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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: Recent experimental findings demonstrate vascular endothelial growth factor C (VEGF-C)-mediated water-free storage of salt in the interstitium, which prevents a salt-sensitive blood pressure state. It is unknown whether this mechanism plays a role in salt homeostasis and regulation of blood pressure in humans as well. Therefore, we investigated circulating VEGF-C levels and blood pressure during different well-controlled salt intake in chronic kidney disease (CKD) patients and in healthy subjects.
In two crossover studies, non-diabetic proteinuric CKD patients (n = 32) and healthy subjects (n = 31) were treated with consecutively a low-sodium diet (LS, aim 50 mmol Na(+)/day) and a high-sodium diet (HS, aim 200 mmol Na(+)/day) in random order, during two 6-week (CKD patients) and two 1-week periods (healthy subjects).
We found that VEGF-C levels are higher during HS than during LS in CKD patients (P = 0.034) with a trend towards higher VEGF-C in healthy subjects as well (P = 0.070). In CKD patients, HS was associated with higher NT-proBNP levels (P = 0.005) and body weight (P = 0.013), consistent with extracellular volume (ECV) expansion and with higher blood pressure (P < 0.001), indicating salt sensitivity. In healthy subjects, blood pressure was not affected by dietary salt (P = 0.14), despite a rise in ECV (P = 0.023).
Our findings support a role for VEGF-C-mediated salt homeostasis in humans. Considering the salt sensitivity of blood pressure, this buffering mechanism appears to be insufficient in proteinuric CKD patients. Future studies are needed to provide causality and to substantiate the clinical and therapeutic relevance of this VEGF-C regulatory mechanism in humans.
Nephrology Dialysis Transplantation 07/2011; 27(3):978-82. · 3.40 Impact Factor
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ABSTRACT: Prevention of progressive renal function loss and its complications remains the main challenge in clinical nephrology. Although current therapeutic strategies aiming at reduction of blood pressure and proteinuria often slow down deterioration of renal function, still many patients progress to end-stage renal disease. The development of novel pharmacological approaches for treatment of chronic kidney disease (CKD) is therefore instrumental. Here we review the renoprotective potential of vitamin D and its analogues. In CKD patients, vitamin D deficiency is common and progression of CKD is associated with low (active) vitamin D levels. Moreover, in animal models of CKD, treatment with vitamin D (analogues) alone or in combination with renin-angiotensin-aldosterone system (RAAS) blockade reduces proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Potential underlying mechanisms include suppression of the RAAS, modulation of immune cell function and direct protective effects on renal cells such as podocytes. Whether vitamin D analogues could further optimize existing therapies in human renal disease is currently under investigation.
Current drug targets 01/2011; 12(1):42-53. · 3.93 Impact Factor
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ABSTRACT: Daily peritoneal exposure to peritoneal dialysis fluid (PDF) induces severe morphological alterations including fibrosis and angiogenesis that lead to a loss of peritoneal ultrafiltration (UF) capacity. Since cyclooxygenase (COX)-2 is involved in fibrosis and angiogenesis, we investigated the in vivo effects of a selective COX-2 inhibitor (celecoxib) in a rat-PD model.
Sixteen rats daily received 10 ml of conventional PDF for 4-5 weeks intraperitoneally. Half of them (n = 8) daily received celecoxib (20 mg/kg BW) via oral gavage, and the other half (n = 8) received vehicle via oral gavage. The study also included two control groups (no PDF instillations), each consisting of n = 8 animals that daily received celecoxib or vehicle, respectively, via oral gavage. Functional, morphological and cellular parameters were analysed.
PDF exposure induced an inflammatory condition evidenced by the increased leucocyte number and synthesis of MCP-1, VEGF and hyaluronic acid. After PDF exposure, the omentum showed intense angiogenesis and milky spots formation. Parietal peritoneum showed increased angiogenesis, lymphangiogenesis, submesothelial matrix thickness and enhanced expression of mesothelial aquaporin1 (Aqp1). Concomitant PDF and celecoxib exposure drastically reduced PGE2 levels, angiogenesis, lymphangiogenesis, fibrosis and milky spot formation in studied tissues, but did not modify mesothelial Aqp1 expression nor the tissue expression of VEGF and inflammatory markers. PDF exposure induced severe UF failure that celecoxib treatment completely prevented.
Altogether, celecoxib treatment improves UF capacity and reduces morphological alterations in our rat PD model.
Nephrology Dialysis Transplantation 09/2009; 24(12):3669-76. · 3.40 Impact Factor
