[Show abstract][Hide abstract] ABSTRACT: Background. Monitoring changes in glomerular filtration rate (GFR) is the recommended method for assessing the progression of kidney disease. The aim of this study was to assess the decline of graft function defined by the annualized change in GFR and the factors which affect it.
Methods. Four thousand four hundred and eighty-eight patients, transplanted during the years 1990, 1994, 1998 and 2002 in 34 centres in Spain with allograft survival of at least 1 year, were included in the study. GFR was estimated using the four-variable equation of the Modification of Diet in Renal Diseases (MDRD) study. Linear mixed effects model was applied to determine the relation between the covariates and the annualized change in GFR after transplantation.
Results. The average GFR at 12 months was 51.4 ± 18.9 mL/min/1.73 m2; most patients were in stage 3 of chronic kidney disease classification. The average patient slope, calculated in a linear model with varying-intercept and varying-slope without covariates, was −1.12 ± 0.05 mL/min/year (slope ± standard error). Some variables were related to both the 12-month GFR (intercept) and the slope: recipient gender, hepatitis C virus (HCV) status, estimated GFR (eGFR) at 3 months and proteinuria at 12 months. Some variables were only related to the slope of eGFR: time on dialysis, primary renal disease and immunosuppression. Others affected only the 12-month GFR: donor age, delayed graft function, acute rejection and systolic blood pressure at 12 months. Higher graft function at 3 months had a negative impact on the GFR slope. Cyclosporine-based immunosuppression had a less favourable effect on the rates of change in allograft function.
Conclusions. There was a slow decline in GFR. Poor graft function was not associated with an increased rate of decline of allograft function. Immunosuppression with cyclosporine displayed the worst declining GFR rate.
NDT Plus 06/2010; 3(Suppl_2):ii2-ii8. DOI:10.1093/ndtplus/sfq063
[Show abstract][Hide abstract] ABSTRACT: Inhibitors of mTOR (mammalian target of rapamycin) are immunosuppressants with less nephrotoxic potential than calcineurin inhibitors and antiproliferative effects, which are advantageous in the case of malignancy. However, a series of adverse events has been reported with the first-generation mTOR inhibitor sirolimus that includes hypersensitivity-like interstitial pneumonitis. To our knowledge, only one case of a pneumonitis associated with everolimus in a heart transplant patient has been reported, and it was related to elevated trough blood levels. We report herein the first case of a kidney graft recipient who developed everolimus-associated pneumonitis with normal trough blood levels that was completely reversed after drug withdrawal.
[Show abstract][Hide abstract] ABSTRACT: This study assays therapy with basiliximab and different patterns of cyclosporin A (CsA) initiation in renal transplant (RT) recipients from expanded criteria donors (ECD) and at high risk of delayed graft function (DGF). A multicentre six-month open-label randomized trial with three parallel groups treated with basiliximab plus steroids, mycophenolate mofetil and different patterns of CsA initiation: early within 24 h post-RT at 3 mg/kg/d (Group 1; n = 38), and at 5 mg/kg/d (Group 2; n = 40), or delayed after 7-10 d at 5 mg/kg/d (Group 3; n = 36). There were no differences among groups in six months GFR (43.1 +/- 12, 48.0 +/- 14 and 47.2 +/- 17 mL/min, respectively), DGF (Group 1: 31%, Group 2: 37%, Group 3: 42%), nor biopsy-proven acute rejection, although clinically treated and biopsy-proven acute rejection was significantly higher in Group 3 (25%) vs. Group 1 (5.3%, p < 0.05). At six months no differences were observed in death-censored graft survival or patient survival. Induction therapy with basiliximab and three CsA-ME initiation patterns in RT recipients from ECD and at high risk of DGF presented good renal function and graft survival at six months. Late onset group did not achieve improvement in DGF rate and showed a higher incidence of clinically treated and biopsy-proven acute rejection.
[Show abstract][Hide abstract] ABSTRACT: Connective tissue growth factor (CTGF) is overexpressed in kidney diseases associated with extracellular matrix accumulation. Angiotensin II (ANG II) participates in renal fibrosis by the upregulation of growth factors, including CTGF, and extracellular matrix proteins, such as type IV collagen. During renal injury, ANG II and the macrophage-produced cytokine interleukin-1beta (IL-1beta) may be present simultaneously in the glomerular environment. However, there are no studies about the interaction between ANG II and IL-1beta in renal fibrosis. For this reason, in cultured mesangial cells (MC), we investigated whether IL-1beta could regulate ANG II-mediated collagen accumulation and the mechanisms underlying this process. In MC, CTGF is a downstream mediator of type IV collagen production induced by ANG II. IL-1beta did not increase the production of CTGF and type IV collagen but significantly inhibited ANG II-induced CTGF and type IV collagen overexpression. Moreover, IL-1beta also inhibited type IV collagen upregulation caused by exogenous recombinant CTGF. Matrix metalloproteinase-9 (MMP-9) is the main enzyme involved in type IV collagen degradation. In MC, coincubation of IL-1beta and ANG II caused a synergistic increase in MMP-9 gene expression and activity, associated with type IV collagen inhibition. The described IL-1beta effects were dependent on activation of ERK/MAPK but independent p38-MAPK, JNK, phosphatidylinositol 3-kinase/Akt, and Rho-associated kinase pathways. In summary, these data indicate that IL-1beta inhibited ANG II-mediated type IV collagen production, via CTGF downregulation, and increased type IV collagen degradation, through MMP-9 upregulation. Our in vitro data show that the proinflammatory cytokine IL-1beta abrogates ANG II-induced CTGF production, describing antagonistic activities of proinflammatory cytokines on ANG II actions.
American journal of physiology. Renal physiology 02/2008; 294(1):F149-60. DOI:10.1152/ajprenal.00129.2007 · 3.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Everolimus (Eve) has shown good efficacy and safety profiles in clinical trials in combination with low doses of cyclosporine but there is limited experience in other modes, especially with calcineurin inhibitor elimination. We developed a retrospective study to analyze its clinical use after approval in Europe in 2005. Herein we have presented the results of a series of 272 patients followed for the first 6 months after Eve introduction. In 93.8% of cases Eve was introduced after the first month posttransplantation (conversion use), and 6 months after introduction, the CNI had been eliminated in 75% of cases. The main indication for Eve introduction was the diagnosis of a malignant neoplasm (42%), whereas the combined indication of prevention and/or treatment of toxicity, especially nephrotoxicity, accounted for 46.3% of cases. Initial doses were low (1.37 mg/d), but were progressively increased up to 2 mg/d at 6 months. Renal function remained unchanged during the follow-up period, whereas proteinuria moderately increased. Only 5 cases (2%) of acute rejection episodes were observed with excellent patient and graft survivals at 6 months after conversion. Further analysis of this extensive series of patients with a longer follow-up is needed.
[Show abstract][Hide abstract] ABSTRACT: 3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II-induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II-induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II-mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.
[Show abstract][Hide abstract] ABSTRACT: Angiotensin II (AngII) is a key factor in the pathogenesis of renal damage. AngII via AngII type 1 receptors activates several intracellular signaling systems, including the small guanosine triphosphatase Rho and its downstream effector Rho-dependent serine-threonine kinase (Rho-kinase). The Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes observed in cardiovascular diseases. However, the data on renal diseases are scarce. The aim of this study was to investigate the effect of Rho-kinase inhibition in AngII-induced renal damage.
We used the model of systemic AngII infusion into normal rats (100 ng/kg per minute; subcutaneous osmotic minipumps), and some animals were treated with the Rho-kinase inhibitor Y-27632 (30 mg/kg per day). In the kidneys of these animals, we evaluated renal lesions, transcription factor activity (by electrophoretic mobility shift assay), and messenger RNA (by polymerase chain reaction) and protein expression levels (by Western blot and/or immunohistochemistry) of proinflammatory and profibrotic factors.
Rats infused with AngII for three days present renal inflammatory cell infiltration and slight tubular damage, which were diminished by treatment with the Rho-kinase inhibitor Y-27632. AngII activates nuclear factor-kappaB and causes overexpression of proinflammatory factors, including cytokines (tumor necrosis factor alpha) and chemokines (monocyte chemotactic protein-1), and of profibrotic factors (connective tissue growth factor). Treatment of AngII-infused rats with Y-27632 decreases the upregulation of these proinflammatory and profibrotic mediators.
These data demonstrate that the Rho-kinase pathway is involved in renal damage caused by AngII through the regulation of proinflammatory and profibrotic mediators. These results suggest that inhibition of the Rho-kinase pathway represents a novel therapy for renal diseases associated with local AngII generation.
[Show abstract][Hide abstract] ABSTRACT: Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardiovascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in vascular fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1-treated cells, showing that CTGF participates in ET-1-induced ECM accumulation. The ETA, but not ETB, antagonist diminished ET-1-induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ETA receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-beta- and angiotensin (Ang) II-induced fibrosis. In VSMCs, ET-1 did not upregulate TGF-beta gene or protein. The presence of neutralizing transforming growth factor (TGF)-beta antibody did not modify ET-1-induced CTGF production, showing a TGF-beta-independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ETA antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-beta and through the activation of several intracellular signals via ETA receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in vascular diseases.
Circulation Research 08/2005; 97(2):125-34. DOI:10.1161/01.RES.0000174614.74469.83 · 11.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An excess rate of apoptosis could lead to the gradual loss of renal mass. In this study, we investigated the role of apoptosis in the renal damage secondary to hypertension.
Spontaneously hypertensive rats with 5/6 renal mass reduction (subtotal nephrectomy) were distributed to receive no-treatment, 200 mg/L quinapril, 360 mg/L losartan, or triple therapy (200 mg/L hydralazine, 4 mg/L reserpine, and 100 mg/L hydrochlorothiazide) for 5 weeks. Sham-operated spontaneously hypertensive rats served as controls. Age-matched Wistar-Kyoto (WKY) rats, with or without subtotal nephrectomy, were also studied.
Nontreated spontaneously hypertensive rats + subtotal nephrectomy developed proteinuria, glomerular sclerosis, and tubulointerstitial lesions. In comparison to spontaneously hypertensive rats, an increment in the number of [proliferating cell nuclear antigen (PCNA)]-positive and apoptotic [terminal deoxynucleotidyl transferase (Tdt)-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL)]-positive tubular and glomerular cells was observed. By contrast, WKY + subtotal nephrectomy rats showed less severe morphologic lesions, and only the number of proliferating cells increased. By Western blot, an up-regulation of renal Bax (apoptosis inducer) was noted both in spontaneously hypertensive rats + subtotal nephrectomy and WKY + subtotal nephrectomy rats. By contrast, Bcl-xL (apoptosis protector) was up-regulated in WKY + subtotal nephrectomy rats but not in spontaneously hypertensive rats + subtotal nephrectomy. The administration of appropriate doses of quinapril, losartan, or triple therapy to spontaneously hypertensive rats + subtotal nephrectomy normalized systolic blood pressure, partially prevented proteinuria, renal lesions and apoptosis, and decreased Bax, but no changes were noted in Bcl-xL. The Bax/Bcl-xL index was significantly increased in spontaneously hypertensive rats + subtotal nephrectomy compared to sham-operated spontaneously hypertensive rats and decreased in treated groups.
The combination of renal mass reduction and hypertension caused severe renal lesions associated to an increment of apoptosis rate, mainly in tubular epithelial cells. Tight blood pressure control decreased the apoptosis rate and morphologic lesions. These studies suggest that changes in the expression of apoptosis-regulatory genes contribute to the progressive damage in hypertensive rats with renal mass reduction.
Kidney International 04/2004; 65(3):811-22. DOI:10.1111/j.1523-1755.2004.00455.x · 8.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Connective tissue growth factor (CTGF) has been described as a novel fibrotic mediator. CTGF is overexpressed in several kidney diseases and is induced by different factors involved in renal injury. Angiotensin II (AngII) participates in the pathogenesis of kidney damage, contributing to fibrosis; however, whether AngII regulates CTGF in the kidney has not been explored. Systemic infusion of AngII into normal rats for 3 days increased renal CTGF mRNA and protein levels. At day 7, AngII-infused rats presented overexpression of CTGF in glomeruli, tubuli, and renal arteries, as well as tubular injury and elevated fibronectin deposition. Only treatment with an AT(1) receptor antagonist, but not an AT(2), diminished CTGF and fibronectin overexpression and ameliorated tubular damage. In rats with immune complex nephritis, renal overexpression of CTGF was diminished by the ACE inhibitor quinapril, correlated with a diminution in fibrosis. In cultured renal cells (mesangial and tubular epithelial cells) AngII, via AT(1), increased CTGF mRNA and protein production, and a CTGF antisense oligonucleotide decreased AngII-induced fibronectin synthesis. Our data show that AngII regulates CTGF in the kidney and cultured in mesangial and tubular cells. This novel finding suggests that CTGF could be a mediator of the profibrogenic effects of AngII in the kidney.
American Journal Of Pathology 11/2003; 163(5):1937-47. DOI:10.1016/S0002-9440(10)63552-3 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiotensin II (Ang II) is a cytokine that participates in the inflammatory response. The nuclear factor kappa B (NFkappaB) is involved in the regulation of many immune and inflammatory factors. Different works have shown that both angiotensin II receptor type 1 (AT1) and type 2 (AT2) receptors are involved in the NFkappaB pathway; however, some aspects remain mysterious. AT1 antagonists increased plasma Ang II levels that could bind to AT2, so understanding the clinical importance of AT2 stimulation or inhibition is an interesting unresolved point.
Experiments were done in wild-type (WT) and AT1a receptor knockout mice that received subcutaneous Ang II infusions (1000 ng/kg/min) for 3 days. Specific blockers of AT1 (losartan 10 mg/kg/day) and AT2 (PD123319 30 mg/kg/day) receptors were administered 1 day before and during Ang II infusion. NFkappaB activity was examined by electrophoretic mobility assay and inflammatory (monocyte/macrophage) cell infiltration by immunohistochemistry
In WT mice, Ang II infusion caused renal NFkappaB activation that was partially diminished by either AT1 or AT2 antagonists. In AT1 knockout mice, Ang II also activated renal NFkappaB, which was only blocked by the AT2 antagonist. Both Ang II-infused WT and AT1 knockout mice showed inflammatory infiltration in tubulointerstitial areas that were suppressed by the AT2, but not AT1, antagonist. Combined therapy of both AT1 and AT2 antagonists blocked renal NFkappaB activation and inflammatory cell infiltration, both in WT and in AT1 knockout mice.
Ang II, via AT1 and AT2 stimulation, leads to NFkappaB activation that was only blocked by combined therapy with both antagonists. The participation of AT2 receptors in the recruitment of inflammatory cells underscores the need of future studies that evaluate the clinical usefulness of this strategy.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study is to assess a Simulect (basiliximab) regimen in routine clinical practice in the Spanish kidney transplantation units to evaluate efficacy and safety.
In this prospective, observational study, data on demographics, parameters of efficacy, and safety in patients who under with kidney transplantation treated with Simulect (basiliximab) were collected through an on-line collection system.
One hundred sixty three patients at 18 kidney transplant units included 12 months follow-up. The patient mean age was 52 years (DS 13,67) including 96 (58.90%) men and 67 (41.10%) women. Cold ischemia time was 19 hours (DS 6,79). Only 2 patients presented with PRA >50%. For prophylactic immunosuppression, 67.13% of patients received triple therapy with CNI (cyclosporine 49.65% or tacrolimus 17.48%), MMF (66.43%) or AZA (10.49%), and steroids. Incidence of acute rejection (AR) at 12 months was 12.27% (1.84% steroid-resistant). In subgroup analysis, AR was 13.5% in nondiabetics and 4.5% in diabetics, including 3 steroid-resistant episodes (1.84%) in nondiabetics and none in diabetics. In relation to donor age, AR was incidence 10.3% in patients with kidneys from donors aged 50 years or younger and 10.6% when donors were older than 50 years, including 1 (1.73%) and 2 (1.93%) steroid-resistant episodes, respectively. The graft and patient survival rates at 12 months were 90% and 98%, respectively.
Simulect (basiliximab) used in routine clinical practice provided good prophylaxis against acute rejection in several kidney transplant patient populations, similar to that observed in randomized clinical studies with excellent tolerability and safety.
[Show abstract][Hide abstract] ABSTRACT: The mechanism by which 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) induce apoptosis in vascular smooth muscle cells (VSMCs) is unknown. In this work, we demonstrate that treatment of VSMCs with simvastatin and atorvastatin inhibited Bcl-2 expression in a time and dose-dependent manner, while Bax expression was not modified. This effect was reversed by mevalonate (100 micromol/l), farnesylpyrophosphate (5 micromol/l) or geranylgeranylpyrophosphate (5 micromol/l), suggesting the involvement of protein prenylation. The treatment of VSMCs with lipophilic statins was associated with decreased prenylation of p-21 Rho A and mevalonate, farnesyl pyrophosphate (F-PP) and geranylgeranyl pyrophosphate (G-PP) reversed prenylation to basal levels. In addition, overexpression of constitutively active Q63L Rho A prevented, at least in part, apoptosis induced by statins and downregulation of Bcl-2. We also investigated the participation of caspases (proteases) in the apoptosis induced by statins. The treatment of VSMCs with lipophilic statins induced activation of the caspase 9, the first caspase of the mitochondrial pathway. Coincubation of VSMCs with the caspase inhibitor ZVAD-fmk (100 micromol/l) significantly inhibited lipophilic statin-induced apoptosis. These findings indicate that the downregulation of Bcl-2 by Rho GTPases mediates statin-induced apoptosis and suggest a new potential mechanism of action for these drugs on the regulation of cell number in the atherosclerotic lesions.
[Show abstract][Hide abstract] ABSTRACT: Endothelin (ET-1) is a potent vasoconstrictor that plays an important role in the control of renal circulation and tubular function. The contribution of this peptide to the pathogenesis of systemic hypertension and renal failure remains largely undefined. In spontaneously hypertensive rats (SHR) uninephrectomized at 20 weeks of age (UNX-SHR) and followed until 45 weeks of age, we determined ET-1 gene expression in renal tissue by reverse transcription-polymerase chain reaction and its localization by in situ hybridization in paraffin-embedded kidney sections. Age-matched SHR and normotensive Wistar-Kyoto (WKY) rats were chosen as controls. At the end of the follow-up, UNX-SHR had high systolic blood pressure, intense proteinuria, mesangial expansion, focal and segmental glomerular sclerosis, and tubulointerstitial lesions. In relation to WKY and SHR, UNX-SHR exhibited an increase in ET-1 gene expression in renal cortex and medulla. By in situ hybridization and immunoperoxidase staining, an overexpression of ET-1 gene and protein were seen in mesangial and glomerular epithelial cells and in some proximal tubules and vessels. Angiotensin-converting enzyme (ACE) activity was significantly increased in the renal brush border. Since in mesangial cells, angiotensin II induces ET-1 synthesis, a group of UNX-SHR received the ACE inhibitor quinapril from the time of UNX. These animals had a decrease in blood pressure, proteinuria, and serum and brush border ACE activity and in the expression and synthesis of ET-1 in all renal areas. On the whole, these data show that UNX-SHR have an upregulation of ET-1 gene and protein in several structures of the kidney compared with SHR and WKY rats. Quinapril diminished ACE activity and ET-1 expression and synthesis coincidentally with an improvement in proteinuria and morphological lesions. The beneficial effects of ACE inhibitors may be due to the diminution of both angiotensin II and ET-1 generation.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: To review the evidence that links angiotensin II and endothelin as growth factors and as modifiers of extracellular matrix synthesis in renal cells, with particular reference to the effects of angiotensin converting enzyme (ACE) inhibition in models of renal injury. IN VITRO STUDIES: In cultured mesangial cells, both angiotensin II and endothelin promote contraction, proliferation/hypertrophy, signal transduction pathways, the activation of early growth genes, and the generation of inflammatory mediators, cytokines and growth factors. Both hormones have been shown to promote the synthesis of fibronectin and collagen in a dose-dependent manner. ACE inhibition attenuates the effect of endothelin-1, one of three isoforms of endothelin. ANIMAL STUDIES: In experimental models of renal injury, chiefly in those characterized by increased intraglomerular pressure, ACE inhibition has reduced proteinuria and glomerular and interstitial sclerosis. HUMAN STUDIES: ACE inhibition has been shown to have major beneficial effects in patients with diabetic nephropathy, even in those with normal blood pressure. CONCLUSIONS: Although the renal-protective effects of ACE inhibitors in experimental and human renal injury may reflect systemic and/or local hemodynamic effects of these drugs, their modulatory actions on extracellular matrix synthesis and proteinuria may contribute to the benefit of ACE-inhibitor therapy.
Journal of hypertension. Supplement: official journal of the International Society of Hypertension 08/1994; 12(4):S51-8. DOI:10.1097/00004872-199407030-00008
[Show abstract][Hide abstract] ABSTRACT: Purpose: To review the evidence that links angiotensin II and endothelin as growth factors and as modifiers of extracellular matrix synthesis in renal cells, with particular reference to the effects of angiotensin converting enzyme (ACE) inhibition in models of renal injury.
In vitro studies In cultured mesangial cells, both angiotensin II and endothelin promote contraction, proliferation/hypertrophy, signal transduction pathways, the activation of early growth genes, and the generation of inflammatory mediators, cytokines and growth factors. Both hormones have been shown to promote the synthesis of fibronectin and collagen in a dose-dependent manner. ACE inhibition attenuates the effect of endothelin-1, one of three isoforms of endothelin.
Animal studies: In experimental models of renal injury, chiefly in those characterized by increased intraglomerular pressure, ACE inhibition has reduced proteinuria and glomerular and interstitial sclerosis.
Human studies: ACE inhibition has been shown to have major beneficial effects in patients with diabetic nephropathy, even in those with normal blood pressure.
Conclusions: Although the renal-protective effects of ACE inhibitors in experimental and human renal injury may reflect systemic and/or local hemodynamic effects of these drugs, their modulatory actions on extracellular matrix synthesis and proteinuria may contribute to the benefit of ACE-inhibitor therapy.
(C) Lippincott-Raven Publishers.
Journal of Hypertension 06/1994; 12. · 4.72 Impact Factor