Elevated urinary kidney injury molecule 1 at discharge strongly predicts early mortality following an episode of acute decompensated heart failure.

INTRODUCTION: Hospitalization for acute decompensation of heart failure (ADHF) is a frequent event associated with long­term adverse effects. Prognosis is even worse if acute kidney injury (AKI) occurs during hospitalization. OBJECTIVES: The study aimed to determine whether kidney damage biomarkers neutrophil gelatinase­associatedlipocalin (NGAL), kidney injury molecule 1 (KIM­1), and interleukin18 (IL­18) might predict AKI and have prognostic value in ADHF. PATIENTS AND METHODS: Serum NGAL on admission and urine NGAL, KIM­1, and IL­18 on discharge were determined in 187 ADHF patients enrolled in a prospective, observational, unblinded study. AKI was diagnosed using the Kidney Disease: Improving Global Outcomes criteria. Patients were followedfor 12 months to record all­cause mortality. RESULTS: A total of 22% patients died during the follow­up, with 52.5% dying within 4 months after discharge. Serum NGAL (P <0.001), urine NGAL (P = 0.047), and urinary KIM­1 (P = 0.014) levels were significantly higher in the deceased patients at discharge. After adjustment for estimated glomerular filtration rate (eGFR), only urinary KIM­1 independently predicted mortality at month 4 (hazard ratio [HR], 3.166; 95% CI, 1.203-8.334; P = 0.020) and month 12 (HR, 1.969; 95% CI, 1.123-3.454; P = 0.018) in Cox regression models. In receiver operating characteristic (ROC) analysis urinary KIM­1 (area under the ROC curve [AUC] = 0.830) outperformed other markers of renal function. The Kaplan-Meier survival analysis showed KIM­1 predictive value as additive to that of AKI incidence and admission eGFR. Admission serum NGAL was higher in AKI patients (P ≤0.001) with a modest diagnostic performance (AUC = 0.667), below that of urea (AUC = 0.732), creatinine (AUC = 0.696), or cystatin C (AUC = 0.676). CONCLUSIONS: Discharge urinary KIM­1 was a strong and independent predictor of mortality, particularly during the most vulnerable period shortly after hospitalization. Admission serum NGAL was inferior to conventional renal function parameters in predicting AKI during ADHF.

Caloric restriction or telmisartan control dyslipidemia and nephropathy in obese diabetic Zücker rats.

BACKGROUND: The obese Zücker diabetic fatty male rat (ZDF:Gmi™-fa) is an animal model of type II diabetes associated with obesity and related metabolic disturbances like dyslipidaemia and diabetic nephropathy. In addition, diabetic dyslipidaemia has been linked to vascular and glomerular damage too. Dietary fat restriction is a current strategy to tackle obesity and, telmisartan, as a renoprotective agent, may mediate cholesterol efflux by activating PPARγ. To test the hypothesis that both therapeutical alternatives may influence dyslipidaemia and nephropathy in the ZDF rat, we studied their effect on development of diabetes. METHODS: Male Zücker Diabetic Fatty (ZDF) rats received a low-calorie diet, vehicle or telmisartan for 9 weeks. Blood samples were obtained for analyses of lipids and lipoproteins, LDL-oxidisability, HDL structural and functional properties. Urinalysis was carried out to estimate albumin loss. At the end of the experimental period, rats were sacrificed, liver extracted and APOA1 mRNA quantified. RESULTS: Results indicated that low-calorie diet and telmisartan can slower the onset of overt hyperglycaemia and renal damage assessed as albuminuria. Both interventions decreased the oxidative susceptibility of LDL and hepatic APOA1 mRNA expression but only dietary restriction lowered hyperlipidaemia. CONCLUSION: Either a dietary or pharmacologic interventions with telmisartan have important beneficial effects in terms of LDL oxidative susceptibility and progression of albuminuria in obesity related type II diabetes.

Selection of reference genes for gene expression studies in rats.

Selection of the most stable reference gene is critical for a reliable interpretation of gene expression data using RT-PCR. In order so, 17 commonly used genes were analyzed in Wistar rat duodenum, jejunum, ileum and liver following a fat gavage and at two time periods. These reference genes were also tested in liver from Zucker (fa/fa) on a long-term dietary trial. Four strategies were used to select the most suitable reference gene for each tissue: ranking according to biological coefficient of variation and further validation by statistical comparison among groups, geNorm, NormFinder and BestKeeper programs. No agreement was observed among these approaches for a particular gene, nor a common gene for all tissues. Furthermore we demonstrated that normalising using an inadequate reference conveyed into false negative and positive results. The selection of genes provided by BestKeeper resulted in more reliable results than the other statistical packages. According to this program, Tbp, Ubc, Hprt and Rn18s were the best reference genes for duodenum, jejunum, ileum and liver, respectively following a fat gavage in Wistar rats and Rn18s for liver in another rat strain on a long-term dietary intervention. Therefore, BestKeeper is highly recommendable to select the most stable gene to be used as internal standard and the selection of a specific reference expression gene requires a validation for each tissue and experimental design.

Hemoglobin variability in nondialysis chronic kidney disease: examining the association with mortality.

BACKGROUND AND OBJECTIVES: Anemia and hemoglobin (Hb) variability are associated with mortality in hemodialysis patients who are on erythropoiesis-stimulating agents (ESA). Our aim was to describe the degree of Hb variability present in nondialysis patients with chronic kidney disease (CKD), including those who were not receiving ESA, and to investigate the association between Hb variability and mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Hb variability was determined using 6 mo of "baseline" data between January 1, 2003, and October 31, 2005. A variety of definitions for Hb variability were examined to ensure consistency and robustness. RESULTS: A total of 6165 patients from 22 centers in seven countries were followed for a mean of 34.0 +/- 15.8 mo; 49% were prescribed an ESA. There was increased Hb variability with ESA use; the residual SD of Hb was 4.9 +/- 4.4 g/L in patients who were not receiving an ESA, compared with 6.8 +/- 4.8 g/L. Hb variability was associated with a small but significantly increased risk for death per g/L residual SD, irrespective of ESA use. Multivariate linear regression model explained only 11% of the total variance of Hb variability. CONCLUSIONS: Hb variability is increased in patients who have CKD and are receiving ESA and is associated with an increased risk for death (even in those who are not receiving ESAs). This analysis cannot determine whether Hb variability causally affects mortality. Thus, the concept of targeting Hb variability with specific agents needs to be examined within the context of factors that affect both Hb variability and mortality.

Association between cytokine gene polymorphisms and outcomes in renal transplantation: a meta-analysis of individual patient data.

BACKGROUND: Cytokine gene polymorphisms have been associated with poor outcomes after renal transplantation such as chronic allograft nephropathy (CAN), graft rejection (GR) and graft failure (GF), but the effects of these polymorphisms are still controversial. We therefore conducted a systematic review, with individual patient data (IPD) where possible, to determine the association between cytokine polymorphisms (TGF-beta1, TNF-alpha and IL-10) and outcomes after renal transplantation. METHODS: Five investigators were willing to participate and provided IPD. The outcomes of interest were GF, GR and CAN. Subjects with at least one of these were classified as having poor outcomes. Heterogeneity of gene effects was assessed. Multiple logistic regression was applied to assess gene effects, adjusting for clinical variables such as HLA matching and age. RESULTS: One-thousand and eighty-seven subjects were included in the IPD meta-analysis. Pooled results showed no evidence of heterogeneity and indicated that the strongest variables determining poor outcomes are HLA mismatching (OR = 1.6-1.8 for >/=3 HLA-A, -B, -DR mismatches compared with those with <3 mismatches) and age (OR = 1.2-1.4 for age 45 years or more). Incremental information on risk of a poor outcome is provided by the TGF-beta1c10 polymorphism (OR = 1.5, P = 0.034, 95% CI: 1.0-2.2 for TC genotype compared to TT genotype). Haplotypes of TGF-beta1 at c10 and c25 were inferred and the C-C haplotype was a marker of a poor outcome (OR = 1.3, P = 0.177, 95% CI: 1.0-2.3). Three polymorphisms of the IL-10 gene at -1082, -819, -592 are in strong linkage disequilibrium with each other (correlation coefficients: 0.6-1) and inferred haplotypes between these three loci show some association, with ACC increasing the risk of poor events compared to GCC (OR = 1.3, P = 0.044, 95% CI: 0.9-1.6). CONCLUSION: Pooled results to date suggest possible association between both the TGF-beta1 c10 polymorphism and a 3-SNP-haplotype of IL-10 and poor outcomes in renal transplantation, but this needs to be confirmed in larger studies.

Association of TGF-beta1 polymorphisms with chronic renal disease.

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) plays an important role in tissue fibrosis and has been found to participate in cardiovascular disease (CVD). This study aimed to evaluate the association of TGF-beta1 polymorphisms with chronic renal disease (CRD), and its progression to dialysis in a retrospective longitudinal study of an end-stage renal disease (ESRD) cohort. METHODS: The Arg/Pro (codon 25) and Leu/Pro (codon 10) polymorphisms were genotyped in 104 ESRD patients aged 64 +/- 14 yrs (mean +/- SD), 62 males, and in 104 matched controls. RESULTS: The genotype distribution of Leu10Pro and Arg25Pro polymorphisms was different between patients and controls: Leu/Leu, Leu/Pro, Pro/Pro: 0.35, 0.50, 0.15 vs. 0.30, 0.24, 0.46 (p=0.001) and Arg/Arg, Arg/Pro, Pro/Pro: 0.79, 0.21, 0 vs. 0.87, 0.10, 0.03 (p=0.019). Similarly, haplotypes constructed with the combination of both polymorphisms were different among groups. There were no differences in CRD progression rate among genotypes. Codon 10 Leu allele was associated with the presence of clinical CVD in the ESRD patients (Leu/Leu, Leu/Pro, Pro/Pro: with CVD 0.49, 0.49, 0.02 vs. without CVD 0.27, 0.51, 0.22 (p=0.01). Combined polymorphism haplotypes were also significantly different between ESRD patients with and without CVD. This association was independent from other risk factors. CONCLUSIONS: TGF-beta1 polymorphisms are associated with ESRD, particularly in patients with associated clinical CVD, and could be useful as genetic markers of CRD and higher cardiovascular risk.

Retrievability of uncoated versus paclitaxel-coated Günther-Tulip IVC filters in an animal model.

PURPOSE: To compare in a pilot study, the retrievability and inferior vena cava (IVC) wall reaction elicited by uncoated and paclitaxel-coated Günther-Tulip filters in the animal model. MATERIALS AND METHODS: Three groups with five pigs each underwent infrarenal IVC implantation of Günther-Tulip filters. Paclitaxel-coated filters were used in Groups A and B and uncoated filters were used in Group C. Filters were removed at 14, 19, 22, 26, and 30 days after implantation. A laparotomy was performed to remove filters from animals in group A and filters from animals in groups B and C that could not be retrieved via the right transjugular approach. Filter-induced venous wall changes were evaluated by examination of IVC venography, feasibility of filter removal at different implantation times, and laparotomy and microscopic findings. Feasibility of filter retrieval and venous wall changes were correlated. RESULTS: IVC cavography showed no abnormality. Filters in animals in group B were uneventfully removed by a right jugular approach. Uncoated filter removal was not feasible in three of five animals in group C (19, 22, and 26 days). Microscopically, animals in group A had absent filter-induced IVC wall changes at 14, 19, 22, and 26 days and minimal changes at 30 days post implantation; animals in group B had absent filter-induced IVC wall changes at 14, 19, and 22 days and minimal changes at 26 and 30 days; animals in group C had moderate filter-induced IVC wall changes at 14 days and severe changes at 19, 22, 26, and 30 days. CONCLUSIONS: This pilot study suggests that endothelial reaction to the presence of IVC filters in the porcine model is diminished by addition of paclitaxel coating to these filters. Further studies are necessary to substantiate these results.

Renoprotective effects of losartan in renal transplant recipients. Results of a retrospective study.

BACKGROUND/AIMS: Chronic allograft nephropathy is the main cause of late graft loss and nonimmunological factors, including hypertension and proteinuria, the principal etiological factors. In this context, blockage of the renin-angiotensin system could be helpful. The aim of the present study was to review the renoprotective efficacy of losartan in a large group of renal transplant patients undergoing long-term follow-up. METHODS: A retrospective analysis of 276 renal transplant patients treated with losartan was performed. The indication for losartan was arterial hypertension in 163 patients, proteinuria in 37 patients and hypertension plus proteinuria in the remaining 76 patients. Clinical and biochemical parameters before starting losartan treatment (-6 months, -3 months and at baseline) and 3, 6, 9, 12, 18 and 24 months after the introduction of losartan were analyzed. RESULTS: Arterial hypertension significantly decreased after the introduction of losartan (p = 0.000). Serum creatinine was significantly decreased by losartan therapy, and changes in the serum creatinine slope (1/sCr) before and after losartan were statistically significant. Proteinuria markedly decreased after the introduction of losartan. Clinical and biochemical tolerance of losartan was excellent in most patients and only 9 out of the 276 patients (3%) treated with losartan discontinued the drug because of an adverse event. During follow-up, only 3 patients required substitutive treatment with dialysis due to progressive deterioration of renal function in the context of chronic allograft nephropathy. CONCLUSION: Losartan demonstrated high efficacy as a renoprotective agent in renal transplant patients and could be useful in the treatment and prevention of chronic allograft nephropathy.

Expression of transforming growth factor-beta1 and hypoxia-inducible factor-1alpha in an experimental model of kidney transplantation.

BACKGROUND: Ischemia-reperfusion syndrome has been recognized as an important pathogenic factor in renal transplantation, not only in the development of delayed graft function but also in the development of acute and chronic rejection. Hypoxia-inducible factor (HIF)-1 activates transcription of several genes implicated in cell survival, such as vascular endothelial growth factor (VEGF), and in tissue repair transforming growth factor (TGF)-beta. The purpose of this study was to characterize TGF-beta1, VEGF, and HIF-1alpha expression profiles during renal transplantation with heart-beating donors (HBD) and non-heart-beating donors (NHBD). METHODS: An experimental model of renal transplantation using 40 pairs of large, white, Landrace pigs and including HBD and NHBD was used. Cold-ischemia time was the same in all groups (6 hr), and three groups of NHBD (30, 45, and 90 min) were studied. Immunosuppressive therapy consisted of cyclosporine, except in one HBD group, which was treated with azathioprine. TGF-beta1, VEGF, and HIF-1alpha expression profiles were performed in renal biopsies obtained at different times: after anesthetic induction (basal); 30, 45, and 90 min after warm ischemia; after cold ischemia; 1 hr after reperfusion; and 5 days after transplantation. RESULTS: TGF-beta1 expression increased after cold ischemia in HBD and remained unaltered during the surgical process in all NHBD groups. HIF-1alpha and VEGF expression were not greatly modified during surgery in the HBD or NHBD groups. All groups showed a significant increase in TGF-beta1 and HIF-1alpha expression as well as down-regulation of VEGF 5 days after transplantation, and these effects were independent of immunosuppressive treatment. There were no statistically significant differences among the groups at 5 days after transplantation, although the increase in TGF-beta1 was more pronounced in the HBD groups, especially in azathioprine-treated animals. CONCLUSIONS: The initial up-regulation of TGF-beta1 observed in HBD immediately after cold ischemia could have a positive effect on epithelial-tubular regeneration. Warm ischemia has a detrimental effect on TGF-beta1 expression during the early phases of renal transplantation and has no effect on VEGF and HIF-1alpha expression. The up-regulation of TGF-beta1 and HIF-1alpha observed after transplantation could have a positive effect on tubular repair. TGF-beta1 expression was lower in animals treated with cyclosporine, probably because of cellular toxicity.

Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis.

Transforming growth factor-beta1 (TGF-beta1) is a cytokine that plays a key role in the development of idiopathic pulmonary fibrosis. There have been reports on the presence of two genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta1 protein, located in codons 10 and 25. The objective of this study was to investigate the association between TGF-beta1 gene polymorphisms in codons 10 and 25 and the susceptibility to idiopathic pulmonary fibrosis and the progression of the disease. Compared with healthy control subjects (n = 140), patients with idiopathic pulmonary fibrosis (n = 128) showed no significant deviations in genotype or allele frequencies. One hundred and ten patients with idiopathic pulmonary fibrosis were followed up for 30.3 +/- 25 months. The presence of a proline allele at codon 10 was independently associated with a significant increase in alveolar arterial oxygen tension difference during follow-up, after controlling for the effect of treatment (coefficient = 0.59; 95% confidence intervals, 0.23 to 0.96; p = 0.002). These findings suggest that (1) TGF-beta1 gene polymorphisms in codons 10 and 25 do not predispose to the development of idiopathic pulmonary fibrosis; and (2) TGF-beta1 gene polymorphisms may affect disease progression in patients with idiopathic pulmonary fibrosis.

Role of ribavirin in membranoproliferative glomerulonephritis associated with hepatitis C virus infection refractory to alpha-interferon.

Chronic hepatitis C virus (HCV) has been associated with several extrahepatic diseases, such as membranoproliferative glomerulonephritis (MPGN). alpha-Interferon is currently the treatment of choice for this association. When this therapy fails clinicians face a difficult challenge due to the lack of useful information in these particularly difficult patients. We report the case of a severe nephrotic syndrome due to MPGN associated HCV infection, in which a triple association--interferon plus ribavirin and cyclophosphamide--was needed to control the disease.

Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients.

Hypertension and hyperfiltration are two important risk factors for the development of chronic allograft nephropathy. Transforming growth factor-beta(1) (TGF-beta(1)) is the main cytokine involved in the fibrotic process that is involved in chronic rejection. Angiotensin II upregulates TGF-beta(1) production. Angiotensin II receptor antagonists therefore could not only control BP but also reduce TGF-beta(1) production in renal transplant patients. The aim of this study was to compare the effects of losartan and amlodipine on renal hemodynamics, as well as TGF-beta(1) and endothelin-1 (ET-1) plasma levels in a group of renal transplant patients who had normal renal function and who were treated with cyclosporine. Seventeen renal transplant patients who were receiving cyclosporine and who had normal graft function were included in a random 2 x 2 crossover trial with amlodipine and losartan (6 wk with each therapy). Three studies were performed (at baseline and at the end of both treatment periods) to determine renal hemodynamics, TGF-beta(1), and ET-1. Both treatments controlled BP to a similar degree, but only amlodipine increased GFR through an increase in the estimated glomerular hydrostatic pressure and filtration fraction. In contrast, losartan maintained GFR and reduced estimated glomerular hydrostatic pressure and filtration fraction significantly. Losartan and amlodipine had opposite effects on TGF-beta(1). Amlodipine did not affect TGF-beta(1) concentrations. In contrast, losartan reduced the plasma levels of TGF-beta(1) by approximately by 50% (from baseline, 5.2 to 2.6 ng/ml; P: = 0.01); the majority of the patients reached normal levels of TGF-beta(1). ET-1 concentrations were significantly higher during amlodipine compared with losartan treatment. The present study documents that with similar control of BP, losartan and amlodipine have opposite effects on renal hemodynamics and on TGF-beta1 concentrations. These differences could be important for the management of chronic allograft nephropathy.