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ABSTRACT: Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. Despite the proven efficacy of RAAS blockade, however, the reduction in proteinuria is insufficient in many patients, and does not prevent further deterioration of renal function. Short-term studies have shown that a variety of treatment intensification strategies have a beneficial effect on blood pressure and proteinuria, including RAAS blockade using either dose escalation or multiple drugs, and restriction of dietary sodium. Large clinical trials have shown that RAAS blockade with multiple drugs does not improve patients' long-term renal or cardiovascular outcome. By contrast, two post-hoc analyses of landmark trials in nephrology show beneficial renal and cardiovascular effects from avoiding excessive dietary sodium intake during single-agent RAAS blockade therapy. The effects of dietary sodium restriction on renal or cardiovascular outcome still require prospective confirmation. However, current data support the implementation of lifestyle changes to reduce dietary sodium intake in combination with single-agent RAAS blockade, rather than dual-agent RAAS blockade, as a potent and feasible strategy to mitigate the burden of renal and cardiovascular disease in patients with CKD.
Nature Reviews Nephrology 12/2012; · 7.09 Impact Factor
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ABSTRACT: OBJECTIVE
Evidence that midregional fragment of pro-A-type natriuretic peptide (MR-proANP) is a marker of mortality in patients with type 2 diabetes is limited. Therefore, we aimed to investigate the capabilities of MR-proANP in predicting mortality. We also investigated whether MR-proANP influences the relationship between blood pressure and mortality in old age.RESEARCH DESIGN AND METHODS
In 1998, 1,143 primary care patients with type 2 diabetes participated in the ZODIAC study. Because blood was drawn for 867 patients (76%) and confounders were missing for 19 patients, the final study sample comprised 848 patients. After a follow-up time of 10 years, we used Cox proportional hazard models to evaluate the relationship between MR-proANP and (cardiovascular) mortality. Harrell C statistic was used to compare models with and without MR-proANP. The regression analyses were repeated without MR-proANP for patients aged older than 75 years.RESULTSMedian MR-proANP in the total study sample was 75 pmol/L (interquartile range, 48-124 pmol/L). During follow-up, 354 (42%) out of 848 patients had died, of whom 152 (43%) deaths were attributable to cardiovascular factors. MR-proANP was independently associated with all-cause and cardiovascular mortality, irrespective of age. During old age, there was a significant inverse relationship between blood pressure and mortality. This relationship did not change after adjustment for MR-proANP.CONCLUSIONSMR-proANP is independently associated with mortality in patients with type 2 diabetes. MR-proANP did not influence the inverse relationship between blood pressure and mortality in elderly patients.
Diabetes care 12/2012; · 8.09 Impact Factor
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ABSTRACT: During proteinuria, renal tubular epithelial cells become exposed to ultrafiltrate-derived serum proteins, including complement factors. Recently, we showed that properdin binds to tubular heparan sulfates (HS). We now document that factor H also binds to tubular HS, although to a different epitope than properdin. Factor H was present on the urinary side of renal tubular cells in proteinuric, but not in normal renal tissues and colocalized with properdin in proteinuric kidneys. Factor H dose-dependently bound to proximal tubular epithelial cells (PTEC) in vitro. Preincubation of factor H with exogenous heparin and pretreatment of PTECs with heparitinase abolished the binding to PTECs. Surface plasmon resonance experiments showed high affinity of factor H for heparin and HS (K(D) values of 32 and 93 nm, respectively). Using a library of HS-like polysaccharides, we showed that chain length and high sulfation density are the most important determinants for glycosaminoglycan-factor H interaction and clearly differ from properdin-heparinoid interaction. Coincubation of properdin and factor H did not hamper HS/heparin binding of one another, indicating recognition of different nonoverlapping epitopes on HS/heparin by factor H and properdin. Finally we showed that certain low anticoagulant heparinoids can inhibit properdin binding to tubular HS, with a minor effect on factor H binding to tubular HS. As a result, these heparinoids can control the alternative complement pathway. In conclusion, factor H and properdin interact with different HS epitopes of PTECs. These interactions can be manipulated with some low anticoagulant heparinoids, which can be important for preventing complement-derived tubular injury in proteinuric renal diseases.
Journal of Biological Chemistry 07/2012; 287(37):31471-81. · 4.77 Impact Factor
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ABSTRACT: Exogenous bilirubin has been shown to protect against oxidative stress in ischemia-reperfusion injury. Oxidative stress has been implicated in the pathophysiology of chronic transplant dysfunction leading to late graft failure after renal transplantation. We prospectively investigated whether high endogenous bilirubin is protective against development of late graft failure in renal transplant recipients (RTR). Baseline data were collected between August 2001 and July 2003 in nonicteric outpatient RTR with a functioning graft for >1 year. At baseline, bilirubin and liver enzymes were measured using routine assays on a Merck Mega analyzer. Graft failure was prospectively recorded until May 19 2009. During follow-up for 7.1 [6.2-7.2] years, 55 RTR developed graft failure. We found that circulating levels of bilirubin are inversely associated with late graft failure in RTR (HR = 0.29 [95% CI: 0.16-0.52], P < 0.001). This association was independent of potential confounders, including creatinine clearance, urinary protein excretion, calcineurin inhibitors, and gender (HR = 0.31 [95% CI: 0.15-0.62] P = 0.001). Our findings are consistent with a protective effect of increased endogenous bilirubin against development of late graft failure in RTR. If our findings are confirmed by other studies, intervention with endogenous or exogenous bilirubin may be of interest for long-term preservation of renal function in RTR.
Transplant International 06/2012; 25(8):876-81. · 2.92 Impact Factor
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ABSTRACT: Many proteinuric renal conditions are accompanied by renal inflammation. Nicotine is known to have anti-inflammatory properties and is used in oral form to help subjects quit smoking. A potential anti-inflammatory role of nicotine in proteinuric renal diseases has not been investigated to date. We therefore evaluated the effects of oral nicotine in a rat model of proteinuria-induced renal inflammation. We used a well-established model of adult (24 wk of age) male Munich-Wistar-Frömter rats. Animals were given three different physiological doses of nicotine in drinking water for 28 wk until 52 wk of age (long term). A group without nicotine served as a parallel control. At 52 wk of age, the control group had a 2.1 times reduction in creatinine clearance, 3.2 times increase in urinary protein excretion, an increased focal glomerulosclerosis (FGS) score, increased glomerular desmin deposition, decreased glomerular podocin, and a higher accumulation of macrophages and myofibroblasts compared with 24-wk-old animals. Oral treatment with nicotine dose dependently preserved renal function and halted proteinuria progression, which were independent of blood pressure reduction. It also reduced FGS, desmin deposition, podocin loss, and density of renal macrophages and myofibroblasts. Nicotine also reduced the level of gene expression of the renal inflammatory markers monocyte chemoattractant protein and vascular cell adhesion molecule-1. In conclusion, long-term oral nicotine preserved kidney function, reduced proteinuria, reduced renal inflammation, and protected progression of renal structural damage in a rat model of proteinuria. We further suggest evaluating nicotine as a potential additional therapeutic option for treating proteinuric kidney diseases.
AJP Renal Physiology 01/2012; 302(7):F895-904. · 4.42 Impact Factor
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ABSTRACT: Formation of advanced glycation endproducts (AGEs), endothelial dysfunction, and low-grade inflammation are intermediate pathways of hyperglycemia-induced vascular complications. We investigated the effect of benfotiamine on markers of these pathways in patients with type 2 diabetes and nephropathy.
Patients with type 2 diabetes and urinary albumin excretion in the high-normal and microalbuminuric range (15-300 mg/24h) were randomized to receive benfotiamine (n = 39) or placebo (n = 43). Plasma and urinary AGEs (N(ε)-(carboxymethyl) lysine [CML], N(ε)-(Carboxyethyl) lysine [CEL], and 5-hydro-5-methylimidazolone [MG-H1]) and plasma markers of endothelial dysfunction (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble intercellular adhesion molecule-1 [sICAM-1], soluble E-selectin) and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid-A [SAA], myeloperoxidase [MPO]) were measured at baseline and after 6 and 12 weeks.
Compared to placebo, benfotiamine did not result in significant reductions in plasma or urinary AGEs or plasma markers of endothelial dysfunction and low-grade inflammation.
Benfotiamine for 12 weeks did not significantly affect intermediate pathways of hyperglycemia-induced vascular complications. TRIAL REGRISTRATION: ClinicalTrials.gov NCT00565318.
PLoS ONE 01/2012; 7(7):e40427. · 4.09 Impact Factor
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Jeffrey Damman,
Julian L Kok,
Harold Snieder,
Henri G Leuvenink,
Harry van Goor,
Jan-Luuk Hillebrands,
Marcory C van Dijk,
Bouke G Hepkema,
Anna Reznichenko,
Jaap van den Born,
Martin H de Borst,
Stephan J Bakker, Gerjan J Navis,
Rutger J Ploeg,
Marc A Seelen
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ABSTRACT: In kidney transplantation, complement activation was found to be induced by donor brain death, renal ischemia-reperfusion injury and allograft rejection. There are three known pathways of complement activation: the classical, lectin and the alternative pathway. The lectin complement pathway can be activated upon pattern recognition by mannan binding lectin (MBL) or ficolins (FCN). Single nucleotide polymorphisms (SNPs) in the genes encoding the lectin pathway proteins determine their functional activity and serum levels. The aim of this study was to investigate the role of the lectin gene profile of the donor and recipient on post-transplant outcome. A total of 12 functional SNPs in the MBL2, FCN2 and MBL-associated serine proteases 2 (MASP2) genes of 1271 donor-recipient pairs were determined. Lectin genotypic variants were analyzed for association with primary non-function (PNF), delayed graft function (DGF), biopsy proven acute rejection, death-censored graft survival and patient survival. Multivariate analyses found no association of donor and recipient MBL2 and MASP2 genotype with allograft outcome. Analysis of separate functional SNPs and haplotypes in the FCN2 gene of the donor and recipient did not reveal an association with transplant outcome. Also, the joint effect of the MBL2 and FCN2 genotype was not associated with allograft outcome.This study shows that the genetic profile of the lectin pathway of complement activation of the donor and recipient is not associated with allograft outcome after kidney transplantation.
Molecular Immunology 12/2011; 50(1-2):1-8. · 2.90 Impact Factor
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ABSTRACT: The incidence of heart failure and renal failure is increasing and is associated with poor prognosis. Moreover, these conditions do often coexist and this coexistence results in worsened outcome. Various mechanisms have been proposed as an explanation of this interrelation, including changes in hemodynamics, endothelial dysfunction, inflammation, activation of renin-angiotensin-aldosterone system, and/or sympathetic nervous system. However, the exact mechanisms initializing and maintaining this interaction are still unknown. In many experimental studies on cardiac or renal dysfunction, the function of the other organ was either not addressed or the authors failed to show any decline in its function despite histological changes. There are few studies in which the dysfunction of both heart and kidney function has been described. In this review, we discuss animal models of combined cardiorenal dysfunction. We show that translation of the results from animal studies is limited, and there is a need for new and better models of the cardiorenal interaction to improve our understanding of this syndrome. Finally, we propose several requirements that a new animal model should meet to serve as a tool for studies on the cardiorenal syndrome.
Heart Failure Reviews 09/2011; 17(3):411-20. · 3.20 Impact Factor
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ABSTRACT: Ace b/l polymorphism in rats is associated with differential tissue angiotensin-converting enzyme (ACE) expression and activity, and susceptibility to renal damage. Same polymorphism was recently found in outbred Wistar rat strain with b allele accounting for higher renal ACE, and provided a model for studying renin-angiotensin-aldosterone system (RAAS) response behind the innate high or low ACE conditions.
We investigated the reaction of these alleles on chronic angiotensin II (AngII) infusion. Wistar rats were selected to breed male homozygotes for the b (WU-B) or l allele (WU-L) (n = 12). For each allele, one group (n = 6) received AngII infusion via an osmotic minipump (435 ng/kg/min) for 3 weeks. The other group (n = 6) served as a control.
WU-B had higher ACE activity at baseline then WU-L. Interestingly, baseline renal ACE2 expression and activity were higher in WU-L. AngII infusion induced the same increase in blood pressure in both genotypes, no proteinuria, but caused tubulo-interstitial renal damage with increased α-SMA and monocyte/macrophage influx only in WU-B (p < 0.05). Low ACE WU-L rats did not develop renal damage.
AngII infusion causes proteinuria-independent renal damage only in rats with genetically predetermined high ACE while rats with low ACE seemed to be protected against the detrimental effect of AngII. Differences in renal ACE2, mirroring those in ACE, might be involved.
Journal of Renin-Angiotensin-Aldosterone System 08/2011; 12(4):420-9. · 2.44 Impact Factor
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ABSTRACT: Properdin binds to proximal tubular epithelial cells (PTEC) and activates the complement system via the alternative pathway in vitro. Cellular ligands for properdin in the kidney have not yet been identified. Because properdin interacts with solid-phase heparin, we investigated whether heparan sulfate proteoglycans (HSPG) could be the physiological ligands of properdin. Kidneys from proteinuric rats showed colocalization of syndecan-1, a major epithelial HSPG, and properdin in the apical membranes of PTEC, which was not seen in control renal tissue. In vitro, PTEC did not constitutively express properdin. However, exogenous properdin binds to these cells in a dose-dependent fashion. Properdin binding was prevented by heparitinase pretreatment of the cells and was dose-dependently inhibited by exogenous heparin. ELISA and surface plasmon resonance spectroscopy (BIAcore) showed a strong dose-dependent interaction between heparan sulfate (HS) and properdin (K(d) = 128 nm). Pretreatment of HSPG with heparitinase abolished this interaction in ELISA. Competition assays, using a library of HS-like polysaccharides, showed that sulfation pattern, chain length, and backbone composition determine the interaction of properdin with glycosaminoglycans. Interestingly, two nonanticoagulant heparin derivatives inhibited properdin-HS interaction in ELISA and BIAcore. Incubation of PTEC with human serum as complement source led to complement activation and deposition of C3 on the cells. This C3 deposition is dependent on the binding of properdin to HS as shown by heparitinase pretreatment of the cells. Our data identify tubular HS as a novel docking platform for alternative pathway activation via properdin, which might play a role in proteinuric renal damage. Our study also suggests nonanticoagulant heparinoids may provide renoprotection in complement-dependent renal diseases.
Journal of Biological Chemistry 02/2011; 286(7):5359-67. · 4.77 Impact Factor
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ABSTRACT: Nephrotic syndrome (NS) is a well-known risk factor for venous thromboembolism (VTE), however preventive measures are not routinely taken. In non-renal populations, statins are associated with lower risk of VTE. Hence, we set up this single-center retrospective cohort study to assess whether statin use influenced VTE risk in NS subjects.
We analyzed 289 consecutive patients with NS (defined by proteinuria ≥ 3.5 g/day) who were aged >18 years at the study entry and followed for at least 6 months. Use of statins and concomitant medication were determined.
Of patients with NS (59% men; mean age, 42 years), 48% used statins for at least 1 month during NS. Using univariate and time-dependent Cox regression analyses, hazard ratio for VTE in statin users versus non-users was 0.2 (95%CI, 0.1-0.7) and 0.6 (95% CI, 0.2 -2.0), respectively. Adjustments for potential confounders did not change outcomes. Three VTE events occurred in a total of 812 statin-years, corresponding to an annual incidence of 0.37% (95%CI, 0.12-1.15). In contrast, 17 VTE occurred in a total of 2106 patient-years without statin exposure, annual incidence 0.81% (95%CI, 0.50-1.30).
Although statistically significant, the hazard ratio of 0.2 for VTE risk in statin users versus non-users could have been biased, but the time-dependent hazard ratio of 0.6 was probably not. As the association was in the same direction for both analyses, we conclude that statin use is associated with a lower risk of VTE in patients with NS.
Thrombosis Research 01/2011; 127(5):395-9. · 2.44 Impact Factor
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Alaa Alkhalaf,
Astrid Klooster,
Willem van Oeveren,
Ulrike Achenbach,
Nanne Kleefstra,
Robbert J Slingerland,
G Sophie Mijnhout,
Henk J G Bilo,
Reinold O B Gans, Gerjan J Navis,
Stephan J L Bakker
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ABSTRACT: To investigate the effect of benfotiamine on urinary albumin excretion (UAE) and the tubular damage marker kidney injury molecule-1 (KIM-1) in patients with type 2 diabetes and nephropathy.
Patients with type 2 diabetes and UAE equivalent to 15-300 mg/24 h, despite ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), were randomly assigned to 12 weeks of benfotiamine (900 mg/day) (n = 39) or placebo (n = 43).
Compared with placebo, benfotiamine treatment resulted in significant improvement of thiamine status (P < 0.001). Benfotiamine treatment did not significantly decrease 24-h UAE or 24-h KIM-1 excretion.
In patients with type 2 diabetes and nephropathy, high-dose benfotiamine treatment for 12 weeks in addition to ACE-Is or ARBs did not reduce UAE or KIM-1 excretion, despite improvement of thiamine status.
Diabetes care 04/2010; 33(7):1598-601. · 8.09 Impact Factor
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David M Maahs,
Justyna Siwy,
Angel Argilés,
Marie Cerna,
Christian Delles,
Anna F Dominiczak,
Nathalie Gayrard,
Alexander Iphöfer,
Lothar Jänsch,
George Jerums, [......],
Kasper Rossing,
Peter Rossing,
Ivan Rychlík,
Eric Schiffer,
Roland E Schmieder,
Thomas C Wascher,
Brigitte M Winklhofer-Roob,
Lukas U Zimmerli,
Petra Zürbig,
Janet K Snell-Bergeon
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ABSTRACT: The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).
Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92-95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81-94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81-88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed.
These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling.
PLoS ONE 01/2010; 5(9). · 4.09 Impact Factor
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Alaa Alkhalaf,
Petra Zürbig,
Stephan J L Bakker,
Henk J G Bilo,
Marie Cerna,
Christine Fischer,
Sebastian Fuchs,
Bart Janssen,
Karel Medek,
Harald Mischak,
Johannes M Roob,
Kasper Rossing,
Peter Rossing,
Ivan Rychlík,
Harald Sourij,
Beate Tiran,
Brigitte M Winklhofer-Roob, Gerjan J Navis
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ABSTRACT: Urine proteome analysis is rapidly emerging as a tool for diagnosis and prognosis in disease states. For diagnosis of diabetic nephropathy (DN), urinary proteome analysis was successfully applied in a pilot study. The validity of the previously established proteomic biomarkers with respect to the diagnostic and prognostic potential was assessed on a separate set of patients recruited at three different European centers. In this case-control study of 148 Caucasian patients with diabetes mellitus type 2 and duration ≥5 years, cases of DN were defined as albuminuria >300 mg/d and diabetic retinopathy (n = 66). Controls were matched for gender and diabetes duration (n = 82).
Proteome analysis was performed blinded using high-resolution capillary electrophoresis coupled with mass spectrometry (CE-MS). Data were evaluated employing the previously developed model for DN. Upon unblinding, the model for DN showed 93.8% sensitivity and 91.4% specificity, with an AUC of 0.948 (95% CI 0.898-0.978). Of 65 previously identified peptides, 60 were significantly different between cases and controls of this study. In <10% of cases and controls classification by proteome analysis not entirely resulted in the expected clinical outcome. Analysis of patient's subsequent clinical course revealed later progression to DN in some of the false positive classified DN control patients.
These data provide the first independent confirmation that profiling of the urinary proteome by CE-MS can adequately identify subjects with DN, supporting the generalizability of this approach. The data further establish urinary collagen fragments as biomarkers for diabetes-induced renal damage that may serve as earlier and more specific biomarkers than the currently used urinary albumin.
PLoS ONE 01/2010; 5(10):e13421. · 4.09 Impact Factor
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ABSTRACT: Chronic transplant dysfunction is the leading cause of long-term renal allograft loss. One of the histologic hallmarks of chronic transplant dysfunction is transplant vasculopathy characterized by accumulation of smooth muscle cells (SMCs) in the arterial subendothelial space, leading to ischemic graft failure. Currently, no therapy is available for transplant vasculopathy, and knowledge of the origin (donor vs. recipient) of neointimal cells may contribute to develop adequate strategies.
Origin of neointimal SMCs, endothelial, and tubular cells was determined in four nephrectomy samples from male recipients transplanted with a female kidney. Recipient-derived cells were detected using X- and Y-chromosome-specific fluorescent in situ hybridization combined with immunofluorescent staining. Specificity and sensitivity of fluorescent in situ hybridization were determined with corresponding controls.
No Y-chromosome-positive cells were detected in the female to female graft, whereas approximately 31% of nucleated cells in male to male grafts had a detectable Y-chromosome. In female to male grafts, a recipient-derived population of neointimal alpha-smooth muscle actin-positive SMCs were detected (6%, range 3%-11%). Percentages of recipient-derived arterial endothelial cells, glomerular endothelial cells, and tubular epithelial cells were 14% (range 4%-32%), 19% (range 7%-31%) and 3% (range 2%-5%), respectively.
Both donor- and recipient-derived cells contribute to vascular remodeling in clinical renal transplantation. The presence of alpha-smooth muscle actin in donor- and recipient-derived cells supports a constructive role for these cells in neointimal formation. However, the predominance of donor-derived cells in the neointima points to these cells as the likely therapeutic target.
Transplantation 12/2009; 88(12):1386-92. · 4.00 Impact Factor
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ABSTRACT: Differential renal expression of a homolog of the angiotensin-converting enzyme (ACE), that is, ACE2, has been implicated as a genetic basis of polygenetic hypertension in the stroke-prone spontaneously hypertensive rat model. However, data on the role of ACE2 in hypertension are still inconclusive. Therefore, we analyzed kidney ACE2 mRNA, ACE2 protein and ACE2 enzyme activities in the adult polygenetic stroke-prone spontaneously hypertensive rat (SHRSP) and the monogenetic TGR(mREN2)27 rat models, in comparison with their normotensive reference strains, Wistar-Kyoto (WKY) and Spraque-Dawley (SD) rats, respectively. Kidney ACE2 mRNA was studied using quantitative real-time reverse transcriptase-PCR (RT-PCR) in cortex and medulla, whereas protein expression was scored semiquantitatively in detail in different renal structures using immunohistochemistry. Furthermore, total renal tissue ACE2 activity was measured using a fluorimetric assay that was specified by the ACE2 inhibitor DX600. In SHRSP and homozygous TGR(mREN2)27 rats with established hypertension, kidney ACE2 mRNA, protein and tissue ACE2 activities were not different from their respective WKY and SD reference strain, respectively. In addition, when we looked at renal localization, we found ACE2 protein to be predominantly present in glomeruli and endothelium with weak staining in distal and negative staining in proximal tubuli. Thus, our data challenge previous work that implicates ACE2 as a candidate gene for hypertension in SHRSP by reporting a significant reduction of ACE2 in the kidneys of SHRSP. Taken together, renal ACE2 is not altered in the SHRSP and TGR(mREN2)27 genetic rat models with established hypertension.
Hypertension Research 11/2009; 33(2):123-8. · 2.58 Impact Factor
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ABSTRACT: In humans, the insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene accounts for half of the variance in plasma ACE activity. The deletion allele is associated with high plasma ACE activity, cardiovascular disease, and renal disease. In rat, a similar association is found between the B and L alleles of a microsatellite marker in the ACE gene. We identified the B/L variation in the Wistar outbred rat and bred two lines homozygous for the two alleles (WU-B and WU-L). ACE activity was measured in serum, heart, kidney, and aorta homogenates. Immunohistochemistry and ACE mRNA expression were performed in heart, kidney, and aortic tissue. Aortic rings were collected and stimulated with AngI, AngII, and AngI with Lisinopril to measure ACE functional activity by vasoconstrictor response. Serum, heart, and kidney ACE activity and kidney mRNA expression were two-fold higher in WU-B. Kidney staining showed a clear difference in tubular ACE expression, with more staining in WU-B. While in aorta ACE activity and mRNA expression was twofold higher in WU-L, functional conversion of AngI was higher in WU-B, indicating either a functional difference in AngI to AngII conversion between the two alleles due to different splicing or the presence of other factors involved in the conversion that are differentially expressed as the result of differences in the ACE alleles. The newly developed WU-B and WU-L lines show tissue-specific differences in ACE expression and activity. This provides an experimental tool to study the pathophysiologic consequences of differences in ACE alleles in renal and cardiovascular disease.
Mammalian Genome 04/2009; 20(3):170-9. · 2.89 Impact Factor
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Nephrology Dialysis Transplantation 03/2009; 24(6):1708-11. · 3.40 Impact Factor
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ABSTRACT: A high sodium (HS) intake is associated to increased cardiovascular and renal risk, especially in overweight subjects. We hypothesized that abnormal sodium and fluid handling is involved, independent of hypertension or insulin resistance. Therefore, we studied the relation between BMI and sodium-induced changes in extracellular fluid volume (ECFV; distribution volume of (125)I-iothalamate) in 78 healthy men, not selected for BMI. A total of 78 subjects with a median BMI of 22.5 (range: 19.2-33.9 kg/m(2)) were studied after 1 week on a low sodium (LS) diet (50 mmol Na(+)/d) and after 1 week on HS (200 mmol Na(+)/d). The change from LS to HS resulted in an increase in ECFV of 1.2 +/- 1.8 l. Individual changes in ECFV were correlated to BMI (r = 0.361, P < 0.01). Furthermore, in response to HS, a higher BMI was associated to a higher rise in filtered load of sodium (FL(Na(+)) = [Na(+)] x GFR, r = 0.281, P < 0.05). Thus, a shift to HS leads to a larger rise in ECFV in healthy subjects with higher BMI, associated with an elevated FL(Na(+)) during HS. Although no hypertension occurred in these healthy subjects, our data provide a potential explanation for the interaction of sodium intake and BMI on cardiovascular and renal risk. Exaggerated fluid retention may be an early pathogenic factor in the cardiorenal complications of overweight.
Obesity 03/2009; 17(9):1684-8. · 4.28 Impact Factor
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Sascha Gross,
Rutger M van Ree,
Leendert H Oterdoom,
Aiko P J de Vries,
Willem J van Son,
Paul E de Jong, Gerjan J Navis,
Mike W Zuurman,
Angelika Bierhaus,
Rijk O B Gans,
Stephan J L Bakker
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ABSTRACT: Infusion of the soluble form of the receptor for advanced glycation end-products (sRAGE) was protective against atherosclerosis and nephropathy in animal models. In this study we investigated determinants of endogenous sRAGE in renal transplant recipients and whether sRAGE was associated with mortality and graft loss.
A total of 591 patients participated at a median time of 6 years after transplantation. Independent determinants of sRAGE were mycophenolate mofetil medication (beta=-0.21, P<0.001), creatinine clearance (beta=-0.15, P<0.001), BMI (beta=-0.12, P=0.003) and fasting insulin concentration (beta=-0.14, P=0.001). Low sRAGE levels were associated with a 2-3 times higher risk for mortality especially after correction for creatinine clearance (P=0.006).
A lack of sRAGE is a risk factor for mortality in renal transplant recipients. The putatively protective role of sRAGE and in particular its association with mycophenolate mofetil usage needs further investigation.
Transplantation 09/2007; 84(5):659-63. · 4.00 Impact Factor
