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ABSTRACT: Background/Aims: Renal ischaemia-reperfusion injury (IRI) is a systemic inflammatory process in which Th1 responses predominate affecting other organs including the lungs. The present study explored the phagocytic and microbicidal capacity of macrophages in rats with lung inflammation that underwent IRI. Methods: The alveolar macrophages of rats sensitised to OVA were evaluated for phagocytosis and bacterial killing 24h after antigen challenge in animals with or without prior submission to 60 min of renal ischaemia. Results: Bronchoalveolar lavage had a high level of cellular infiltrate in immunised animals (420%) compared with control animals; IRI significantly reduced this infiltration (52%). Macrophages from animals immunised and challenged with OVA presented a 10x increase in phagocytic capacity compared to the control group, whereas immunised animals subjected to IRI showed a reduction in the phagocytic index of 68%. The killing of Klebsiella pneumoniae by macrophages from immunised animals was higher (56%) compared with the control group but reduced in animals submitted to IRI (45%). Immunised and challenged group showed an increase in gene expression levels of IL-10(450%), HO-1 (259%), INF-γ (460%) and MCP-1 (370%) compared to the immunised group subjected to IRI. Conclusions: Renal ischaemia and reperfusion injury apparently alters the phagocytic and microbicidal capacity of macrophages, reducing lung inflammation to OVA.
Cellular Physiology and Biochemistry 02/2013; 31(2-3):179-188. · 2.86 Impact Factor
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ABSTRACT: IL-4 produced by Th2 cells can block cytokine production by Th1 cells, and Th1 IFN-γ is known to counterregulate Th2 immune response, inhibiting allergic eosinophilia. As intrauterine undernutrition can attenuate lung inflammation, we investigated the influence of intrauterine undernourishment on the Th1/Th2 cytokine balance and allergic lung inflammation. Intrauterine undernourished offspring were obtained from dams fed 50% of the nourished diet of their counterparts and were immunized at 9 weeks of age. We evaluated the cell counts and cytokine protein expression in the bronchoalveolar lavage, mucus production and collagen deposition, and cytokine gene expression and transcription factors in lung tissue 21 days after ovalbumin immunization. Intrauterine undernourishment significantly reduced inflammatory cell airway infiltration, mucus secretion and collagen deposition, in rats immunized and challenged. Intrauterine undernourished rats also exhibited an altered cytokine expression profile, including higher TNF-α and IL-1β expression and lower IL-6 expression than well-nourished rats following immunization and challenge. Furthermore, the intrauterine undernourished group showed reduced ratios of the IL-4/IFN-γ and the transcription factors GATA-3/T-Bet after immunization and challenge. We suggest that the attenuated allergic lung inflammation observed in intrauterine undernourished rats is related to an altered Th1/Th2 cytokine balance resulting from a reduced GATA-3/T-bet ratio.
Cellular Physiology and Biochemistry 07/2012; 30(3):552-62. · 2.86 Impact Factor
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ABSTRACT: The present study investigated the early presence of inflammatory response in renal tissue of young offspring from diabetic mothers. The effect of L-arginine (L-arg) supplementation was also investigated. The offspring was divided into four groups: group CO (controls); group DO (diabetic offspring); group CA (CO receiving 2% L-arg solution) and group DA (DO receiving the 2% L-arg solution). Glycemia, arterial pressure and renal function were evaluated; gene and protein expression of pro-inflammatory cytokines were also measured. Blood pressure levels were significantly increased in 2 and 6 month-old DO rats, whereas L-arg administration caused a significant decrease in the DA group, at both ages. DO rats showed a significantly blunted glycemic response to exogenous insulin. In 2 month-old DO animals, renal protein expression of pro-inflammatory molecules was significantly increased. At six months of age, we also observed an increase in gene expression of pro-inflammatory molecules, whereas L-arg supplementation prevented this increase at both ages. Our data suggest that activation of inflammatory pathways is present early in the kidney of DO rats, and that L-arg can attenuate the expression of these markers of tissue inflammation. Our results also reinforce the concept that intrauterine environmental factors are a fundamental determinant in the development of metabolic and vascular diseases later in life.
European journal of pharmacology 05/2012; 689(1-3):233-40. · 2.59 Impact Factor
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Rafael L Pereira,
Vanessa O Reis,
Patricia Semedo,
Bruna N Buscariollo,
Cassiano Donizetti-Oliveira,
Marcos A Cenedeze,
Maria Fernanda Soares,
Alvaro Pacheco-Silva,
Paul B Savage, Niels O S Câmara,
Alexandre C Keller
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ABSTRACT: A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis (FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro-Th1 activity on invariant Natural Killer T (iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin(ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro-fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1α, IL-1β, IL-17, TNF-α, and chemokines, such as RANTES and eotaxin. In addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-β analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-β could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-β, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-β through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. In conclusion, our work demonstrates that the iNKT agonist GSL-1 modulates the pathogenesis of ADM-induced glomerulosclerosis and may provide an alternative approach to disease management.
PLoS ONE 01/2012; 7(3):e32454. · 4.09 Impact Factor
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Rafael L Pereira,
Bruna N Buscariollo,
Matheus Corrêa-Costa,
Patricia Semedo,
Cassiano D Oliveira,
Vanessa O Reis,
Edgar Maquigussa,
Ronaldo C Araújo,
Tárcio T Braga,
Maria F Soares,
Ivan C Moura,
Denise M A C Malheiros,
Alvaro Pacheco-Silva Filho,
Alexandre C Keller, Niels O S Câmara
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ABSTRACT: Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and α-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling.
Kidney International 03/2011; 79(11):1217-27. · 6.61 Impact Factor
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Matheus Correa-Costa,
Patricia Semedo,
Ana Paula F S Monteiro,
Reinaldo C Silva,
Rafael L Pereira,
Giselle M Gonçalves,
Georgia Daniela Marcusso Marques,
Marcos A Cenedeze,
Ana C G Faleiros,
Alexandre C Keller,
Maria H M Shimizu,
Antônio C Seguro,
Marlene A Reis,
Alvaro Pacheco-Silva, Niels O S Câmara
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ABSTRACT: The tubule-interstitial fibrosis is the hallmark of progressive renal disease and is strongly associated with inflammation of this compartment. Heme-oxygenase-1 (HO-1) is a cytoprotective molecule that has been shown to be beneficial in various models of renal injury. However, the role of HO-1 in reversing an established renal scar has not yet been addressed.
We explored the ability of HO-1 to halt and reverse the establishment of fibrosis in an experimental model of chronic renal disease.
Sprague-Dawley male rats were subjected to unilateral ureteral obstruction (UUO) and divided into two groups: non-treated and Hemin-treated. To study the prevention of fibrosis, animals were pre-treated with Hemin at days -2 and -1 prior to UUO. To investigate whether HO-1 could reverse established fibrosis, Hemin therapy was given at days 6 and 7 post-surgery. After 7 and/or 14 days, animals were sacrificed and blood, urine and kidney tissue samples were collected for analyses. Renal function was determined by assessing the serum creatinine, inulin clearance, proteinuria/creatininuria ratio and extent of albuminuria. Arterial blood pressure was measured and fibrosis was quantified by Picrosirius staining. Gene and protein expression of pro-inflammatory and pro-fibrotic molecules, as well as HO-1 were performed.
Pre-treatment with Hemin upregulated HO-1 expression and significantly reduced proteinuria, albuminuria, inflammation and pro-fibrotic protein and gene expressions in animals subjected to UUO. Interestingly, the delayed treatment with Hemin was also able to reduce renal dysfunction and to decrease the expression of pro-inflammatory molecules, all in association with significantly reduced levels of fibrosis-related molecules and collagen deposition. Finally, TGF-β protein production was significantly lower in Hemin-treated animals.
Treatment with Hemin was able both to prevent the progression of fibrosis and to reverse an established renal scar. Modulation of inflammation appears to be the major mechanism behind HO-1 cytoprotection.
PLoS ONE 01/2010; 5(12):e14298. · 4.09 Impact Factor
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ABSTRACT: Renal ischemia and reperfusion injury (IRI) is considered an inflammatory syndrome. To move forward in its pathogenesis, we exploited the role of several cytokines on renal damages triggered by IRI. Specifically to evaluate the role of Th1 immune profile in this system, IL-12, IFN-gamma, and IFN-gamma/IL-12 deficient (KO) mice on C57BL/6 background and their controls were subjected to IRI. In each group, blood and kidney samples were harvested. Renal function was evaluated by serum creatinine and renal morphometric analyses. Gene expression of IL-6 and HO-1 were also investigated by Q-PCR. IFN-gamma KO animals presented the highest impairment in renal function compared to controls. Conversely, IL-12 KO animals were absolutely protected and, in a lesser extent, IFN-gamma/IL-12 KO double knockout was also protected from IRI. Gene expression analyses showed higher expression of HO-1, a cytoprotective gene, and IL-6, a pro-inflammatory cytokine, in IFN-gamma deficient animals subjected to IRI. Our results confirm that Th1 related cytokines such as IL-12 and IFN-gamma are critically involved in renal ischemia and reperfusion injury.
International immunopharmacology 01/2009; 9(6):668-72. · 2.21 Impact Factor
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ABSTRACT: B lymphocyte infiltration in renal acute allograft rejection has been associated with steroid resistance and poor outcomes. We aimed to measure CD20 mRNA in urine of renal transplant patients with graft dysfunction and correlate with the histological diagnosis and immunohistochemical (IH) staining for CD20. A total of 48 urine samples were analyzed (21 with acute rejection, 10 with chronic allograft nephropathy, 11 with unspecific tubular lesions, 3 with acute pyelonephritis and 3 with polyomavirus nephropathy). Higher urinary CD20 levels associated with a positive IH staining for CD20 (>50 positive cells/HPF) in renal tissue (p=0.04), with a sensitivity of 83.3% and a specificity of 51.6%. Within the acute rejection group, a positive staining for CD20 was not associated with graft loss, steroid resistance or lack of return to basal creatinine after treatment, but was associated with higher serum creatinine at 3 and 6 months, 1 and 2 years after the acute episode (p<0.05). In conclusion, we showed that urinary levels of CD20 detected by RT-PCR had a high sensitivity for CD20+ staining in the corresponding renal tissue, but with a low specificity. Patients with clusters of CD20+ cells >50/HPF had higher serum creatinine after 2 years of follow up.
International immunopharmacology 12/2008; 9(6):663-7. · 2.21 Impact Factor
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Carla Q Feitoza,
Giselle M Gonçalves,
Patrícia Semedo,
Marcos A Cenedeze,
Hélady S Pinheiro,
Felipe Caetano Beraldo,
Oscar Fernando Pavão dos Santos,
Vicente de Paula A Teixeira,
Marlene A dos Reis,
Marilda Mazzali,
Alvaro Pacheco-Silva, Niels O S Câmara
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ABSTRACT: Ischemia and reperfusion injury (IRI) contributes to the development of chronic interstitial fibrosis/tubular atrophy in renal allograft patients. Cyclooxygenase (COX) 1 and 2 actively participate in acute ischemic injury by activating endothelial cells and inducing oxidative stress. Furthermore, blockade of COX 1 and 2 has been associated with organ improvement after ischemic damage. The aim of this study was to evaluate the role of COX 1 and 2 in the development of fibrosis by performing a COX 1 and 2 blockade immediately before IRI. We subjected C57Bl/6 male mice to 60 min of unilateral renal pedicle occlusion. Prior to surgery mice were either treated with indomethacin (IMT) at days -1 and 0 or were untreated. Blood and kidney samples were collected 6 wks after IRI. Kidney samples were analyzed by real-time reverse transcription-polymerase chain reaction for expression of transforming growth factor beta (TGF-beta), monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta, IL-10, heme oxygenase 1 (HO-1), vimentin, connective-tissue growth factor (CTGF), collagen I, and bone morphogenic protein 7 (BMP-7). To assess tissue fibrosis we performed morphometric analyses and Sirius red staining. We also performed immunohistochemical analysis of anti-actin smooth muscle. Renal function did not significantly differ between groups. Animals pretreated with IMT showed significantly less interstitial fibrosis than nontreated animals. Gene transcript analyses showed decreased expression of TGF-beta, MCP-1, TNF-alpha, IL-1-beta, vimentin, collagen I, CTGF, and IL-10 mRNA (all P < 0.05). Moreover, HO-1 mRNA was increased in animals pretreated with IMT (P < 0.05). Conversely, IMT treatment decreased osteopontin expression and enhanced BMP-7 expression, although these levels did not reach statistical significance when compared with control expression levels. The blockade of COX 1 and 2 resulted in less tissue fibrosis, which was associated with a decrease in proinflammatory cytokines and enhancement of the protective cellular response.
Molecular Medicine 08/2008; 14(11-12):724-30. · 3.76 Impact Factor
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ABSTRACT: Previously we have demonstrated that bradykinin B1 receptor deficient mice (B1KO) were protected against renal ischemia and reperfusion injury (IRI). Here, we aimed to analyze the effect of B1 antagonism on renal IRI and to study whether B1R knockout or antagonism could modulate the renal expression of pro and anti-inflammatory molecules. To this end, mice were subjected to 45 minutes ischemia and reperfused at 4, 24, 48 and 120 hours. Wild-type mice were treated intra-peritoneally with antagonists of either B1 (R-954, 200 microg/kg) or B2 receptor (HOE140, 200 microg/kg) 30 minutes prior to ischemia. Blood samples were collected to ascertain serum creatinine level, and kidneys were harvested for gene transcript analyses by real-time PCR. Herein, B1R antagonism (R-954) was able to decrease serum creatinine levels, whereas B2R antagonism had no effect. The protection seen under B1R deletion or antagonism was associated with an increased expression of GATA-3, IL-4 and IL-10 and a decreased T-bet and IL-1beta transcription. Moreover, treatment with R-954 resulted in lower MCP-1, and higher HO-1 expression. Our results demonstrated that bradykinin B1R antagonism is beneficial in renal IRI.
PLoS ONE 02/2008; 3(8):e3050. · 4.09 Impact Factor
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PLoS ONE 02/2008; 3(9). · 4.09 Impact Factor
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ABSTRACT: Tim-3 was recently described as a Th1-specific molecule, participating in the regulation of immune responses and in the induction of allograft tolerance. Here, we studied Tim-3 mRNA expression together with molecular markers of T-cell activation and cytotoxicity, in rejected human kidney grafts.
Twenty human kidney grafts that had undergone nephrectomy due to an irreversible acute rejection episode were studied. We quantified intragraft expression of Tim-3, granzyme B, perforin, IFN-gamma and Fas-ligand mRNA by real-time RT-PCR, with probes and primers TaqMan. Protocol biopsies were studied as controls. Statistical analyses were performed to compare groups, and to investigate the potential association with gene transcripts measures and rejection.
All molecules studied were up-regulated in the rejection group compared with controls (p<0.001). Acute rejection type III (Banff 97) profiles were associated with higher values, where granzyme B and perforin presented the highest (5672.51+/-9002.16 and 1866.59+/-2426.38, respectively) and Tim-3 had the lowest ones (166.62+/-174.94). Tim-3 had also a lower expression in those patients that did not respond to anti-rejection therapy. There was a positive correlation between Tim-3 and IFN-gamma mRNA expression levels (r(2)=0.73; p<0.001).
Our results corroborate the concept that acute rejection is an active process, where inflammatory as well as regulatory factors have their roles. Severe episodes of acute rejection were associated with higher expression of cytotoxic molecules and lower expression of potential regulatory molecule.
Transplant Immunology 04/2007; 17(3):215-22. · 1.46 Impact Factor
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ABSTRACT: Ischemia-reperfusion injury (IRI) is a common event in organ transplantation, being implicated as a potential contributor for the development of chronic allograft nephropathy. There are new evidences showing a tissue inflammatory response following renal IRI. Cyclooxygenases (COX) 1 and 2 can be detected in tissue submitted to IRI and may have impact on organ function outcome. We evaluated the role of COX inhibition on the renal tissue damage that follows IRI. Mice were submitted to 45 min of renal pedicle ligature and allowed to reperfuse for 24, 48, 72 and 120 h. Blood and kidney samples were collected at reperfusion times. mRNA was extracted from the kidney samples to amplify COX-1, COX-2 and beta-actin genes. Animals were pretreated with indomethacin or rofecoxib before the surgery. Indomethacin treatment induced a better renal function (serum urea) when compared to control animals at 24, 48 and 72 h (219+/-54.5 vs. 338+/-51 mg/dl; 106+/-51 vs. 326+/-86 mg/dl; 94+/-14 vs. 138+/-38 mg/dl, respectively). Surprisingly, rofecoxib use was associated with even better renal improvement following IR. Animals treated with the later drug showed lower urea values at 24 h post reperfusion compared to indomethacin-treated animals (128+/-33 vs. 219+/-54.5 mg/dl, P<0.05). Blockade of COX-1 and -2 resulted in a decrease of tubular necrosis. mRNA COX-2 was up-regulated post IRI and considerable inhibited after indomethacin or rofecoxib treatment. Our data show COX-1/-2 participates in the inflammatory tissue response to IR injury and its inhibition is associated with an improvement in renal function.
International Immunopharmacology 02/2005; 5(1):79-84. · 2.38 Impact Factor
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ABSTRACT: Cytomegalovirus (CMV) infection is highly prevalent in transplant patients, especially in those submitted to a more intense immunosuppression. We monitored CMV infection in 34 patients during 60 days after antilymphocyte therapy without CMV prophylaxis. Six patients received sirolimus and 28 received no sirolimus as immunosuppression. During 60 days of follow-up time, 24/28 (86%) patients who did not use sirolimus developed CMV infection at a mean time of 32.43+/-13.67 days after antilymphocyte treatment. In contrast, no patient on sirolimus had CMV infection during the same follow-up (p<0.001). During a further 4-month follow-up, six patients on sirolimus-free therapy had recurrence of CMV, 46.5+/-18.5 days after the first episode. During this same period, one patient receiving sirolimus had one positive cell for CMV antigenemia, 169 days after antilymphocyte therapy. In conclusion, the use of sirolimus significantly reduced the incidence of CMV infection in patients treated with antilymphocyte antibodies.
International Immunopharmacology 02/2005; 5(1):103-6. · 2.38 Impact Factor
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ABSTRACT: Chronic allograft nephropathy is the major cause of graft loss after the first year of transplantation. Although many conditions are associated with its development, there is no method that can anticipate its risk in patients with good renal function.
We prospectively studied 92 renal-transplant recipients with good and stable allograft function and correlated the development of chronic allograft nephropathy and graft loss with their levels of urinary retinol binding protein (uRBP). Patients were divided in two groups regarding the level of their tubular protein: high, above 0.400 mg/L, and normal levels, 0.400 mg/L or less.
Forty-eight (52%) patients had high levels of uRBP. At the enrollment time, patients with high and normal uRBP had comparable serum creatinine and cyclosporine trough levels. During a 5-year follow-up period, chronic allograft nephropathy was detected in 23 (25%) patients, 19 (82.6%) of whom had high levels of uRBP. Five-year chronic allograft nephropathy-free and graft survivals were significantly worse in patients with higher levels of uRBP than in patients with normal levels (57.5% vs. 89.9% P=0.0004; 70.7% vs. 100%, respectively, P=0.0002). High levels of uRBP were the strongest factor associated with the development of chronic allograft nephropathy (RR=5.3, 95% confidence interval 1.45-19.58, P=0.012).
Among renal-transplant patients with good and stable graft function, high levels of uRBP identify those having a high risk of developing chronic allograft nephropathy.
Transplantation 08/2004; 78(2):269-75. · 4.00 Impact Factor
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ABSTRACT: Little data are available concerning post-transplantation glomerulonephritis (PTx-GN) and its prognostic factors associated with graft outcomes.
We retrospectively evaluated patients with de novo and recurrent PTx-GN to identify the factors associated with their negative impact on graft and patient outcomes. PTx-GN was diagnosed in 55 patients, wherein 17 (31%) had recurrent glomerulonephritis (GN) and 16 (29%) had de novo.
Our enrolled population consisted of 34 +/- 13.7-yr-old male patients (72%), on hemodialysis for a median of 18 months (0-204) and mainly grafted from living donors (76%). The median onset time of proteinuria and hematuria was 50 d (10-2160) and 30 d (4-1170), respectively. One-yr graft survival rates after PTx-GN diagnosis was 64%. The most frequent de novo GN was membranous GN (26%), while focal segmental glomerulosclerosis was the most frequent recurrent GN (41%), with a very early onset (median of three months). One-yr graft survival was better in the recurrent disease than in the de novo patients, 76% vs. 55% (p = 0.24). The best predictor factors that correlated with graft survival were: proteinuria <3.5 g [relative risk (RR) = 0.24, p = 0.017], serum creatinine below 2.0 mg/dL (RR = 0.06, p = 0.016) at the time of biopsy and the use of angiotensin-converting enzyme inhibitors (ACEI) (RR = 0.12, p = 0.005). The use of ACEI markedly improved one-yr graft survival rates (92% vs. 47%, p < 0.001).
PTx-GN has a strong negative impact on kidney graft survival. De novo GN appears to have a poorer prognosis than the recurrent type. Patients who used ACEI showed a better survival rate in the follow-up.
Clinical Transplantation 21(3):363-70. · 1.67 Impact Factor
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ABSTRACT: Renal ischemia and reperfusion injury (IRI) is considered an inflammatory syndrome. To move forward in its pathogenesis, we exploited the role of several cytokines on renal damages triggered by IRI. Specifically to evaluate the role of Th1 immune profile in this system, IL-12, IFN-γ, and IFN-γ/IL-12 deficient (KO) mice on C57BL/6 background and their controls were subjected to IRI. In each group, blood and kidney samples were harvested. Renal function was evaluated by serum creatinine and renal morphometric analyses. Gene expression of IL-6 and HO-1 were also investigated by Q-PCR. IFN-γ KO animals presented the highest impairment in renal function compared to controls. Conversely, IL-12 KO animals were absolutely protected and, in a lesser extent, IFN-γ/IL-12 KO double knockout was also protected from IRI. Gene expression analyses showed higher expression of HO-1, a cytoprotective gene, and IL-6, a pro-inflammatory cytokine, in IFN-γ deficient animals subjected to IRI. Our results confirm that Th1 related cytokines such as IL-12 and IFN-γ are critically involved in renal ischemia and reperfusion injury.
International Immunopharmacology.
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