Progression Of Chronic Renal Disease Research Articles

The dyslipidemia of chronic renal disease: effects of statin therapy

Dyslipidemia is a prevalent condition in patients with chronic renal disease, but is often left untreated. Statin treatment constitutes an effective way to improve lipid abnormalities. This review summarizes present studies on dyslipidemia and its treatment in patients with chronic renal disease. The specific dyslipidemia in renal disease is associated with the presence of proteinuria and decreased creatinine clearance, and may even adversely affect the progression of chronic renal disease. Statin therapy may have renoprotective effects due to a combination of lipid lowering and pleiotropic effects. Statins exert several anti-inflammatory properties and lead to a decrease of proteinuria. Post-hoc analyses of large-scale lipid lowering trials have shown that the reduction of cardiovascular risk was equivalent to the reduction achieved in patients without chronic renal failure. We feel, however, that if intervention with statins is postponed until patients reach end-stage renal disease, statins have limited benefit. Present studies suggest that patients with renal disease should be screened early for dyslipidemia and that statins have to be considered as the lipid lowering therapy of choice. These drugs reduce cardiovascular risk. Further studies are needed to firmly establish whether statins preserve renal function.

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

In 1984, Loskutoff et al. ([1][1]) purified plasminogen activator inhibitor-1 (PAI-1) from conditioned media of cultured endothelial cells. This 50-kd glycoprotein is the primary physiologic inhibitor of the serine proteases tissue-type and urokinase-type plasminogen activators (tPA and uPA,

A protective role for programmed death 1 in progression of murine adriamycin nephropathy

Programmed death 1 (PD-1) is a novel member of the CD28/cytotoxic T-lymphocyte-associated protein-4 superfamily, which plays an important role in the regulation of activated T cells. However, it is not clear how PD-1 is expressed in normal and diseased kidney, nor if it has a role in progression of chronic renal disease. PD-1 expression and the effect of monoclonal anti-PD-1 antibody (Ab) were examined in murine adriamycin nephropathy (AN). BALB/c mice were divided into three groups: (a) normal mice, (b) adriamycin (ADR) with control immunoglobulin (Ig)G (ADR-IgG), and (c) ADR with anti-PD-1 Ab (ADR-Ab). AN was induced by a single intravenous injection of ADR. Anti-PD-1 Ab was given by intraperitoneal injection on alternate days from day 0 to day 10, or to day 18. Animals were killed at week 4. Renal function, histological change, and cytokine expression were examined. PD-1 mRNA was detected in kidney tissue of mice with AN in a dose- and time-dependent manner. PD-1 was mainly expressed on injured tubule cells and some interstitial cells, which co-stained with alpha-smooth muscle actin in AN, but not in normal kidney. Anti-PD-1 treatment up to day 18, but not to day 10, worsened glomerular and tubulointerstitial injury. The ratio of urinary protein/creatinine was significantly higher in ADR-Ab mice than ADR-IgG mice. The number of macrophages was significantly increased in ADR-Ab mice compared with ADR-IgG mice. Blockade of PD-1 worsened progressive renal histopathological and functional injury in murine AN. This suggests a possible protective role for PD-1 in chronic renal disease, and its potential as a treatment to slow disease progression.

Should Dialysis Patients Ever Receive Warfarin and for What Reasons?

It has been common practice for dialysis patients with problematic vascular access to receive warfarin for the purposes of keeping the access functional. This, of course, increases the risk for bleeding. Also, in light of new knowledge, vascular calcification may be enhanced by warfarin (1). Therefore, a reexamination of this common practice seems warranted because the efficacy of anticoagulation for access maintenance has never been established. The available evidence does not allow an evidence-based approach. Therefore, this article is an opinion, based on what is published. The issue obviously warrants a prospective study because the clinical practice is widespread. The most common indication for prescribing warfarin in hemodialysis patients is to maintain vascular access. In dialysis patients with comorbid rhythm disturbances such as atrial fibrillation or patients with prosthetic valves, warfarin may be indicated to prevent stroke. The benefit/harm ratio for this indication needs to be considered separately because the efficacy of warfarin to prevent thromboembolism is well established. A small percentage of warfarin use in ESRD is in patients who have documented hypercoagulable states. The major risk of warfarin in dialysis patients obviously is bleeding, adding to the already present uremic platelet dysfunction that accompanies progressive chronic renal disease. Another major issue regarding warfarin use in dialysis patients is potential bleeding in the event of unplanned or emergency surgery, such as in patients who are awaiting deceased-donor renal transplant. In these cases, surgery may be necessary before the warfarin can be withdrawn. In this situation, even fresh-frozen plasma and vitamin K do not fully reverse the patient’s anticoagulation. In the general population, a rare complication of warfarin is dramatic skin necrosis, presumably as a result of vitamin K deficiency. Risk factors for this adverse reaction are proteins C and S deficiencies and diffuse vascular disease. Because protein S frequently …

Emerging global epidemic of obesity: the renal perspective.

Obesity, as a core component of the metabolic syndrome, is among the top ten global health risks classified by the World Health Organization (WHO) as being strongly associated with the development and progression of chronic renal disease—a widely prevalent but often silent condition. Obesity carries elevated risks of cardiovascular morbidity and mortality besides having an array of metabolic complications. Maladaptive glomerular hemodynamics with increased intraglomerular pressure in association with vasoactive, fibrogenic substances released from adipocytes, in addition to cytokines and hormones, are the key factors in the causation of renal injury and the progression of nephron loss among obese subjects.

Stabilized incidence of diabetic patients referred for renal replacement therapy in Denmark

Despite an improvement in diabetes care during the last 20 years, the number of diabetic patients starting renal replacement therapy (RRT) has continued to increase in the Western world. The aim was to study the incidence of patients starting RRT in Denmark from 1990 to 2004. Data were obtained from The Danish National Registry; Report on Dialysis and Transplantation, where all patients actively treated for end-stage renal disease have been registered since 1990. The incidence of end-stage renal disease increased until 2001. Thereafter the incidence stabilized on 130 per million people (pmp). The number of diabetic patients starting RRT increased steadily from: 52 (number of patients) in 1990, 113 in 1995, 150 in 2000, 168 in 2001, and 183 in 2002. However, during the years 2003 and 2004 this number was significantly reduced by 15% to 156 and 155, respectively. This was mainly due to a 22% reduction in the number of non-insulin- treated (type II) diabetic patients (number of patients): 98, 82, and 76 in 2002, 2003, and 2004, respectively. The mean age in the background population, the mean age in diabetic patients starting RRT and the incidence of type I and type II diabetes increased during the study period. The encouraging stabilization in the incidence of diabetic patients referred for RRT observed in Denmark could be the result of implementation of a multifactorial and more intensive renoprotective intervention in patients with diabetes and chronic progressive renal disease.

The renin-angiotensin system in lupus: physiology, genes and practice, in animals and humans

Although multiple studies suggest a potential role for angiotensin II in inflammation, most were performed either in vitro or in animals with non-immune-complex-mediated diseases. Extrapolation of these findings to humans, particularly patients with lupus, which involves multiple immunoregulatory pathways, is unclear. In autoimmune-prone MRL/lpr mice, angiotensin-converting-enzyme (ACE) inhibition improved survival although to a lesser degree than cyclophosphamide and diminished the glomerular histopathologic damage, proteinuria, lymphoid hyperplasia, dermatitis, and hypergammaglobulinemia, with a reduction in TGF-beta1 and beta 2 expression in the kidneys and renal chemokine mRNA expression. Spleen levels of IL-4 and IL-10 were also reduced. Uncontrolled studies in patients with treatment-refractory lupus nephritis showed a significant reduction in proteinuria with ACE-inhibitors and Angiotensin receptor blockers treatment. The 'masking' effect of ACE-inhibitors should be taken into consideration, as an exacerbation of lupus nephritis may be missed when estimated by the magnitude of proteinuria, which is decreased by these treatments. No single ACE genotype was consistently associated with subsets of SLE patients. In retrospective analyses, ACE-inhibitor use predicted a favourable outcome in 94 cases of pauci-immune vasculitis. The attenuating effect of angiotensin II inhibitors on the progression of chronic renal disease is well recognized. The data on the role of this intervention in lupus is limited.

Simvastatin protection against acute immune-mediated glomerulonephritis in mice

In addition to cholesterol lowering, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors limit inflammatory changes associated with atherosclerosis. There is also support for their use as inhibitors of progression in chronic renal disease, irrespective of cause. In this study, their capacity to limit acute renal inflammation was evaluated. For this purpose, mice were treated with Simvastatin either prior to, at the time of, or shortly after induction of nephrotoxic nephritis. The severity of disease was determined by evaluation of blood urea nitrogen (BUN), proteinuria, and renal histologic changes. The reversibility of benefit was evaluated by the administration of mevalonic acid along with nephrotoxic serum (NTS) and Simvastatin The severity of the acute nephritis, including proteinuria, elevated BUN, and histologic changes, was ameliorated in a dose-dependent manner, when Simvastatin was administered either prior to NTS injection or at the time of NTS injection. By contrast, Simvastatin did not alter the course of established nephritis. Coadministration of mevalonic acid, the immediate substrate following HMG-CoA reductase, abolished Simvastatin's renoprotective effect, indicating that the benefit is, at least in part, due to interference with HMG-CoA reductase and biosynthetic substrates downstream from the enzyme. These findings provide the rationale for the evaluation of the efficacy of HMG-CoA reductase inhibitors in patients with recurrent forms of renal inflammation, to limit the severity of acute exacerbations of disease, prevent renal scarring and slow the rate of progression.

Indoxyl sulfate induces complex redox alterations in mesangial cells

Indoxyl sulfate is a protein metabolite that is concentrated in the serum of patients with chronic renal insufficiency. It also is a uremic toxin that has been implicated in the progression of chronic renal disease in rodent models. We have shown previously that mesangial cell redox status is related to activation of mitogen-activated protein kinases and cell proliferation, which are factors related to glomerular damage. We used three methods to examine the ability of indoxyl sulfate to alter mesangial cell redox as a possible mechanism for its toxicity. Indoxyl sulfate increases mesangial cell reduction rate in a concentration-dependent manner as demonstrated by redox microphysiometry. Alterations occurred at concentrations as low as 100 microM, with more marked alterations occurring at higher concentrations associated with human renal failure. We demonstrated that indoxyl sulfate induces the production of intracellular reactive oxygen species (ROS) in mesangial cells (EC50 = 550 microM) by using the ROS-sensitive fluorescent dye CM-DCF. ROS generation was only partially (approximately 50%) inhibited by the NADPH oxidase inhibitor diphenylene iodinium at low (< or = 300 microM) indoxyl sulfate concentrations. Diphenylene iodinium was without effect at higher concentrations of indoxyl sulfate. We also used electron paramagnetic spin resonance spectroscopy with extracellular and intracellular spin traps to show that indoxyl sulfate increases extracellular SOD-sensitive O2-* production and intracellular hydroxyl radical production that may derive from an initial O2-* burst. These results document that indoxyl sulfate, when applied to renal mesangial cells at pathological concentrations, induces rapid and complex changes in mesangial cell redox.

Losartan, an Angiotensin-II Receptor Antagonist, Retards the Progression of Advanced Renal Insufficiency

Chronic renal disease with elevated level of serum creatinine (Cr) often progresses to end-stage renal disease. Although blockade of the renin-angiotensin system has been shown to slow the progression of chronic renal disease, it remains uncertain whether one could expect such a renoprotective effect even when the treatment is initiated late in the course of renal disease. The purpose of the present study was to examine the effect of losartan, an angiotensin-II receptor antagonist, on the progression of advanced renal insufficiency. We retrospectively analyzed eight hypertensive patients, whose baseline Cr levels exceeded 2.0 mg/dl (2.2-5.5); the subjects included 6 non-diabetic glomerular diseases, 1 diabetic nephropathy and 1 polycystic kidney disease. Losartan was given at the dosage of 25-50 mg/day. Changes in mean blood pressure (MBP) and serum levels of Cr, potassium (K) and uric acid were evaluated after treatment for 24 weeks. Slopes of reciprocal of serum Cr plotted against time (1/sCr slope), which indicate the rate of renal function loss before and after the treatment period, were compared. There was a significant reduction of 1/sCr slope after losartan (-0.004 +/- 0.002 dl/mg/week before and -0.001 +/- 0.002 dl/mg/week after the treatment, p < 0.05). MBP and serum levels of Cr, K and uric acid were not changed significantly by losartan treatment. However, improvement of 1/sCr slope was correlated to the degree of MBP changes. Based on the available data from 4 patients, proteinuria was decreased in 3 patients. These results suggest that losartan may retard the progression of advanced renal insufficiency.

Systemic and glomerular hypertension and progression of chronic renal disease: The dilemma of nephrosclerosis

The link between the kidney and hypertension has been considered a villain-victim relationship. High blood pressure levels are a well-recognized feature in chronic renal disease, but the ability of mild-to-moderate hypertension to produce renal insufficiency has been questioned. Nephrosclerosis, benign nephrosclerosis, and hypertensive kidney disease are terms that clinicians use when renal damage is thought to be secondary to essential hypertension. Many cases of end-stage renal disease are ascribed to so-called benign nephrosclerosis. This entity could actually be a primary renal disease affecting the preglomerular microvasculature, perhaps genetically mediated and ethnically influenced, and showing a heterogeneous clinical expression. African Americans suffer from nephrosclerosis more frequently than Caucasians. Nephrosclerosis affecting Caucasians seems to show a less aggressive pattern and could represent early age-related renal sclerosis. The risk of end-stage renal disease is increased when atherosclerotic lesions in large renal arteries coexist. Age, systolic blood pressure, proteinuria, and concomitant cardiovascular disease are well-known promoters of renal failure. A multifactorial strategy, including antihypertensive and antiproteinuric drugs, and lipid-lowering and anti-platelet agents, could improve cardiovascular and renal outcomes in patients with nephrosclerosis.

Role of hypoxia in the pathogenesis of renal disease

The kidney shows a remarkable discrepancy between blood supply and oxygenation. Despite high blood flow and oxygen delivery, oxygen tensions in the kidney are comparatively low, in particular in the renal medulla. The reason for this lies in the parallel arrangement of arterial and venous preglomerular and postglomerular vessels, which allows oxygen to pass from arterioles into the postcapillary venous system via shunt diffusion. The limitation in renal tissue oxygen supply renders the kidney susceptible to hypoxia and has long been recognized as an important factor in the pathogenesis of acute renal injury. In recent years, evidence has accumulated that hypoxia does also play a significant role in the pathogenesis and progression of chronic renal disease, because different types of kidney disease are usually associated with a rarefication of postglomerular capillaries. In both acute and chronic diseases, tissue hypoxia does not only imply the risk of energy deprivation but also induces regulatory mechanisms and has a profound influence on gene expression. In particular, the transcription factor hypoxia inducible factor (HIF) is involved in cellular regulation of angiogenesis, vasotone, glucose metabolism, and cell death and survival decisions. HIF has been shown to be activated in renal disease and presumably plays a major role in protective responses to oxygen deprivation. Recent insights into the regulation of HIF increase our understanding of the role of hypoxia in disease progression and open new options to improve hypoxia tolerance and to induce nephroprotection.

Is there a pharmacologic basis for combination renin axis blockade?

Is there a pharmacologic basis for combination renin axis blockade?

Advanced glycation end products and the kidney

Advanced glycation end products (AGEs) are a heterogeneous group of protein and lipids to which sugar residues are covalently bound. AGE formation is increased in situations with hyperglycemia (e.g., diabetes mellitus) and is also stimulated by oxidative stress, for example in uremia. It appears that activation of the renin-angiotensin system may contribute to AGE formation through various mechanisms. Although AGEs could nonspecifically bind to basement membranes and modify their properties, they also induce specific cellular responses including the release of profibrogenic and proinflammatory cytokines by interacting with the receptor for AGE (RAGE). However, additional receptors could bind AGEs, adding to the complexity of this system. The kidney is both: culprit and target of AGEs. A decrease in renal function increases circulating AGE concentrations by reduced clearance as well as increased formation. On the other hand, AGEs are involved in the structural changes of progressive nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy. These effects are most prominent in diabetic nephropathy, but they also contribute to renal pathophysiology in other nondiabetic renal diseases. Interference with AGE formation has therapeutic potential for preventing the progression of chronic renal diseases, as shown from data of animal experiments and, more recently, the first clinical trials.

Combination therapy with ACE inhibitors and angiotensin II receptor blockers in chronic renal disease: New therapeutic world beyond blood pressure reduction

To the Editor: We read the recent article by Wolf et al comprehensively reviewing pathophysiology and indication of combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers in chronic renal disease1.Wolf G. Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications.Kidney Int. 2005; 67: 799-812Google Scholar. As one author of the COOPERATE study, I would like to comment on several issues quoted by them. First, because the COOPERATE study was the fixed dose-design, during a run-in period, the dose of trandolapril had been adjusted to reach a maximal reduction in proteinuria, but not in blood pressure (BP). We had noticed that the maximally licensed dose of trandolapril (up to 2 mg/day) was not sufficient to reduce proteinuria maximally, which required 3 mg daily. Therefore, we determined 3 mg of trandolapril in the core COOPERATE study2.Nakao N. Yoshimura A. Morita H. et al.Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial.Lancet. 2003; 361: 117-124Google Scholar. Second, as Wolf et al speculated, 24-hour BP might be different among 3 groups. In this issue, we have recently published the results of the COOPERATE-ABP substudy3.Nakao N. Seno H. Kasuga H. et al.Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: A COOPERATE-ABP substudy.Am J Nephrol. 2004; 24: 543-548Google Scholar. In this substudy, 92 patients enrolled in the COOPERATE trial underwent 24-hour ambulatory blood pressure (ABP) monitoring at randomization and at month 6, year 1, year 2, and year 3 on randomized treatment. Both office blood pressure (OPB) and ABP were similarly reduced among 3 groups at all measurement points and throughout the whole study period. No significant correlation between the change in 24-hour ABP and the change in proteinuria was seen. Therefore, ABPM did not seem to have any benefits over OBP. Third, the study agents were administrated 3 times a day, and the dose on each arm was gradually and carefully up-titrated Figure 1 . Therefore, it seems unlikely that a difference at the time of peak actions of the agents might be attributable to the superior antiproteinuric effect in the combination therapy. The COOPERATE-ABP substudy did not detect any difference of daily BP profile3.Nakao N. Seno H. Kasuga H. et al.Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: A COOPERATE-ABP substudy.Am J Nephrol. 2004; 24: 543-548Google Scholar. Last, both OBP and ABP were not selected as a significant risk factor in Cox-multivariable model for renal survival2.Nakao N. Yoshimura A. Morita H. et al.Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial.Lancet. 2003; 361: 117-124Google Scholar , 3.Nakao N. Seno H. Kasuga H. et al.Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: A COOPERATE-ABP substudy.Am J Nephrol. 2004; 24: 543-548Google Scholar. In conclusion, combination therapy with ACE inhibitors and angiotensin II receptor blockers can halt progression of chronic renal disease beyond BP reduction.

Long-Term Blood Pressure Control Prevents Oxidative Renal Injury

Arterial hypertension is a leading contributor to the progression of chronic renal disease. Short-term studies had addressed the role of oxidative stress in hypertensive nephropathy. We have now studied oxidative stress and caspase activation in a long-term model of hypertensive renal injury. Nontreated spontaneously hypertensive rats with uninephrectomy displayed severe arterial hypertension over a 36-week follow-up. Uncontrolled high blood pressure in the context of modest renal mass reduction resulted in significant histological renal injury. Blood pressure control by the angiotensin-converting enzyme (ACE) inhibitor, quinapril, or the AT1 receptor antagonist, losartan, decreased the degree of renal injury. Hypertensive renal injury was associated with evidence of activation of the apoptotic pathway (increased activation of caspase-3) and local renal (increased staining for 4-hydroxy-2-nonenal) and systemic [increased serum levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha)] lipid oxidation when compared with normotensive control rats. In addition, severe hypertension decreased the renal antioxidant defenses, as exemplified by decreased expression of Cu/Zn superoxide dismutase. Treatment with quinapril or losartan decreased caspase-3 activation, 4-hydroxy-2-nonenal staining, and 8-iso-PGF2alpha levels and increased Cu/Zn superoxide dismutase expression. These results suggest that hypertension-associated oxidative stress and its consequences may be decreased by either ACE inhibition or AT1 receptor antagonist, emphasizing the role of angiotensin II in hypertensive renal damage.

Temporal changes in renal endoglin and TGF-β1 expression following ureteral obstruction in rats

Chronic renal disease is characterized by the accumulation of extracellular matrix proteins in the kidney and a loss of renal function. Tubulointerstitial fibrosis has been reported to play an important role in the progression of chronic renal diseases. Transforming growth factor-beta1 (TGF-beta1) is a profibrotic cytokine playing a major contribution to fibrotic kidney disease. Endoglin is a membrane glycoprotein of the TGF-beta1 receptor system. The aim of this work was to determine the time-course expression of renal type I and IV collagens, endoglin and TGF-beta1 in a rat model of induced tubulointerstitial fibrosis at 1, 3, 10 and 17 days after unilateral ureteral obstruction (UUO). In 17 days-ligated (L)-renal samples, a marked interstitial fibrosis was detected by Masson's trichromic and Sirius red staining, accompanied by an increase in type I collagen expression as shown by immunohistochemical analysis. Northern blot studies revealed a progressive increase in collagen alpha2(I), TGF-beta1 and endoglin mRNA expression in L kidneys when compared with the corresponding non-ligated (NL) kidneys from the animals subjected to left UUO. Seventeen days after UUO, significant increases in collagen alpha2(I), collagen alpha1(IV), TGF-beta1 and endoglin mRNA levels were detected in L kidneys vs NL kidneys. Significantly higher levels of the protein endoglin were found in L kidneys than in NL kidneys 10 and 17 days following obstruction. A marked increase expression for endoglin and TGF-beta1 was localized in renal interstitium by immunohistochemical studies 17 days after obstruction. In conclusion, this work reports the upregulation of endoglin coincident to that of its ligand TGF-beta1 in the kidneys of rats with progressive tubulointerstitial fibrosis induced by UUO.

Das Renin–Angiotensin–Aldosteron–System – komplexer als bisher gedacht

ZusammenfassungHintergrund:Angiotensin II (ANG II) ist ein wichtiger Faktor für das Fortschreiten von Nierenerkrankungen. Neben der bekannten blutdrucksteigernden Wirkung hat ANG II eine Vielzahl von pleiotropen Effekten wie proinflammatorische und profibrogene Wirkungen auf die Niere.Neue Erkenntnisse: Organe haben lokale ANG–II–generierende Systeme, die vom klassischen endokrinen Renin–Angiotensin–Aldosteron–System (RAAS) völlig unabhängig sind. So können beispielsweise proximale Tubuluszellen der Niere in den Primärharn ANG–II–Konzentrationen abgeben, die bis zu 10 000fach über dem Serumspiegel liegen. Diese lokalen Systeme werden durch Standarddosen von ACE–Hemmern oder AT1–Blockern nur unvollständig gehemmt. Es gibt neben ACE auch andere Enzymsysteme, die ANG II generieren können. Durch alternative Stoffwechselwege können Peptide erzeugt werden, die wie Angiotensin 1–7 gegenteilige Wirkung im Vergleich zu ANG II haben. Abbauprodukte von ANG II wie Angiotensin IV binden an separate Rezeptoren und können Fibrose initiieren. Die Entdeckung von AT1–Rezeptor–Dimeren und agonistischen Antikörpern kompliziert das System zusätzlich.Klinische Bedeutung: Aufgrund der Komplexität des RAAS ist aus pathophysiologischen Überlegungen heraus eine Doppelblockade des Systems mit ACE–Hemmern wie auch AT1–Rezeptor–Antagonisten sinnvoll. Erste Studien haben gezeigt, dass in bestimmten Risikopopulationen die Progression der chronischen Niereninsuffizienz durch eine solche Doppelblockade im Vergleich zur Monotherapie signifikant verlangsamt werden kann. Dies zeigt, dass neue pathophysiologische Erkenntnisse Eingang in die Klinik finden.

Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach

Mechanisms of progression of chronic renal diseases, a major healthcare burden, are poorly understood. Angiotensin II (AngII), the major renin-angiotensin system effector, is known to be involved in renal deterioration, but the molecular pathways are still unknown. Here, we show that mice overexpressing a dominant negative isoform of epidermal growth factor receptor (EGFR) were protected from renal lesions during chronic AngII infusion. Transforming growth factor-alpha (TGF-alpha) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated. AngII-induced lesions were substantially reduced in mice lacking TGF-alpha or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-alpha and TACE accumulation as well as renal lesions after nephron reduction. These findings indicate a crucial role for AngII-dependent EGFR transactivation in renal deterioration and identify in TACE inhibitors a new therapeutic strategy for preventing progression of chronic renal diseases.

Stimulation of soluble guanylate cyclase slows progression in anti-thy1-induced chronic glomerulosclerosis

A critical role of soluble guanylate cyclase and nitric oxide-dependent cyclic 3',5'-guanosine monophosphate (cGMP) production for glomerular matrix expansion has recently been documented in a rat model of acute anti-thy1 glomerulonephritis. The present study analyzes the renal activity of the nitric oxide-cGMP signaling cascade in and the effect of the specific soluble guanylate cyclase stimulator Bay 41-2272 on a progressive model of anti-thy1-induced chronic glomerulosclerosis. Anti-thy1 glomerulosclerosis was induced by injection of anti-thy1 antibody into uninephrectomized rats. One week after disease induction, animals were randomly assigned to chronic glomerulosclerosis, chronic glomerulosclerosis plus Bay 41-2272 (10 mg/kg body weight/day) or chronic glomerulosclerosis plus hydralazine (15 mg/kg body weight/day). In week 16, analysis included effects on systolic blood pressure, proteinuria, kidney function, glomerular and tubulointerstitial matrix protein accumulation, expression of transforming growth factor-beta1 (TGF-beta1), fibronectin and plasminogen activator inhibitor type 1 (PAI-1), macrophage infiltration, cell proliferation, basal and nitric oxide-stimulated cGMP production as well as tubulointerstitial mRNA expression of alpha 1 and beta 1 soluble guanylate cyclase. The moderately elevated systolic blood pressure seen in the chronic glomerulosclerosis group was comparably decreased by both treatments. Compared to normal controls, soluble guanylate cyclase mRNA expression and nitric oxide-stimulated cGMP production were up-regulated in the tubulointerstitium of the untreated chronic glomerulosclerosis animals, while its activity was decreased in glomeruli. Bay 41-2272 treatment enhanced glomerular and tubulointerstitial nitric oxide-cGMP signaling significantly. This went along with markedly reduced glomerular and tubulointerstitial macrophage infiltration, number of proliferating cells, matrix expression and accumulation, as well as improved kidney function. In contrast, hydralazine therapy did not significantly affect renal nitric oxide-cGMP signaling, macrophage number, cell proliferation, matrix protein expression and accumulation. Glomerular and tubulointerstitial soluble guanylate cyclase activity are discordantly altered in anti-thy1-induced chronic glomerulosclerosis. Stimulation of soluble guanylate cyclase signaling by Bay 41-2272 limits the progressive course of this model toward tubulointerstitial fibrosis and impaired renal function at least in part in a blood pressure-independent manner. The results suggest that soluble guanylate cyclase activation counteracts fibrosis and progression in chronic renal disease.