX. It is concluded that in experimental renal failure abrogation of hyperparathyroidism by administration of a calcimimetic or PTX similarly attenuates progression of renal failure. Furthermore, it interferes with the development of cardiovascular risk factors and cardiac remodeling.

MCP-1 Induces Inflammatory Activation of Human Tubular Epithelial Cells: Involvement of the Transcription Factors, Nuclear Factor-κB and Activating Protein-1

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine synthesized by several cell types, e.g., inflammatory cells, such as monocytes, and resident renal cells, such as human tubular epithelial cells (TECs). Besides induction of monocyte recruitment, MCP-1 has been suggested to induce non-leukocytes to produce cytokines and adhesion molecules. Inflammation of the tubulointerstitium is a hallmark of many renal diseases and contributes to progression of renal failure; the purpose therefore of this study was to investigate the influence of MCP-1 on markers of inflammatory activation in human TECs. MCP-1 stimulated interleukin-6 (IL-6) secretion and intercellular adhesion molecule-1 (ICAM-1) synthesis in a time- and dose-dependent manner. In parallel, MCP-1 increased IL-6 and ICAM-1 mRNA expression in human TECs. Pretreatment with pertussis toxin, GF109203X, BAPTA-AM, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 and ICAM-1 synthesis, suggesting the involvement of Gi-proteins, protein kinase C, intracellular Ca(2+), and nuclear factor-kappaB (NF-kappaB) in MCP-1 signaling. Using electrophoretic gel mobility shift assay, we observed that MCP-1 stimulated binding activity of NF-kappaB. Binding activity of the activator protein-1 (AP-1), which has been implicated to regulate induction of the IL-6 gene together with NF-kappaB, was also stimulated by MCP-1. In the present experiments, NF-kappaB and AP-1 were involved in the MCP-1-mediated induction of IL-6, as demonstrated by cis element double-stranded (decoy) oligonucleotides (ODN). In contrast to IL-6 release, MCP-1-induced ICAM-1 expression was predominantly dependent on NF-kappaB activation. These results document for the first time that MCP-1 induces an inflammatory response in human TECs. This may be an important new mechanism in the pathogenesis of tubulointerstitial inflammation.

The renal risks of smoking: an update

Purpose of reviewSmoking increases the renal risk both in diabetic and in nondiabetic renal disease. The purpose of the present review is to summarize the current state of knowledge about this important remediable renal risk factor. Recent findingsThe deleterious effect of smoking on renal function extends beyond patients with primary or secondary renal disease and patients with a renal transplant, because recent studies document a relation between smoking and loss of filtration rate, even in cardiovascular high-risk populations without primary renal disease such as the elderly, the patient with severe essential hypertension, or the patient with widespread atherosclerosis. Furthermore, recent studies show that in nondiabetic patients without primary renal disease, albuminuria, a potential surrogate marker of glomerular damage, is correlated with smoking. The mechanisms underlying the adverse renal effects of smoking are still incompletely understood. Beyond its effect on progression of renal failure, smoking is also an important cardiovascular risk factor in the patient with renal failure or the patient with a renal transplant. SummarySmoking is one of the most important remediable renal risk factors. The exact mechanisms of smoking-induced renal damage remain to be determined. For all the above reasons cessation of smoking should be recommended to renal patients - a recommendation which is infrequently given and even less frequently followed.

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.

Nephroprotection of an ETA-Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

Abstract —The present study was designed to assess whether the orally active and highly specific endothelin A (ETA) receptor antagonist LU 135252 affects progressive renal dysfunction in a hypertensive rat model of renal damage, ie, the uninephrectomized (UNX) stroke-prone spontaneously hypertensive rat (SHRsp). The animals were examined on a normal salt (0.25%) diet and, to sensitize the kidney to hypertensive injury, also on a high salt (3%) diet. Stereological methods were used to quantify indices of glomerulosclerosis, vascular damage, and tubulointerstitial damage. Treatment with LU 135252 (100 mg/kg body wt) did not affect systolic blood pressure (BP) in animals on a normal salt diet during the whole period of the experiment (18 weeks) or in salt-loaded animals until week 10; subsequently, BP was slightly but significantly lower in salt-loaded UNX-SHRsp given LU 135252. Between weeks 6 and 12, 40% of the untreated UNX-SHRsp on a high salt diet, but none on a standard salt diet, died; such mortality was completely prevented by LU 135252. Indices of renal damage were more abnormal in salt-loaded UNX-SHRsp compared with UNX-SHRsp on a normal salt diet. Development of glomerulosclerosis and tubulointerstitial and vascular damage in UNX-SHRsp on high salt was completely prevented by LU 135252. The respective indices were no longer significantly different from those of salt-loaded sham-operated SHRsp controls. In the less severely damaged kidneys of UNX-SHRsp on normal salt, treatment with LU 135252 tended to ameliorate the indices, but the difference was not statistically significant. The results document a role of the ET system, specifically of ETA receptors, in the development of progressive renal injury in salt-loaded UNX-SHRsp. LU 135252 completely prevented death and renal damage resulting from salt loading.

Rats with moderate renal failure show capillary deficit in heart but not skeletal muscle

In previous studies on experimental renal failure, hypertrophy of cardiomyocytes, diminished capillarization, and increased intercapillary distances had been observed, abnormalities that will expose the heart to reduced ischemia tolerance. It has not been established, however, whether such structural alterations are unique for the heart (eg, as a consequence of left ventricular hypertrophy) or are demonstrable in other tissues as well. Clarification of this point is important to test hypotheses on some potential mechanisms for cardiac undercapillarization. To address this issue further, we compared capillary length density (by stereologic techniques) in perfusion-fixed skeletal muscle (m. psoas) and hearts of subtotally nephrectomized (SNX) rats with moderate renal failure to those in sham-operated pair-fed controls. The duration of renal failure was 8 weeks. SNX rats had significantly higher mean systolic blood pressure (128 mm Hg v 109 mm Hg), serum creatinine, and urea levels. Despite pair feeding, the mean body weight was significantly lower in the SNX rats (409 g v 471 g), but the left ventricular weight to body weight ratio tended to be higher than in the sham-operated controls (2.39 mg/g v 2.13 mg/g). In the heart, myocyte mean cross-sectional area (675 +/- 112 microm2 v 545 +/- 111 microm2) and volume density of nonvascular interstitial tissue (3.47 +/- 1.04 v 1.33 +/- 0.22) were significantly higher in the SNX rats than in the controls. In parallel, myocardial capillary length density was significantly reduced after subtotal nephrectomy (3,036 +/- 535 mm/mm3 v 3,916 +/- 615 mm/mm3). In contrast, in skeletal muscle, myocyte cross-sectional area (3,109 +/- 783 microm2 v 3,042 +/- 639 microm2), capillary length density (718 +/- 248 mm/mm3 v 717 +/- 184 mm/mm3), and three-dimensional capillary fiber ratio (2.10 +/- 0.26 v 2.13 +/- 0.4) were similar in SNX and control rats. These data document a selective defect of capillarization in the heart of animals with moderate renal failure, pointing to tissue-specific abnormalities of cardiac capillarogenesis.

The conundrum of chronic kidney disease classification and end-stage renal risk prediction in the elderly--what is the right approach?

The worldwide high prevalence of chronic kidney disease (CKD) and the increasing number of patients reaching end-stage renal disease (ESRD) are a matter of major concern. The most widely accepted classification system of CKD is that proposed by the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2002. When applying this system, it has become apparent that the prevalence of CKD is particularly high in elderly subjects. The fact that this system is mainly based on estimated glomerular filtration rate (eGFR), subdividing the severity of CKD into five stages, is a matter of debate. A main issue is that although a reduced eGFR is often encountered in elderly subjects, most of these subjects do not have a renal disease leading to an increased risk of ESRD, i.e. the predictive power of ESRD is unsatisfactory. Recent advances have been put forward to improve (1) estimation of GFR and (2) prediction of ESRD. In this review, we discuss the currently available data with a focus on the elderly and propose an improved classification system of CKD which is characterized by a substantially better diagnostic accuracy for progression to ESRD. This is simply and cost-effectively accomplished by subdividing stage 3 CKD into two groups (eGFR 30–44 and 45–59 ml/min/1.73 m2) and by complementing all levels of eGFR with information about urinary albumin excretion, i.e. whether normoalbuminuria, microalbuminuria, or macroalbuminuria is present. The consequence should be a revision of the 2002 KDOQI CKD classification system according to these findings, which would be a significant step forward, particularly for elderly CKD patients.