19 results on '"Ardiles, LG"'
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2. Autoantibodies against bactericidal/permeability-increasing protein in patients with cystic fibrosis
- Author
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Zhao, MH, Jayne, DR, Ardiles, LG, Culley, F, Hodson, ME, and Lockwood, CM
- Published
- 1996
3. Obesity and renal disease: Benefits of bariatric surgery.
- Author
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Ardiles LG
- Abstract
The prevalence of obesity, a preventable and reversible condition with a high impact on health, continues to rise, especially after the COVID-19 pandemic. Severe overweight is well recognized as a risk factor for diabetes and hypertension, among other conditions, that may increase cardiovascular risk. Obesity has grown simultaneously with a rise in the prevalence of chronic kidney disease, and a pathophysiological link has been established, which explains its role in generating the conditions to facilitate the emergence and maximize the impact of the risk factors of chronic kidney disease and its progression to more advanced stages. Knowing the mechanisms involved and having different tools to reverse the overweight and its consequences, bariatric surgery has arisen as a useful and efficient method, complementary or alternative to others, such as lifestyle changes and/or pharmacotherapy. In a detailed review, the mechanisms involved in the renal consequences of obesity, the impact on risk factors, and the potential benefit of bariatric surgery at different stages of the disease and its progression are exposed and analyzed. Although the observational evidence supports the value of bariatric surgery as a renoprotective measure in individuals with obesity, diabetic or not, randomized studies are expected to establish evidence-based recommendations that demonstrate its positive risk-benefit balance as a complementary or alternative therapeutic tool., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ardiles.)
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- 2023
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4. The health system in Chile: the nephrologist perspective.
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Ardiles LG, Poblete H, Ortiz M, Elgueta S, Cusumano AM, Vukusich A, and Mezzano S
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- Adolescent, Adult, Aged, Aged, 80 and over, Chile epidemiology, Chronic Disease, Delivery of Health Care economics, Female, Health Care Costs statistics & numerical data, Health Surveys, Humans, Kidney Diseases economics, Kidney Transplantation economics, Kidney Transplantation statistics & numerical data, Male, Middle Aged, Peritoneal Dialysis economics, Peritoneal Dialysis statistics & numerical data, Prevalence, Registries, Renal Dialysis economics, Renal Dialysis statistics & numerical data, Renal Replacement Therapy economics, Renal Replacement Therapy statistics & numerical data, Retrospective Studies, Young Adult, Delivery of Health Care statistics & numerical data, Kidney Diseases epidemiology, Kidney Diseases therapy, Renal Replacement Therapy methods
- Abstract
Chile is a country with 17 million inhabitants, 13% of them living in rural areas, and with a per capita income of approximately US $14,500. Three percent of national income is assigned to the health budget, with a mixed public and private system, with guaranteed medical benefits from the state to cover chronic kidney disease (CKD) and renal replacement therapy (RRT). Hemodialysis has reached in 2009 a prevalence of 857 patients per million population (pmp). Peritoneal dialysis is less developed, with a prevalence of 40 patients pmp. Both therapies show good quality indexes with a patient mortality rate close to 12% per year. A centralized national renal transplantation program registered 5,949 renal transplants performed up to 2009. Renal survival at 5 years is 86% for living and 76% for cadaveric donor transplants. Organ donation is relatively low with 7.1 cadaveric donors pmp in 2009, despite legal and educational strategies to increase it. Although the country demonstrates one of the highest standards for RRT indexes in Latin America, the proportion of resources invested makes it necessary to improve early diagnosis and renal prevention policies to avoid having the growing incidence of CKD constrain the national health budget.
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- 2011
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5. Modulation of renal kallikrein by a high potassium diet in rats with intense proteinuria.
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Ardiles LG, Loyola F, Ehrenfeld P, Burgos ME, Flores CA, Valderrama G, Caorsi I, Egido J, Mezzano SA, and Figueroa CD
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- Animals, Bradykinin analogs & derivatives, Bradykinin pharmacology, Female, Hypertension etiology, Hypertension prevention & control, Kallikreins urine, Kidney pathology, Proteinuria complications, Proteinuria pathology, Rats, Rats, Sprague-Dawley, Renin-Angiotensin System physiology, Systole, Kallikreins biosynthesis, Kidney metabolism, Potassium, Dietary administration & dosage, Proteinuria metabolism
- Abstract
Injury of the renal tubulointerstitial compartment is recognized to play an important role in hypertension. Its damage may in turn, impair the activity of vasodepressor systems, like the kallikrein-kinin, in blood pressure regulation. The overload proteinuria model induces tubulointerstitial injury with activation of the renin-angiotensin system, but renal kallikrein and the development of hypertension have not received special attention. Sprague-Dawley rats received seven intraperitoneal doses of bovine serum albumin (BSA) 2 g/day under normosodic diet and were hydrated ad libitum. A second group received a high potassium diet to stimulate kallikrein production during the previous four weeks and while under BSA administration. A third one received potassium and BSA in the same schedule, but with the kinin B2 receptor antagonist, HOE140, added during the protein load phase. A control group received seven saline injections. Kallikrein protein was detected by immune labeling on renal sections and enzymatic activity in the urine. The BSA group showed massive proteinuria followed by intense tubulointerstitial damage. Blood pressure increased after the third dose in BSA animals, remaining elevated throughout the experiment, associated with significant reductions in renal expression and urinary activity of kallikrein, compared with controls. An inverse correlation was found between blood pressure and immunohistochemistry and urinary activity of kallikrein. Potassium induced a significant increase in both urinary activity and renal kallikrein expression, associated with significant reduction in blood pressure. The HOE140 antagonist blunted the antihypertensive effect of kallikrein stimulation in proteinuric rats. Loss of renal kallikrein, produced by tubulointerstitial injury, may participate in the pathogenesis of the hypertension observed in this model.
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- 2006
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6. Late onset of familial nephrotic syndrome associated with a compound heterozygous mutation of the podocin-encoding gene.
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Ardiles LG, Carrasco AE, Carpio JD, and Mezzano SA
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- Adult, Glomerulosclerosis, Focal Segmental complications, Glomerulosclerosis, Focal Segmental genetics, Glomerulosclerosis, Focal Segmental pathology, Humans, Intracellular Signaling Peptides and Proteins, Kidney pathology, Male, Nephrotic Syndrome etiology, Nephrotic Syndrome pathology, Heterozygote, Membrane Proteins genetics, Mutation, Nephrotic Syndrome genetics
- Abstract
A case of two young adult brothers with nephrotic syndrome secondary to focal segmental glomerulosclerosis is reported. Steroid resistance prompted us to perform genetic studies. These showed a compound heterozygous mutation of NPHS2, the gene encoding podocin. It was composed of a missense mutation in exon 7 (A284V) and the non-neutral polymorphism R229Q in exon 5. We review literature supporting the genetic basis of the disease.
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- 2005
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7. No gender-associated differences of cyclosporine pharmacokinetics in stable renal transplant patients treated with diltiazem.
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Aros CA, Ardiles LG, Schneider HO, Flores CA, Alruiz PA, Jerez VR, and Mezzano SA
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- Area Under Curve, Calcium Channel Blockers therapeutic use, Cyclosporine blood, Drug Interactions, Female, Humans, Immunosuppressive Agents blood, Immunosuppressive Agents pharmacokinetics, Immunosuppressive Agents therapeutic use, Kidney Transplantation physiology, Male, Sex Characteristics, Cyclosporine pharmacokinetics, Cyclosporine therapeutic use, Diltiazem therapeutic use, Kidney Transplantation immunology
- Abstract
Cytochrome-P450 enzymes metabolize cyclosporine both in the liver and in the intestinal wall. Diltiazem, by competitive inhibition of these enzymes, may increase the absorption and the bioavailability of cyclosporine. Some evidence points to a higher activity of some specific enzymes in women, such as CYP3A, that may influence differences in cyclosporine pharmacokinetics. We examined possible gender-associated differences in pharmacokinetic profiles of cyclosporine in 19 stable renal transplant recipients cotreated with diltiazem. Ten women and nine men, chronically using diltiazem associated with cyclosporine, azathioprine, and prednisone were randomly assigned to an 8-week period of continued controlled treatment with diltiazem (10 patients) or a wash-out period discontinuing diltiazem (nine patients). At the end of this period, the time-concentration curves of cyclosporine in the first 4 hours were performed after a single dose of cyclosporine. Thereafter, a cross-over between groups was performed, and time-concentration curves repeated. A specific RIA was used to measure cyclosporine concentrations. Comparisons between male and female patients in doses of cyclosporine and other pharmacokinetics parameters (C(0), C(2), AUC(0-4)), with or without diltiazem, did not show any difference related to gender. The association of diltiazem allowed a similar degree of reduction in Neoral dosage in male and female patients (21%). No changes in serum creatinine, blood urea nitrogen, potassium, uric acid, or blood pressure, or other adverse event were observed during the study. In these groups of patients, gender was not an important factor to be considered when diltiazem is added to cyclosporine therapy.
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- 2005
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8. Valsartan-induced hematocrit changes in renal transplant patients.
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Flores CA, Ardiles LG, Aros CA, Muñoz CC, Schneider HO, Ramírez JA, Jerez V, Valderrama MG, and Mezzano SA
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- Adult, Aged, Blood Pressure drug effects, Creatinine blood, Drug Therapy, Combination, Female, Humans, Immunosuppressive Agents therapeutic use, Kidney Transplantation immunology, Male, Middle Aged, Potassium blood, Valine therapeutic use, Valsartan, Antihypertensive Agents therapeutic use, Hematocrit, Kidney Transplantation physiology, Tetrazoles therapeutic use, Valine analogs & derivatives
- Abstract
Background: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARB) are frequently prescribed for renal transplant patients. The main reasons for their use are that their antihypertensive and antifibrogenic effects may prevent chronic renal allograft dysfunction, potentially improving transplant survival. Furthermore, ACE and ARB have been used to reduce the hematocrit in patients with posttransplant erythrocytosis. We evaluated the effects of the ARB valsartan on the evolution of hematocrit in stable renal transplant patients treated with cyclosporine (CsA), azathioprine (Aza), and prednisone., Patients and Methods: Twenty-six stable renal transplant patients treated with valsartan 80 mg/d orally were followed for 6 months. Evaluations were performed prior to as well as at 3 and 6 months following the initiation of valsartan., Results: The hematocrit levels decreased significantly at 3 months (46.1 +/- 7.3 vs 39.9 +/- 5.8 ; P < .0001) in patients with a normal hematocrit, namely a level over 38%, with no further reduction at 6 months. In recipients with an hematocrit less than 38%, there was no significant reduction, either at 3 or 6 months follow-up. Valsartan was well tolerated without significant side effects., Conclusion: We postulate that inhibition of the proerythropoietic effects of angiotensin II and/or the reduction in hypoxia within the renal tubulointerstitium as well as the vasodilator effects on the efferent arterioles, represent possible mechanisms for the reduction and stabilization of the hematocrit in stable renal transplant patients.
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- 2005
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9. Correlation Between C2 and AUC(0-4) in Renal Transplant Patients Treated With Diltiazem.
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Aros CA, Schneider HO, Flores CA, Ardiles LG, Alruiz PA, Jerez V, and Mezzano SA
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- Adult, Aged, Area Under Curve, Cyclosporine blood, Cyclosporine pharmacokinetics, Cyclosporine therapeutic use, Diltiazem blood, Diltiazem therapeutic use, Drug Monitoring methods, Humans, Immunosuppressive Agents pharmacokinetics, Immunosuppressive Agents therapeutic use, Middle Aged, Vasodilator Agents therapeutic use, Diltiazem pharmacokinetics, Kidney Transplantation immunology, Vasodilator Agents pharmacokinetics
- Abstract
Background: The area-under-the-curve (AUC) of cyclosporine (CsA) reflects exposure to the drug, but this monitoring strategy is time-consuming and not cost-effective. Recently, it has been suggested that the concentration at 2 hours after dosing (C2) shows the best correlation with AUC. The C2 has been replacing the trough measurement (C0) to monitor CsA therapy, but in patients receiving diltiazem there is not much information about this issue. We investigated the correlations between C2 and C0 with absorption AUC over the first 4 hours (AUC(0-4)) in renal stable transplant patients receiving CsA therapy with or without diltiazem., Patients and Methods: Ten patients (five men) of ages 23 to 68 years and 6 to 84 months after transplantation, were randomly assigned to an 8-week initial period of either diltiazem washout or controlled treatment with diltiazem. Time-concentration curves of cyclosporine were performed at the end of this period using a specific RIA measurement of blood samples. Thereafter, a crossover of the groups was performed and after another 8 weeks, a second curve was obtained. Drugs that change the pharmacokinetics of cyclosporine or diltiazem were not allowed., Results: The cyclosporine daily dose was lower with diltiazem (173 +/- 4 mg vs 213 +/- 4 mg, P = .002), but despite a dose reduction of only 19% +/- 1.5%, there was a trend to a larger AUC/dose (28 +/- 5 ng x h/mL x mg vs 17 +/- 2 ng x h/mL x mg, P = .1) and a trend to an increased C2 when treatment included diltiazem (1035 +/- 156 ng/mL vs 652 +/- 126 ng/mL, P = NS). Moreover, we confirmed that C2 showed the best correlation with AUC(0-4), (r = 0.7, P = .04), a correlation that improved with diltiazem (r = 0.9, P < .002)., Conclusion: C2 is the point that correlates best with AUC(0-4) with or without diltiazem. C2 in the presence of diltiazem was associated with a stronger, more significant correlation with AUC(0-4).
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- 2005
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10. Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy.
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Mezzano S, Droguett A, Burgos ME, Ardiles LG, Flores CA, Aros CA, Caorsi I, Vío CP, Ruiz-Ortega M, and Egido J
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- Chemokines metabolism, Humans, In Vitro Techniques, Inflammation Mediators metabolism, Kidney metabolism, Kidney pathology, NF-kappa B metabolism, Nephritis pathology, Up-Regulation, Diabetic Nephropathies complications, Diabetic Nephropathies metabolism, Nephritis etiology, Renin-Angiotensin System
- Abstract
Background: The molecular mechanisms of renal injury in diabetic nephropathy (DN) are not completely understood, although inflammatory cells play a key role. The renin-angiotensin system (RAS) is involved in kidney damage; however, few studies have examined the localization of RAS components in human DN. Our aim was to investigate in renal biopsies the expression of RAS and their correlation with proinflammatory parameters and renal injury., Methods: The biopsies from 10 patients with type 2 diabetes mellitus and overt nephropathy were studied for the expression of RAS components by immunohistochemistry (IH). In addition, by Southwestern histochemistry we studied the in situ detection of the activated nuclear factor kappa B (NFkappaB), and by IH and/or in situ hybridization (ISH), the expression of monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES), whose genes are regulated by NFkappaB., Results: Angiotensin-converting enzyme (ACE) immunostaining was elevated in tubular cells and appeared in interstitial cells. Elevated levels of angiotensin II (Ang II) immunostaining were observed in tubular and infiltrating interstitial cells. There was also a down-regulation of AT1 and up-regulation of AT2 receptors. An activation of NFkappaB and a marked up-regulation of NFkappaB-dependent chemokines mainly in tubular cells was observed. Elevated levels of NFkappaB, chemokines, and Ang II in tubules were correlated with proteinuria and interstitial cell infiltration., Conclusions: Our results show that in human DN, RAS components are modified in renal compartments, showing elevated local Ang II production, activation of tubular cells, and induction of proinflammatory parameters. These data suggest that Ang II contributes to the renal inflammatory process, and may explain the molecular mechanisms of the beneficial effect of RAS blockade.
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- 2003
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11. Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy.
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Mezzano SA, Aros CA, Droguett A, Burgos ME, Ardiles LG, Flores CA, Carpio D, Vío CP, Ruiz-Ortega M, and Egido J
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- Becaplermin, Glomerulonephritis, Membranous metabolism, Glomerulonephritis, Membranous pathology, Humans, Platelet-Derived Growth Factor metabolism, Proto-Oncogene Proteins c-sis, Renin-Angiotensin System, Transforming Growth Factor beta metabolism, Up-Regulation, Angiotensin II metabolism, Fibroblasts pathology, Glomerulonephritis, Membranous physiopathology, Kidney metabolism, Myocytes, Smooth Muscle pathology
- Abstract
Background: The molecular mechanisms of renal injury and fibrosis in proteinuric nephropathies are not completely elucidated but the renin-angiotensin system (RAS) is involved. Idiopathic membranous nephropathy (MN), a proteinuric disease, may progress to renal failure. Our aim was to investigate the localization of RAS components in MN and their correlation with profibrotic parameters and renal injury., Methods: Renal biopsies from 20 patients with MN (11 with progressive disease) were studied for the expression of RAS components [angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)] by immunohistochemistry. Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by alpha-smooth muscle actin (alpha-SMA) staining., Results: ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in alpha-actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-beta and PDGF mRNAs were up-regulated mainly in cortical tubular epithelial cells in progressive disease (P < 0.01) and correlated with the myofibroblast transdifferentiation (r = 0.8, P < 0.01 for TGF-beta; r = 0.6, P < 0.01 for PDGF). Moreover, in serial sections of progressive cases, the ACE and Ang II over-expression was associated with the tubular expression of these pro-fibrogenic factors, and with the interstitial infiltration and myofibroblast activation., Conclusion: Intrarenal RAS is selectively activated in progressive MN. De novo expression of ACE at sites of tubulointerstitial injury suggests that the in situ Ang II generation could participate in tubular TGF-beta up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.
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- 2003
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12. Renal kallikrein-kinin system damage and salt sensitivity: insights from experimental models.
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Ardiles LG, Figueroa CD, and Mezzano SA
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- Animals, Enzyme Inhibitors pharmacology, Kidney pathology, NG-Nitroarginine Methyl Ester pharmacology, Nephrectomy methods, Nitric Oxide antagonists & inhibitors, Nitric Oxide Synthase antagonists & inhibitors, Proteinuria complications, Proteinuria metabolism, Proteinuria pathology, Hypertension etiology, Hypertension physiopathology, Kallikrein-Kinin System, Kidney metabolism, Sodium Chloride pharmacology
- Abstract
The importance of tubulointerstitial injury in the pathophysiology of human essential hypertension, and particularly salt sensitivity, is increasingly recognized. Since the renal kallikrein-kinin system (KKS) is located in the tubulointerstitial region of the kidney it is reasonable to expect that injury to this area, whatever the cause, may impair KKS production and compromise its role in blood pressure regulation. In this review we discuss evidence of injury in the renal kallikrein-producing structures in three different experimental models characterized by prominent tubulointerstitial lesions: subtotal nephrectomy; inhibition of nitric oxide synthase; and overload proteinuria. These three experimental models have in common the development of important tubulointerstitial damage and salt-sensitive hypertension expressed after the initial injury has ceased. In these three models, reduced KKS activity may contribute to the establishment of a pathophysiologic state characterized by unopposed hyperactivity of the renin-angiotensin system, resulting in salt retention.
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- 2003
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13. Effect of mycophenolate mofetil on kallikrein expression in the kidney of 5/6 nephrectomized rats.
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Ardiles LG, Ehrenfeld P, Quiroz Y, Rodriguez-Iturbe B, Herrera-Acosta J, Mezzano S, and Figueroa CD
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- Animals, Blood Pressure, Hypertension etiology, Hypertension physiopathology, Immunohistochemistry, Kallikreins antagonists & inhibitors, Kidney pathology, Kidney Tubules pathology, Male, Mycophenolic Acid analogs & derivatives, Rats, Rats, Sprague-Dawley, Immunosuppressive Agents pharmacology, Kallikreins metabolism, Kidney metabolism, Mycophenolic Acid pharmacology, Nephrectomy adverse effects, Nephrectomy methods
- Abstract
It has recently been proposed that tubulointerstitial damage plays a key role in the pathogenesis of sodium-dependent hypertension. Since components, enzymes and substrates, of the kallikrein-kinin system (KKS) are synthesized by connecting and collecting tubules, respectively, it is expected that damage of any origin, involving the tubulointerstitial compartment, may affect the functionality of these nephron segments and impair blood pressure control. Therefore, we analyzed renal kallikrein expression in the 5/6 renal ablation model, which is characterized by a progressive tubulointerstitial damage and systemic hypertension. In addition, we studied the renal expression of this enzyme after treatment of healthy and 5/6 nephrectomized rats with mycophenolate mofetil (MMF), an immunosuppressive drug known to reduce tubulointerstitial damage in this model. Twenty-six male Sprague-Dawley rats were included in this study. Seven 5/6 nephrectomized rats (Nx), 4 sham-operated (Sham) rats and 5 Nx rats treated with MMF (Nx + MMF) were studied 4 weeks after surgery. For comparison, 6 healthy rats treated with MMF at the same dose were compared with 4 vehicle-treated controls. Tubulointerstitial damage was significantly high in Nx compared with Nx-MMF and sham-operated rats. Blood pressure was significantly higher in Nx (178 +/- 7.8 mm Hg) than in Sham (120 +/- 2.0 mm Hg, p < 0.05) and Nx + MMF animals (154 +/- 5.6 mm Hg, p < 0.05). Renal kallikrein expression, quantified by a computer image system was significantly lower in the Nx group (1,696 +/- 437 density/mm(2)) than in Sham (9,779 +/- 4,068 density/mm(2), p < 0.05), and in Nx + MMF groups (4,640 +/- 1,578 density/mm(2), p < 0.05). Healthy animals treated with MMF did not show tubulointerstitial damage, changes in blood pressure nor changes in the expression of immunoreactive renal kallikrein suggesting that improvement in kallikrein expression after MMF treatment of 5/6 nephrectomy was not due to a direct effect of the drug on kallikrein-producing cells. Our results suggest that protection of the KKS after 5/6 nephrectomy may have additional renoprotective effects and may reduce the progression of renal disease., (Copyright 2002 S. Karger AG, Basel)
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- 2002
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14. Tubular NF-kappaB and AP-1 activation in human proteinuric renal disease.
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Mezzano SA, Barría M, Droguett MA, Burgos ME, Ardiles LG, Flores C, and Egido J
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- Adolescent, Adult, Chemokines metabolism, Child, Child, Preschool, Female, Glomerulonephritis, Membranous urine, Histocytochemistry, Humans, Immunohistochemistry, In Situ Hybridization, Inflammation Mediators metabolism, Male, Nephrosis, Lipoid urine, Proteinuria etiology, Reference Values, Glomerulonephritis, Membranous physiopathology, Kidney Tubules metabolism, NF-kappa B physiology, Nephrosis, Lipoid physiopathology, Transcription Factor AP-1 physiology
- Abstract
Background: Nuclear factor-kappaB (NF-kappaB) and activated protein-1 (AP-1) are transcription factors that regulate many genes involved in the progression of renal disease. Recent data have shown that NF-kappaB is activated in tubules and glomeruli in various experimental models of renal injury. In vitro studies also suggest that proteinuria could be an important NF-kappaB activator. We therefore approached the idea that NF-kappaB may be an indicator of renal damage progression., Methods: Paraffin-embedded renal biopsy specimens from 34 patients with intense proteinuria [14 with minimal change disease (MCD) and 20 with idiopathic membranous nephropathy (MN)] and from 7 patients with minimal or no proteinuria (IgA nephropathy) were studied by Southwestern histochemistry for the in situ detection of activated transcription factors NF-kappaB and AP-1. In addition, by immunohistochemistry, we performed staining for the NF-kappaB subunits (p50 and p65) and AP-1 subunits (c-fos, c-jun). By immunohistochemistry and/or in situ hybridization, the expression of some chemokines [monocyte chemoattractant protein-1 (MCP-1), RANTES, osteopontin (OPN)] and profibrogenic cytokines [transforming growth factor-beta (TGF-beta)], whose genes are regulated by NF-kappaB and/or AP-1, were studied further., Results: NF-kappaB was detected mainly in the tubules of proteinuric patients, but rarely in nonproteinuric IgA nephropathy (IgAN) patients. In addition, there was a significant relationship between the intensity of proteinuria and NF-kappaB activation in MCD (r = 0.64, P = 0.01) and MN patients (r = 0.64, P < 0.01). Unexpectedly, patients with MCD had a significantly higher NF-kappaB tubular activation than those with MN (P < 0.01). To assess whether there was a different composition of NF-kappaB protein components, immunostaining was performed for the NF-kappaB subunits p50 and p65. However, no differences were noted between MCD and MN patients. In those patients, there was a lower tubular activation of AP-1 compared with NF-kappaB. Moreover, a strong correlation in the expression of both transcription factors was observed only in MN (r = 0.7, P = 0.004). Patients with progressive MN had an overexpression of MCP-1, RANTES, OPN, and TGF-beta, mainly in the proximal tubules, while no significant expression was found in MCD patients., Conclusions: On the whole, our results show that a tubular overactivation of NF-kappaB and AP-1 and a simultaneous up-regulation of certain proinflammatory and profibrogenic genes are markers of progressive renal disease in humans. Increased activation of solely NF-kappaB and/or AP-1 may merely indicate the response of tubular renal cells to injury.
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- 2001
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15. Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy.
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Mezzano SA, Droguett MA, Burgos ME, Ardiles LG, Aros CA, Caorsi I, and Egido J
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- Adult, Aged, Female, Fibroblasts metabolism, Glomerulonephritis, Membranous pathology, Humans, Immunohistochemistry, In Situ Hybridization, Kidney metabolism, Macrophages pathology, Male, Middle Aged, Chemokines genetics, Cytokines genetics, Glomerulonephritis, Membranous metabolism
- Abstract
Unlabelled: Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy., Background: Proteinuria plays a central role in the progression of glomerular disease, and there is growing evidence suggesting that it may determine tubular cell activation with release of chemokines and fibrogenic factors, leading to interstitial inflammatory reaction. However, most studies on this subject have been performed in experimental models, and the experience in human kidney biopsies has been scarce. We analyzed the tissue sections of patients with idiopathic membranous nephropathy (IMN), a noninflammatory glomerular disease that may follow a progressive disease with heavy persistent proteinuria, interstitial cell infiltration, and decline of renal function., Methods: Paraffin-embedded biopsy specimens from 25 patients with IMN (13 progressive and 12 nonprogressive) were retrospectively studied by immunohistochemistry [monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted chemokine (RANTES), osteopontin (OPN), platelet-derived growth factor-BB (PD-GF-BB)] and in situ hybridization [MCP-1, RANTES, PDGF-BB, transforming growth factor-beta1 (TGF-beta1)]. Moreover, we studied the presence of myofibroblasts, which were identified by the expression of alpha-smooth muscle actin (alpha-SMA), the monocytes/macrophages (CD68-positive cells), and T-cell infiltration (CD4+ and CD8+ cells). All of the patients were nephrotic and without treatment at time of the biopsy., Results: A strong up-regulation of MCP-1, RANTES, and OPN expression was observed, mainly in tubular epithelial cells, with a significant major intensity in the progressive IMN patients. A strong correlation between the mRNA expression and the corresponding protein was noted. The presence of these chemokines and OPN was associated with interstitial cell infiltration. TGF-beta and PDGF were also up-regulated, mainly in tubular epithelial cells, with a stronger expression in the progressive IMN, and an association with the presence of myofibroblasts was found., Conclusions: Patients with severe proteinuria and progressive IMN have an overexpression in tubular epithelial cells of the chemokines MCP-1, RANTES, and OPN and the profibrogenic cytokines PDGF-BB and TGF-beta. Because this up-regulation was associated with an interstitial accumulation of mononuclear cells and an increase in myofibroblastic activity, it is suggested that those mediators are potential predictors of progression in IMN. Finally, based on experimental data and the findings of this article, we speculate that severe proteinuria is the main factor responsible for the up-regulation of these factors in tubular epithelial cells.
- Published
- 2000
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16. Anticardiolipin antibodies in classic pediatric hemolytic-uremic syndrome: a possible pathogenic role.
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Ardiles LG, Olavarría F, Elgueta M, Moya P, and Mezzano S
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- Child, Preschool, Female, Hemolytic-Uremic Syndrome etiology, Humans, Immunoglobulin Isotypes blood, Infant, Male, Antibodies, Anticardiolipin blood, Hemolytic-Uremic Syndrome blood
- Abstract
Anticardiolipin (aCL) antibodies have been associated with thrombocytopenia, hemolytic anemia and an increased risk of thrombosis in different vascular locations, even in the absence of lupus. The classic hemolytic-uremic syndrome is a postinfectious acute renal failure characterized by hemolytic anemia, thrombocytopenia and the presence of widespread glomerular thrombosis in the kidney, with pathogenic mechanisms that remain to be identified. In order to establish the frequency of aCL antibodies in this syndrome and to identify a possible role in the pathogenesis and clinical manifestations, 17 patients were studied during the reactant phase of the disease looking for an association between the presence of aCL antibodies (isotypes IgG, IgA and IgM) and the main clinical variables of the syndrome. In 8 patients IgG aCL was present, 2 patients had IgM aCL, and 1 had IgA antibodies on the solid-phase ELISA aCL assays, but no association could be demonstrated with the clinical variables studied. Although it might correspond to an epiphenomenon related to the triggering intestinal infection, a pathogenic role cannot be discarded and additional studies should be performed.
- Published
- 1998
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17. Incidence and studies on antigenic specificities of antineutrophil-cytoplasmic autoantibodies (ANCA) in poststreptococcal glomerulonephritis.
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Ardiles LG, Valderrama G, Moya P, and Mezzano SA
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- Acute Disease, Adolescent, Adult, Aged, Child, Child, Preschool, Enzyme-Linked Immunosorbent Assay, Female, Fluorescent Antibody Technique, Indirect, Glomerulonephritis microbiology, Glomerulonephritis pathology, Humans, Impetigo immunology, Incidence, Longitudinal Studies, Male, Middle Aged, Sensitivity and Specificity, Antibodies, Antineutrophil Cytoplasmic analysis, Autoantigens immunology, Epitopes immunology, Glomerulonephritis immunology, Streptococcal Infections complications
- Abstract
Sera from 210 patients with Acute Poststreptococcal Glomerulonephritis (APSGN) and 14 patients with streptococcal impetigo without glomerular disease were tested for the presence of IgG-ANCA using an indirect immunofluorescence assay (IIF) on ethanol fixed normal human neutrophils. In the group of nephritic patients, ANCA were detected by IIF in 9% (18 out of 210 cases) in an atypical diffuse cytoplasmic pattern (a-ANCA) in 14 cases and in a (p-ANCA) perinuclear staining in the remaining 4 cases. Longitudinal studies performed on six IIF positive patients, showed persistence of the phenomenon for up to six months, without relationship with activity of disease. No patient with streptococcal impetigo showed positivity on the IIF assay. Positive sera were analyzed on ELISA plates for their IgG reactivity against specific purified ANCA antigens: Proteinase-3 (PR3), Myeloperoxidase (MPO). Cathepsin-G and Bactericidal/Permeability Increasing Protein (BPI). Anti-MPO antibodies were present in 4 cases (3 a-ANCA and 1 p-ANCA). No reactivity was identified against PR-3, BPI and Catepsin-G in any of the samples. The presence of ANCA was significantly associated with a more severe glomerular disease as assessed by the serum creatinine and the crescents formation. Further studies are required to identify other antigenic specificities of these autoantibodies. Their absence in the streptococcal impetigo control group might suggest that their presence in APSGN could play some pathogenic role in kidney disease.
- Published
- 1997
18. Complete remission of nephrotic syndrome after steroid-chlorambucil in a previous failed short-term steroidal treatment of a primary membranous nephropathy.
- Author
-
Ardiles LG and Mezzano SA
- Subjects
- Adult, Follow-Up Studies, Glomerulonephritis, Membranous complications, Humans, Male, Nephrotic Syndrome etiology, Remission Induction, Antineoplastic Agents, Alkylating therapeutic use, Chlorambucil therapeutic use, Glomerulonephritis, Membranous drug therapy, Glucocorticoids therapeutic use, Methylprednisolone therapeutic use, Nephrotic Syndrome drug therapy, Prednisone therapeutic use
- Published
- 1996
19. Autoantibodies against bactericidal/permeability-increasing protein in patients with cystic fibrosis.
- Author
-
Zhao MH, Jayne DR, Ardiles LG, Culley F, Hodson ME, and Lockwood CM
- Subjects
- Adolescent, Adult, Antibodies, Antineutrophil Cytoplasmic, Antimicrobial Cationic Peptides, Biomarkers blood, Blotting, Western, Cross-Sectional Studies, Cystic Fibrosis complications, Cystic Fibrosis physiopathology, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulin A blood, Immunoglobulin G blood, Lung physiopathology, Male, Vasculitis complications, Vasculitis immunology, Autoantibodies blood, Blood Proteins immunology, Cystic Fibrosis immunology, Membrane Proteins
- Abstract
Cystic fibrosis (CF), a genetic disorder, is characterized by chronic pulmonary infection/inflammation which leads to respiratory failure. The presence of anti-neutrophil cytoplasmic autoantibodies (ANCA) has previously been observed in the sera of patients with CF. In view of the known relationship of ANCA with primary vasculitis and of their putative pathogenetic role in these disorders, we studied the presence, specificity and isotype of ANCA and their clinical associations in 66 adult CF patients. None of the 66 CF samples had autoantibodies to the major ANCA antigens, proteinase 3 or myeloperoxidase. However, 60/66 (91%) CF samples contained IgG, and 55/66 (83%) IgA, autoantibodies to bactericidal/permeability-increasing protein (BPI), a recently-characterized ANCA specificity. All the IgA anti-BPI-positive samples were also IgG anti-BPI-positive. The autoantibody specificity was confirmed by inhibition assay and immunoblotting of CF sera against a neutrophil granule preparation. Furthermore, in this cross-sectional study, anti-BPI levels were inversely correlated with the observed reductions in FEV1 and FVC (IgA anti-BPI & FEV1: r = -0.508, p < 0.0001), and both IgG and IgA anti-BPI levels were higher in CF patients with secondary vasculitis (n = 6) than in those without (p < 0.05). ANCA with specificity for BPI were present in the majority of CF sera in this study and autoimmune processes may be associated with the development of pulmonary injury in CF.
- Published
- 1996
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