Publications by authors named "Willem J van Son"

65 Publications

Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter.

Sci Transl Med 2020 11;12(569)

Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Adoptive cell transfer of ex vivo expanded regulatory T cells (T) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such T therapies to the clinic has been slow. Because T homeostasis is known to require continuous T cell receptor (TCR) ligation and exogenous interleukin-2 (IL-2), some investigators have explored the use of low-dose IL-2 injections to increase endogenous T responses. Systemic IL-2 immunotherapy, however, can also lead to the activation of cytotoxic T lymphocytes and natural killer cells, causing adverse therapeutic outcomes. Here, we describe a drug delivery platform, which can be engineered to autostimulate T with IL-2 in response to TCR-dependent activation, and thus activate these cells in sites of antigen encounter. To this end, protein nanogels (NGs) were synthesized with cleavable bis(-hydroxysuccinimide) cross-linkers and IL-2/Fc fusion (IL-2) proteins to form particles that release IL-2 under reducing conditions, as found at the surface of T cells receiving stimulation through the TCR. T surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified T or T stimulated with systemic IL-2. We demonstrate that murine and human NG-modified T carrying an IL-2 cargo perform better than conventional T in suppressing alloimmunity in murine and humanized mouse allotransplantation models. In all, the technology presented in this study has the potential to improve T transfer therapy by enabling the regulated spatiotemporal provision of IL-2 to antigen-primed T.
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http://dx.doi.org/10.1126/scitranslmed.aaw4744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519505PMC
November 2020

Intradialytic Complement Activation Precedes the Development of Cardiovascular Events in Hemodialysis Patients.

Front Immunol 2018 13;9:2070. Epub 2018 Sep 13.

Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Hemodialysis (HD) is a life-saving treatment for patients with end stage renal disease. However, HD patients have markedly increased rates of cardiovascular morbidity and mortality. Previously, a link between the complement system and cardiovascular events (CV-events) has been reported. In HD, systemic complement activation occurs due to blood-to-membrane interaction. We hypothesize that HD-induced complement activation together with inflammation and thrombosis are involved in the development of CV-events in these patients. HD patients were followed for the occurrence of CV-events during a maximum follow-up of 45 months. Plasma samples were collected from 55 patients at different time points during one HD session prior to follow-up. Plasma levels of mannose-binding lectin, properdin and C3d/C3 ratios were assessed by ELISA. In addition, levels of von Willebrand factor, TNF-α and IL-6/IL-10 ratios were determined. An model of HD was used to assess the effect of complement inhibition. During median follow-up of 32 months, 17 participants developed CV-events. In the CV-event group, the C3d/C3-ratio sharply increased 30 min after the start of the HD session, while in the event-free group the ratio did not increase. In accordance, HD patients that developed a CV-event also had a sustained higher IL-6/IL-10-ratio during the first 60 min of the HD session, followed by a greater rise in TNF-α levels and von Willebrand factor at the end of the session. In the HD model, we found that complement activation contributed to the induction of TNF-α levels, IL-6/IL-10-ratio and levels of von Willebrand factor. In conclusion, these findings suggest that early intradialytic complement activation predominantly occurred in HD patients who develop a CV-event during follow-up. In addition, in these patients complement activation was accompanied by a pro-inflammatory and pro-thrombotic response. Experimental complement inhibition revealed that this reaction is secondary to complement activation. Therefore, our data suggests that HD-induced complement, inflammation and coagulation are involved in the increased CV risk of HD patients.
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http://dx.doi.org/10.3389/fimmu.2018.02070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146103PMC
September 2019

The Complement System in Dialysis: A Forgotten Story?

Front Immunol 2018 25;9:71. Epub 2018 Jan 25.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, Netherlands.

Significant advances have lead to a greater understanding of the role of the complement system within nephrology. The success of the first clinically approved complement inhibitor has created renewed appreciation of complement-targeting therapeutics. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition in renal diseases and kidney transplantation. Although, complement has been known to be activated during dialysis for over four decades, this area of research has been neglected in recent years. Despite significant progress in biocompatibility of hemodialysis (HD) membranes and peritoneal dialysis (PD) fluids, complement activation remains an undesired effect and relevant issue. Short-term effects of complement activation include promoting inflammation and coagulation. In addition, long-term complications of dialysis, such as infection, fibrosis and cardiovascular events, are linked to the complement system. These results suggest that interventions targeting the complement system in dialysis could improve biocompatibility, dialysis efficacy, and long-term outcome. Combined with the clinical availability to safely target complement in patients, the question is not if we should inhibit complement in dialysis, but when and how. The purpose of this review is to summarize previous findings and provide a comprehensive overview of the role of the complement system in both HD and PD.
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http://dx.doi.org/10.3389/fimmu.2018.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788899PMC
February 2019

A delicate balance between rejection and BK polyomavirus associated nephropathy; A retrospective cohort study in renal transplant recipients.

PLoS One 2017 13;12(6):e0178801. Epub 2017 Jun 13.

Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Background: The immunosuppressive agents mycophenolate acid (MPA) and tacrolimus (Tac) are associated with a higher incidence of BK polyomavirus nephropathy (BKPyVAN). In this observational retrospective cohort study, the frequency of BK polyomavirus (BKPyV) complications over a 24-month period was studied.

Methods: 358 renal transplant recipients (RTR) treated with MPA, with either cyclosporine A (CsA) (CsAM group) or Tac (TacM group) and mostly prednisolone, were included.

Results: Incidence of BKPyV-viremia was not significantly different between the CsAM (n = 42/191) (22.0%) and the TacM (n = 36/167) (21.6%) group. Biopsy proven BKPyVAN occurred more often in the TacM group (6.6%) versus the CsAM group (2.1%) (p = 0.03). Longitudinal data analysis showed a significant earlier decline of viral load in plasma in the CsAM group compared to the TacM group (p = 0.005). The incidence of biopsy proven acute rejection (BPAR) was significantly higher in the CsAM (19.9%) compared to the TacM (10.8%) (p = 0.02) group. Graft loss, estimated glomerular filtration rate and mortality rate did not differ in both treatment groups.

Conclusion: In conclusion, this study shows that immunosuppressive treatment with Tac and MPA compared to CsA and MPA is associated with a lower incidence of BPAR, but at the cost of an increased risk of developing BKPyVAN in the first two years post-transplant.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178801PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469458PMC
October 2017

High human cytomegalovirus DNAemia early post-transplantation associates with irreversible and progressive loss of renal function - a retrospective study.

Transpl Int 2017 Aug 15;30(8):817-826. Epub 2017 Jun 15.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Transplant recipients are prone to viral infections, which could affect renal transplantation outcome. Our aim was to assess the effects of early human cytomegalovirus (CMV) DNAemia on transplant renal function. A total of 264 (age 50.9 ± 13.5; male 55%) renal transplantation recipients undergoing preemptive anti-CMV therapy were retrospectively categorized based on early (<3 months post-Tx) CMV peak viral load (PVL); PVL ≤ 536, PVL536-6310, or PVL > 6310 International Units/ml (IU/ml). Estimated glomerular filtration rate (eGFR) was analyzed between 1 and 36 months post-transplantation with Kruskal-Wallis test, linear regression, and a linear mixed-effects model. CMV infection was detectable in 113 (43%) recipients within 49 [38-67] days. Subjects with PVL > 6310 had statistically significant ~5-13 ml/min lower eGFR between 3 and 36 months compared to PVL ≤ 536 and PVL536-6310. eGFR declined from 46.1 to 40.7 ml/min/1.73 m (-12%) over 3 years, and the annual decrease for pronounced infection with high PVL was 2.0 ml/min/1.73 m faster than for noninfected or mildly infected subjects. In conclusion, high CMV DNAemia early after renal transplantation was associated with significant loss of renal function, from which subjects did not recover. The severity of infection (high PVL early post-transplantation), more than the infection per se, was related to irreversible and progressive loss of renal function.
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http://dx.doi.org/10.1111/tri.12972DOI Listing
August 2017

Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury.

FASEB J 2017 07 10;31(7):3193-3204. Epub 2017 Apr 10.

Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands;

The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The 2 receptors for complement anaphylatoxin C5a (C5aR1 and C5aR2) are expressed on leukocytes as well as on renal epithelium. Extensive evidence shows that C5aR1 inhibition protects kidneys from IR injury; however, the role of C5aR2 in IR injury is less clear as initial studies proposed the hypothesis that C5aR2 functions as a decoy receptor. By Using wild-type, C5aR1, and C5aR2 mice in a model of renal IR injury, we found that a deficiency of either of these receptors protected mice from renal IR injury. Surprisingly, C5aR2 mice were most protected and had lower creatinine levels and reduced acute tubular necrosis. Next, an migration study demonstrated that leukocyte chemotaxis was unaffected in C5aR2 mice, whereas neutrophil activation was reduced by C5aR2 deficiency. To further investigate the contribution of renal cell-expressed C5aR2 leukocyte-expressed C5aR2 to renal IR injury, bone marrow chimeras were created. Our data show that both renal cell-expressed C5aR2 and leukocyte-expressed C5aR2 mediate IR-induced renal dysfunction. These studies reveal the importance of C5aR2 in renal IR injury. They further show that C5aR2 is a functional receptor, rather than a decoy receptor, and may provide a new target for intervention.-Poppelaars, F., van Werkhoven, M. B., Kotimaa, J., Veldhuis, Z. J., Ausema, A., Broeren, S. G. M., Damman, J., Hempel, J. C., Leuvenink, H. G. D., Daha, M. R., van Son, W. J., van Kooten, C., van Os, R. P., Hillebrands, J.-L., Seelen, M. A. Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury.
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http://dx.doi.org/10.1096/fj.201601218RDOI Listing
July 2017

Incidence and outcome of BK polyomavirus infection in a multicenter randomized controlled trial with renal transplant patients receiving cyclosporine-, mycophenolate sodium-, or everolimus-based low-dose immunosuppressive therapy.

Transpl Infect Dis 2017 Jun 4;19(3). Epub 2017 May 4.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: It remains unclear whether overall degree of immunosuppression or specific effects of individual immunosuppressive agents are causal for increased occurrence of BK polyomavirus (BKPyV) infection in renal transplant recipients (RTR).

Methods: A prospective, multicenter, open-label randomized controlled trial in 361 de novo RTR was performed. A total of 224 RTR were randomized at 6 months into three treatment groups with dual therapy consisting of prednisolone (Pred) plus either cyclosporine (CsA), mycophenolate sodium (MPS), or everolimus (EVL). Primary outcomes were incidence of BK viruria, BK viremia, and BKPyV-associated nephropathy (BKVAN).

Results: From 6 months, incidence of BK viruria in the MPS group (43.6%) was significantly higher than in the other groups (CsA: 16.9%, EVL: 19.8%) (P=.003). BKVAN was diagnosed in 3 patients, all treated with MPS (7.8%, P=.001). Longitudinal data analysis showed a lower BKPyV load and a significantly faster clearance of BK viruria in the CsA group compared to the MPS group (P=.03).

Conclusions: Treatment with MPS was associated with an increased incidence of BK viruria. Dual immunosuppressive therapy with CsA and Pred was associated with the lowest rate of BKPyV replication and the fastest clearance of the virus.
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http://dx.doi.org/10.1111/tid.12687DOI Listing
June 2017

Erratum to: Strong predictive value of mannose-binding lectin levels for cardiovascular risk of hemodialysis patients.

J Transl Med 2016 08 24;14(1):245. Epub 2016 Aug 24.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1186/s12967-016-1004-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997692PMC
August 2016

Strong predictive value of mannose-binding lectin levels for cardiovascular risk of hemodialysis patients.

J Transl Med 2016 08 5;14(1):236. Epub 2016 Aug 5.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Hemodialysis patients have higher rates of cardiovascular morbidity and mortality compared to the general population. Mannose-binding lectin (MBL) plays an important role in the development of cardiovascular disease. In addition, hemodialysis alters MBL concentration and functional activity. The present study determines the predictive value of MBL levels for future cardiac events (C-event), cardiovascular events (CV-event) and all-cause mortality in HD patients.

Methods: We conducted a prospective study of 107 patients on maintenance hemodialysis. Plasma MBL, properdin, C3d and sC5b-9 was measured before and after one dialysis session. The association with future C-events, CV-events, and all-cause mortality was evaluated using Cox regression models.

Results: During median follow-up of 27 months, 36 participants developed 21 C-events and 36 CV-events, whereas 37 patients died. The incidence of C-events and CV-events was significantly higher in patients with low MBL levels (<319 ng/mL, lower quartile). In fully adjusted models, low MBL level was independently associated with increased CV-events (hazard ratio 3.98; 95 % CI 1.88-8.24; P < 0.001) and C-events (hazard ratio 3.96; 95 % CI 1.49-10.54; P = 0.006). No association was found between low MBL levels and all-cause mortality. Furthermore, MBL substantially improved risk prediction for CV-events beyond currently used clinical markers.

Conclusions: Low MBL levels are associated with a higher risk for future C-events and CV-events. Therefore, MBL levels may help to identify hemodialysis patients who are at risk to develop cardiovascular disease.
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http://dx.doi.org/10.1186/s12967-016-0995-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974702PMC
August 2016

Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro.

Transplantation 2017 03;101(3):531-540

1 Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 2 Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, the Netherlands. 3 Department of Medicine, Center for Molecular Medicine, Unit for Microbial Pathogenesis, Karolinska Institutet, Solna, Stockholm, Sweden. 4 Division of Pathology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 5 Division of Clinical Virology, Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 6 Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Background: Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling.

Methods: Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro.

Results: Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller.

Conclusions: In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.
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http://dx.doi.org/10.1097/TP.0000000000001289DOI Listing
March 2017

Precision-cut human kidney slices as a model to elucidate the process of renal fibrosis.

Transl Res 2016 Apr 25;170:8-16.e1. Epub 2015 Nov 25.

Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.

Chronic kidney disease is a major health concern, and experimental models bridging the gap between animal studies and clinical research are currently lacking. Here, we evaluated precision-cut kidney slices (PCKSs) as a potential model for renal disease. PCKSs were prepared from human cortical tissue obtained from tumor nephrectomies and cultured up to 96 hours. Morphology, cell viability, and metabolic functionality (ie, uridine 5'-diphospho-glucuronosyltransferase and transporter activity) were determined to assess the integrity of PCKSs. Furthermore, inflammatory and fibrosis-related gene expressions were characterized. Finally, to validate the model, renal fibrogenesis was induced using transforming growth factor β1 (TGF-β1). Preparation of PCKSs induced an inflammatory tissue response, whereas long-term incubation (96 hours) induced fibrogenesis as shown by an increased expression of collagen type 1A1 (COL1A1) and fibronectin 1 (FN1). Importantly, PCKSs remained functional for more than 48 hours as evidenced by active glucuronidation and phenolsulfonphthalein uptake. In addition, cellular diversity appeared to be maintained, yet we observed a clear loss of nephrin messenger RNA levels suggesting that our model might not be suitable to study the role of podocytes in renal pathology. Moreover, TGF-β1 exposure augmented fibrosis, as illustrated by an increased expression of multiple fibrosis markers including COL1A1, FN1, and α-smooth muscle actin. In conclusion, PCKSs maintain their renal phenotype during culture and appear to be a promising model to investigate renal diseases, for example, renal fibrosis. Moreover, the human origin of PCKSs makes this model very suitable for translational research.
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http://dx.doi.org/10.1016/j.trsl.2015.11.007DOI Listing
April 2016

Assessment of Cotinine Reveals a Dose-Dependent Effect of Smoking Exposure on Long-term Outcomes After Renal Transplantation.

Transplantation 2015 Sep;99(9):1926-32

1 Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands. 2 Department of Laboratory Medicine, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands. 3 Department of Epidemiology, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands.

Background: Smoking is a risk factor for poor late outcomes in renal transplant recipients (RTR). Smoking exposure can be assessed by self-report and cotinine measurements. We investigated whether use of cotinine as a biomarker for smoking exposure can serve as an alternative for self-report and to compare associations of smoking exposure by self-report and cotinine with outcomes in RTR and assess dose dependency.

Methods: Renal transplant recipients were classified as never, former, light (≤10 cigarettes/day), and heavy smokers (>10 cigarettes/day) according to self-report and analogous categories for urine and plasma cotinine. First, we assessed agreement of self-reported smoking exposure with smoking exposure according urine and plasma cotinine. Second, we compared the associations with graft failure and mortality.

Results: Of 603 RTR (age 51.5 ± 12.1 years, 55% men), 36.0% RTR were never, 42.3% former, 10.6% light, and 11.1% heavy smokers according to self-report. The majority (98.6%) of never smokers had nondetectable cotinine. However, 14 and 13 RTR reporting no active smoking had respective urine or plasma cotinine consistent with active smoking. Cotinine-based measurements were dose-dependently associated with mortality and graft failure.

Conclusions: Plasma and urine cotinine can serve as an alternative to self-report and were dose-dependently associated with poor late outcomes in RTR.
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http://dx.doi.org/10.1097/TP.0000000000000636DOI Listing
September 2015

Renal expression of Toll-like receptor 2 and 4: dynamics in human allograft injury and comparison to rodents.

Mol Immunol 2015 Mar 29;64(1):82-9. Epub 2014 Nov 29.

Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands.

Activation of the innate immunity through Toll-like receptors (TLRs) has been postulated to play an important role in the pathophysiology of renal allograft dysfunction. TLR2 and TLR4 dynamics in different human post-transplant pathological entities has never been studied. Therefore, we evaluated pre- and post-transplantation protein expression of TLR2 and TLR4 in human kidney biopsies. Human kidney biopsies obtained from living kidney donors and patients with acute tubular necrosis, acute cellular and vascular rejection and interstitial fibrosis/tubular atrophy (IF/TA) were used. Translating results from animal studies to the clinical situation is highly important considering the upcoming clinical studies with TLR inhibitors in human renal transplantation. Hence, the TLR2 and TLR4 expression in healthy mouse and rat kidneys was analyzed and compared with human kidneys. In healthy human kidneys, TLR2 is expressed on the endothelium and Bowman's capsule, while TLR4 is expressed on the endothelium only. No tubular staining was found for both receptors in human kidneys. In contrast to human biopsies, TLR2 and TLR4 expression in rodents was observed on tubular epithelial cells. In all acute rejection human biopsies, increased infiltration of TLR4(+) leukocytes was observed. In conclusion, a discrepancy exists between human and rodent renal TLR expression, which suggests careful attention when translating results from rodent studies to the human situation. Additionally, this study revealed human TLR2 and TLR4 expression dynamics in human biopsies pre- and post-transplantation.
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http://dx.doi.org/10.1016/j.molimm.2014.11.003DOI Listing
March 2015

N-octanoyl dopamine treatment of endothelial cells induces the unfolded protein response and results in hypometabolism and tolerance to hypothermia.

PLoS One 2014 13;9(6):e99298. Epub 2014 Jun 13.

Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, Mannheim, Germany.

Aim: N-acyl dopamines (NADD) are gaining attention in the field of inflammatory and neurological disorders. Due to their hydrophobicity, NADD may have access to the endoplasmic reticulum (ER). We therefore investigated if NADD induce the unfolded protein response (UPR) and if this in turn influences cell behaviour.

Methods: Genome wide gene expression profiling, confirmatory qPCR and reporter assays were employed on human umbilical vein endothelial cells (HUVEC) to validate induction of UPR target genes and UPR sensor activation by N-octanoyl dopamine (NOD). Intracellular ATP, apoptosis and induction of thermotolerance were used as functional parameters to assess adaptation of HUVEC.

Results: NOD, but not dopamine dose dependently induces the UPR. This was also found for other synthetic NADD. Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury.

Conclusions: We provide for the first time evidence that NADD induce the UPR in vitro. It remains to be assessed if UPR induction is causally associated with hypometabolism and thermotolerance. Further pharmacokinetic studies are warranted to address if the NADD concentrations used in vitro can be obtained in vivo and if this in turn shows therapeutic efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099298PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057113PMC
October 2015

The clinical course of hepatitis E virus infection in patients of a tertiary Dutch hospital over a 5-year period.

J Clin Virol 2013 Nov 4;58(3):509-14. Epub 2013 Sep 4.

Department of Medical Microbiology, Division of Clinical Virology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Background: Hepatitis E virus (HEV) has long been known as a major cause of acute hepatitis in developing countries with occasional travel-related cases in developed countries, most of them belonging to genotype 1. Currently, genotype 3 HEV is recognized as an emerging public health issue in developed countries and can cause a chronic hepatitis in immunocompromised patients.

Objectives: The aim of this study was to get an overview of the clinical course of HEV infection, from July 2007 to December 2012, and further characterize HEV in patients of the University Medical Center Groningen (UMCG) over a 5-year time period.

Methods: Since the second half of 2007, patients in the UMCG with unexplained hepatitis were screened for HEV and clinical data were collected. HEV was characterized by sequencing of the ORF1 and ORF2 regions.

Results: In total, 34 patients of the 1129 tested patients showed HEV viremia. The majority of the infected patients were immunocompromised; 18 were solid organ transplant (SOT) patients and 9 were patients immunocompromised for other reasons. Seven patients diagnosed with HEV were immunocompetent. Viral genotyping revealed genotype 3 isolates, mostly genotype 3c.

Conclusion: Non-travel related HEV hepatitis is an important diagnosis. In immunocompromised patients HEV infection often has major clinical impact, necessitating medical intervention including antiviral treatment. In immunocompetent patients, the detection could expand our understanding about the route of transmission and the relation with the zoonotic origin. Therefore, besides an increasing awareness for HEV among clinicians and medical microbiologists, diagnostics should be routinely incorporated into standard patients care.
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http://dx.doi.org/10.1016/j.jcv.2013.08.022DOI Listing
November 2013

The role of diet and physical activity in post-transplant weight gain after renal transplantation.

Clin Transplant 2013 Jul-Aug;27(4):E484-90. Epub 2013 Jun 13.

Department of Nephrology, University Medical Center Groningen, Sector A, PO Box 30.001, 9700 RB Groningen, The Netherlands.

Background: Long-term survival of renal transplant recipients (RTR) has not improved over the past 20 yr. The question rises to what extent lifestyle factors play a role in post-transplant weight gain and its associated risks after transplantation.

Methods: Twenty-six RTR were measured for body weight, body composition, blood lipids, renal function, dietary intake, and physical activity at six wk, and three, six, and 12 months after transplantation.

Results: Weight gain ranged between -2.4 kg and 19.5 kg and was largely due to increase in body fat. RTR who remained body fat stable, showed more daily physical activity (p = 0.014), tended to consume less energy from drinks and dairy (p = 0.054), consumed less mono- and disaccharides (sugars) (p = 0.021) and ate more vegetables (p = 0.043) compared with those who gained body fat. Gain in body fat was strongly related to total cholesterol (r = 0.46, p = 0.017) and triglyceride (r = 0.511, p = 0.011) at one yr after transplantation.

Conclusions: Gain in adiposity after renal transplantation is related to lifestyle factors such as high consumption of energy-rich drinks, high intake of mono- and disaccharides and low daily physical activity. RCTs are needed to investigate potential benefits of lifestyle intervention on long-term morbidity and mortality.
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http://dx.doi.org/10.1111/ctr.12149DOI Listing
March 2014

Impact of depression on long-term outcome after renal transplantation: a prospective cohort study.

Transplantation 2012 Nov;94(10):1033-40

Department of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands.

Background: Renal transplantation is the treatment of choice for end stage renal disease. Although there is more depression in wait-listed versus transplant patients, depression persists after transplantation. We investigated the determinants of depression in renal transplantation recipients (RTRs) and the association with cardiovascular (CV) and all-cause-mortality and graft failure.

Methods: RTR were investigated between 2001 and 2003. Depression was assessed using the Depression Subscale of the Symptom Checklist (SCL-90). Mortality and graft failure were recorded until May 2009.

Results: A total of 527 RTR (age, 51±12 years; 55% men) were studied; 31% of the RTR were indicated with depression. Independent variables associated with depression were medically unfit for work, proteinuria, lower physical activity level, and longer dialysis duration. During follow-up for 7.0 (6.2-7.5) years, 114 RTR (59 CV) died. In Cox regression analyses, depression was strongly associated with increased risk for CV (HR=2.12 [1.27-3.53], P=0.004) and all-cause mortality (HR=1.96 [1.36-2.84], P<0.001). Adjustments for confounders did not materially change these associations. The association with graft failure (HR=1.77 [1.01-3.10]. P=0.047) disappeared after adjustment for kidney function (P=0.6).

Conclusions: Although our study has several limitations, including the lack of pretransplant depression status, we identified medically unfit for work, proteinuria, lower physical activity level, and longer dialysis duration as independent variables associated with depression. We furthermore found that depression is associated with CV and all-cause mortality in RTR.
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http://dx.doi.org/10.1097/TP.0b013e31826bc3c8DOI Listing
November 2012

Novel insights in localization and expression levels of C5aR and C5L2 under native and post-transplant conditions in the kidney.

Mol Immunol 2013 Mar 6;53(3):237-45. Epub 2012 Sep 6.

Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Postbus 30001, 9700 RB Groningen, The Netherlands.

Aims: The complement system, and especially C5a, plays an important role in the pathophysiology of renal diseases and post-transplant renal injury. The two receptors for C5a are C5a receptor (C5aR) and C5a-like-receptor-2 (C5L2). Only renal C5aR expression has been reported, although exact localization and alterations in expression after transplantation are unknown.

Materials And Results: Renal C5aR and C5L2 expression and localization were analyzed immunohistochemically. C5aR and C5L2 expression was analyzed in human kidney biopsies obtained from living donors and patients suffering from acute tubular necrosis, acute cellular and vascular rejection or IF/TA. C5aR was expressed in the thick ascending limb of Henle's loop and first part of the distal convoluted tubule (DCT). Under inflammatory conditions, C5aR was de novo expressed in proximal tubuli. C5L2 was expressed in the kidney and localized to DCT1, DCT2 and connecting tubule. Persistent distal tubular expression of both receptors was demonstrated after renal transplantation.

Conclusions: This study shows distinct renal expression patterns for C5aR and C5L2. Our findings suggest a functional role for renal C5L2 rather than being a C5a decoy receptor. Future studies focusing on renal C5a-C5aR interaction should take differential C5aR and C5L2 expression into account, alongside abundant C5aR expression on infiltrating cells.
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http://dx.doi.org/10.1016/j.molimm.2012.08.013DOI Listing
March 2013

A randomized clinical trial of living donor nephrectomy: a plea for a differentiated appraisal of mini-open muscle splitting incision and hand-assisted laparoscopic donor nephrectomy.

Transpl Int 2012 Sep 31;25(9):976-86. Epub 2012 Jul 31.

Departments of Surgery, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700RB Groningen, The Netherlands.

A randomized controlled trial was designed to compare various outcome variables of the retroperitoneal mini-open muscle splitting incision (MSI) technique and the transperitoneal hand-assisted laparoscopic technique (HAL) in performing living donor nephrectomies. Fifty living kidney donors were randomized to MSI or HAL. Primary endpoint was pain experience scored on a visual analogue scale (VAS). After MSI living donors indicated lower median (range) VAS scores at rest than HAL living donors on postoperative day 2.5 [10 (0-44) vs. 15 (0-70), P = 0.043] and day 3 [7 (0-28) vs. 10 (0-91), P = 0.023] and lower VAS scores while coughing on postoperative day 3 [20 (0-73) vs. 42 (6-86), P = 0.001], day 7 [8 (0-66) vs. 33 (3-76), P < 0.001] and day 14 [2 (0-17) vs. 12 (0-51), P = 0.009]. The MSI technique also resulted in reduced morphine requirement, better scores on three domains of the RAND-36, reduced costs and reduced CRP and IL-6 levels. The HAL technique was superior in operating time and postoperative decrease of hemoglobin level. The MSI technique is superior to the HAL technique in performing living donor nephrectomies with regard to postoperative pain experience. This study reopens the discussion of the way to go in performing the living donor nephrectomy.
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http://dx.doi.org/10.1111/j.1432-2277.2012.01525.xDOI Listing
September 2012

Latent cytomegalovirus infection is an independent risk factor for late graft failure in renal transplant recipients.

Med Sci Monit 2011 Nov;17(11):CR609-617

Renal Transplant Program, University Medical Center Groningen and University of Groningen, The Netherlands.

Background: Cytomegalovirus (CMV) is a risk factor for rejection and mortality soon after renal transplantation. Little is known about its consequences longer after transplantation. We prospectively investigated whether latent CMV infection is a risk factor for graft failure and mortality long after transplantation.

Material/methods: Our study included 606 renal transplant recipients (RTR) with a functioning graft for >1 year. CMV serology was determined using ELISA. RTRs were divided into CMV-seronegative and latent CMV (seropositive + seroconverted).

Results: We measured CMV IgG at 6.0 [2.6-11.4] years post-transplant. During follow-up (7.0 [6.2-7.5] years), 54 (9%) RTRs experienced graft failure and 137 (23%) RTRs died. Risk for graft failure and mortality was significantly higher in RTRs with latent CMV compared to CMV-seronegative RTRs (HR=3.1, P=0.005 and HR=2.0, P=0.002, respectively). After adjustment for potential confounders, latent CMV infection remained an independent risk factor for graft failure (HR=4.6, P=0.001), but not for mortality (HR=1.4, P=0.2).

Conclusions: Latent CMV is an independent risk factor for graft failure long after renal transplantation and carries a higher risk for graft failure than for mortality. These findings confirm the notion that latent CMV can be harmful in transplanted kidneys.
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http://dx.doi.org/10.12659/msm.882045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539501PMC
November 2011

Smoking is a risk factor for graft failure and mortality after renal transplantation.

Am J Nephrol 2011 9;34(1):26-31. Epub 2011 Jun 9.

Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.

Background: Smoking in renal transplant recipients (RTR) is an acknowledged cardiovascular risk factor. It is, however, unclear whether smoking also increases the risk of graft failure (GF).

Method: In this study, we prospectively assessed the association of current smoking versus past and never smoking with GF and mortality in 604 RTR (age 51.5 ± 12.1 years, 55% male).

Results: At inclusion, 133 (22%) were current smokers, 255 (42%) were past smokers and 216 (36%) never smoked. During follow-up of 5.3 (4.7-5.7) years, 41 (7%) RTR experienced GF and 95 RTR (16%) died. Current smoking RTR had higher risk for GF compared to never smoking RTR (hazard ratio, HR = 3.3, 95% CI 1.5-7.1, p = 0.002). Past smoking RTR had similar risk of GF as never smoking RTR (HR = 1.1, 95% CI 0.5-2.6, p = 0.7). Current smoking RTR and past smoking RTR were at higher risk for death than never smoking RTR (HR = 2.1, 95% CI 1.1-3.8, p = 0.016, and HR = 2.4, 95% CI 1.4-4.0, p = 0.001, respectively).

Conclusion: Smoking after renal transplantation is associated with risk for GF and mortality. Since past smoking is a risk factor for mortality but not for GF, smoking cessation may be beneficial to RTR in delaying GF in long term.
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http://dx.doi.org/10.1159/000328903DOI Listing
December 2011

Long-term health and work outcomes of renal transplantation and patterns of work status during the end-stage renal disease trajectory.

J Occup Rehabil 2011 Sep;21(3):325-34

Department of Health Sciences, University Medical Center Groningen, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands.

Introduction: The aim of this study was to examine the health- and work outcomes of renal transplant recipients long-term after transplantation as well as the pattern of work status, work ability and disability benefits during the end-stage renal disease (ESRD) trajectory that precedes transplantation.

Methods: 34 transplant recipients completed interviews 3, 13 months and >6 years posttransplantation. Health status (SF-36), work ability (WAI), and fatigue (CIS) were assessed by questionnaires, clinical data were derived from medical charts, and data on functional limitations were extracted from the social security system database. The work status trajectory preceding transplantation was examined retrospectively.

Results: Of the 34 third wave transplant recipients, 29% were severely fatigued. Compared with the general working population, recipients experienced worse general health and less vitality. Non-working recipients had worse renal function and general health, and more limitations in physical functioning compared to working recipients. The WAI score indicated moderate work ability for 60% of the employed recipients. Although 67% were employed (45% parttime), 30% of those working still received some disability benefits. Social insurance physicians found variable levels of functional limitations. The mean work status trajectory showed more sickness absence and less work ability during dialysis, but after transplantation, both work status and work ability generally improved.

Conclusions: Transplant recipients have a compromised health status which leads to functional limitations and disability. Although work status improved after transplantation, a substantial number of the transplant recipients received disability benefits. The negative health consequences of anti-rejection medications may play an important role in long-term work ability. These results indicate that a 'new' kidney has advantages over dialysis with respect to work, but does not necessarily leads to 'normal' work outcomes.
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http://dx.doi.org/10.1007/s10926-011-9317-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173627PMC
September 2011

Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury.

Am J Transplant 2011 Apr;11(4):660-9

Surgery Nephrology, University Medical Center Groningen, Groningen, The Netherlands Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen activated protein kinases (MAPKs) might be the key molecules linking both the complement and TLR pathways together. Complement and TLRs are important mediators of renal ischemia-reperfusion injury (IRI). Besides IRI, complement C3 can also be upregulated and activated in the kidney before transplantation as a direct result of brain death (BD) in the donor. This local upregulation and activation of complement in the donor kidney has been proven to be detrimental for renal allograft outcome. Also TLR4 and several of its major ligands are upregulated by donor BD compared to living donors. Important and in line with the observations above, kidney transplant recipients have a benefit when receiving a kidney from a TLR4 Asp299Gly/Thr399Ile genotypic donor. The role of complement and TLRs and crosstalk between these two innate immune systems in relation to renal injury during donor BD and ischemia-reperfusion are focus of this review. Future strategies to target complement and TLR activation in kidney transplantation are considered.
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http://dx.doi.org/10.1111/j.1600-6143.2011.03475.xDOI Listing
April 2011

Renal function equations before and after living kidney donation: a within-individual comparison of performance at different levels of renal function.

Clin J Am Soc Nephrol 2010 Nov 8;5(11):1960-8. Epub 2010 Jul 8.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, Netherlands.

Background And Objectives: The Modification of Diet in Renal Disease (MDRD) study equation and the Cockcroft-Gault (CG) equation perform poorly in the (near-) normal range of GFR. Whether this is due to the level of GFR as such or to differences in individual characteristics between healthy individuals and patient with chronic kidney disease (CKD) is unknown.

Design, Setting, Participants, & Measurements: We evaluated the performance of MDRD, CG per BSA (CG/(BSA)) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with measured GFR (mGFR; I-iothalamate) at 4 months before and 2 months after donation in 253 consecutive living kidney donors.

Results: mGFR declined from 103 ± 15 to 66 ± 11 ml/min per 1.73 m(2) after donation. All equations underestimated mGFR at both time points. Arithmetic performance analysis showed improved performance after donation of all equations, with significant reduction of bias after donation. Expressed as percentage difference, mGFR-estimated GFR (eGFR) bias was reduced after donation only for CG/(BSA). Finally, in 295 unselected individuals who were screened for donation, mGFR was below the cutoff for donation of 80 ml/min per 1.73 m(2) in 19 individual but in 166, 98, and 74 for MDRD, CDK-EPI, and CG/(BSA), respectively.

Conclusions: A higher level of GFR as such is associated with larger absolute underestimation of true GFR by eGFR. For donor screening purposes, eGFR should be interpreted with great caution; when in doubt, true GFR should be performed to prevent unjustified decline of prospective kidney donors.
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http://dx.doi.org/10.2215/CJN.08761209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001772PMC
November 2010

Body mass index and creatinine clearance are associated with steady-state serum concentrations of the cell damage marker S100B in renal transplant recipients.

Med Sci Monit 2010 Jul;16(7):CR318-24

Kidney Center, Dept. of Internal Medicine, University Medical Center Groningen, Hanzeplein 1, Groningen, The Netherlands.

Background: S100B is a prominent cell damage marker which can lead to sustained pro-inflammatory signaling. The aim was to investigate cross-sectional associations of steady-state S100B concentrations, particularly with C-reactive protein (CRP), in renal transplant recipients (RTRs) and also to investigate prospectively whether S100B would predict graft failure or mortality.

Material/methods: Outpatient RTRs with a graft functioning for >1 year were eligible for participation in this study. S100B was determined at baseline from serum. Mortality and the occurrence of graft failure were recorded until September 2007. Multivariable linear regression analyses were performed to identify potential determinants of S100B. Multivariable Cox regression analyses were performed to investigate S100B as a potential predictor of mortality or graft failure.

Results: Five hundred eighty-one RTRs participated in the study. The median S100B concentration was 0.19 (0.14-0.25) microg/l. Recipient age (beta=0.009, p=0.02), body mass index (BMI) (beta=0.021, p<0.001), and creatinine clearance (beta=-015, p<0.001) were independently associated with S100B. During follow-up, 95 RTRs (16.4%) died and 41 (7.1%) developed graft failure. S100B levels did not predict mortality or graft failure.

Conclusions: BMI, creatinine clearance, and age are determinants of steady-state serum S100B concentrations in renal transplant recipients. The association of BMI with S100B suggests that S100B might be a new adipokine.
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July 2010

Influence of C-reactive protein and urinary protein excretion on prediction of graft failure and mortality by serum albumin in renal transplant recipients.

Transplantation 2010 May;89(10):1247-54

University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

Background: Hypoalbuminemia is an established predictor of poor outcome in renal transplant recipients (RTR). It is considered to reflect inflammation, poor nutritional status, or proteinuria. We explored the roles of high-sensitivity C-reactive protein (hsCRP) and urinary protein excretion in prediction of graft failure and mortality by serum albumin in RTR.

Methods: We included 605 RTR at a median (interquartile range) time of 6.0 years (2.5-11.5 years) after transplantation for baseline measurements.

Results: At baseline, urinary protein excretion (beta=-0.242, P<0.0001), hsCRP concentration (beta=-0.207, P<0.0001), recipient age (beta=-0.115, P=0.004), living kidney donor (beta=0.100, P=0.01), and a history of myocardial infarction (beta=-0.084, P=0.03) were independently related to serum albumin. Prospectively, 94 RTR died and 42 had graft failure during 5.3 years (4.7-5.7 years) of follow-up. After adjustment for potential confounders, including hsCRP and urinary protein excretion in Cox-regression analyses, low serum albumin was significantly associated with graft failure (hazard ratio=0.34 [95% confidence interval=0.15-0.76] per g/dL, P=0.008) and mortality (hazard ratio=0.43 [95% confidence interval=0.24-0.78] per g/dL, P=0.005), with significant modification of the effect of serum albumin on graft failure by urinary protein excretion (P=0.003).

Conclusion: Low serum albumin concentrations predict graft failure and mortality in RTR independent of hsCRP and urinary protein excretion. The effect of serum albumin on graft failure is strongly modified by urinary protein excretion. These results suggest that chronic low-grade inflammation is not an important mechanism underlying inverse associations of serum albumin with graft failure and mortality. They also suggest that proteinuria is involved in the association of low serum albumin with graft failure.
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http://dx.doi.org/10.1097/TP.0b013e3181d720e3DOI Listing
May 2010

Gastrointestinal symptoms in kidney transplant recipients: what about silent sufferers?

Prog Transplant 2010 Mar;20(1):75-80

University Medical Centre Groningen, The Netherlands.

Context: Transplantation improves health-related quality of life in patients with end-stage renal disease. However, primarily because of adverse effects of medication, among other gastrointestinal symptoms, health-related quality of life is not completely restored to normal. Although many patients have various gastrointestinal symptoms only a small proportion may be reported spontaneously.

Objective: To evaluate the prevalence of gastrointestinal symptoms in kidney transplant recipients, also the difference between spontaneously reported symptoms and symptoms elicited by specific questioning was assessed. The burden of these symptoms in daily life also was analyzed.

Design: A single-center, sequential, mixed method study to assess the difference between spontaneous patient reports of gastrointestinal symptoms and active screening by a questionnaire in kidney transplant patients.

Patients: In February 2008, patients received a questionnaire on gastrointestinal symptoms; notes in medical records were consulted for patients scoring less than 100. In June 2008, those patients received a second, extended questionnaire aimed to assess the burden of gastrointestinal symptoms in daily life.

Results: Ninety-two of 513 patients eventually proved to have gastrointestinal symptoms. Completed questionnaires were compared with notes in the patients' files of the past year. A total of 51 of these 92 patients appeared to have not mentioned their gastrointestinal symptoms during the outpatient clinic visits. Of these 51 patients, 37 reported a significant impact of gastrointestinal symptoms on daily life.

Conclusions: The silent sufferer exists. Specific questioning helps to improve communication concerning bothersome gastrointestinal symptoms. To assess the burden of these symptoms, a validated questionnaire should be developed.
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March 2010

Copeptin, a surrogate marker of vasopressin, is associated with accelerated renal function decline in renal transplant recipients.

Transplantation 2009 Aug;88(4):561-7

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Chronically elevated vasopressin (VP) plasma levels have been shown to induce accelerated renal function decline in rats with chronic renal failure. Whether endogenous VP is a renal risk factor in humans has not been investigated yet. We aimed to investigate whether, in renal transplant recipients, VP concentration is associated with change in renal function during follow-up.

Methods: In this prospective study, all consecutive patients visiting our kidney transplant outpatient clinic between August 2001 and July 2003 were asked to participate. Serum creatinine was assessed at baseline and at follow-up. Copeptin, the C-terminal portion of the precursor of VP, was determined at baseline (immunoassay). Univariate and multivariate regression analyses were performed to investigate the association between copeptin and renal function decline.

Results: Overall, 548 patients were included 6.0 (2.8-11.6) years after transplantation (men 54%, age 52 [43-60] years). Median follow-up was 3.2 (2.7-3.7) years. Median copeptin level was 9.1 (5.0-18.6) pmol/L at baseline. Copeptin was significantly associated with change in estimated Glomerular Filtration Rate (eGFR; MDRD) during follow-up. When our study population was subdivided according to gender-stratified tertiles of increasing copeptin concentration, mean changes in eGFR during follow-up were -0.03, -0.44, and -1.06 mL/min/1.73 m2 per year. In multivariate regression analysis, the association of copeptin at baseline with change in eGFR during follow-up remained significant after adjustment for age, gender, baseline eGFR, and known risk factors for renal function decline.

Conclusions: These findings suggest that in renal transplant patients, VP may play a role in renal function decline.
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http://dx.doi.org/10.1097/TP.0b013e3181b11ae4DOI Listing
August 2009

Plasma procalcitonin is an independent predictor of graft failure late after renal transplantation.

Transplantation 2009 Jul;88(2):279-87

Department of Internal Medicine, Renal Transplant Program, University Medical Center Groningen and University of Groningen, 9700 RB Groningen, The Netherlands.

Background: Chronic low-grade inflammation is involved in chronic transplant dysfunction after renal transplantation. Procalcitonin (PCT), known to reflect microbial inflammation, may also reflect ongoing noninfectious chronic low-grade inflammation in organ parenchyma, including transplanted kidneys. We aimed to compare predictive performance of plasma PCT for development of graft failure in renal transplant recipients (RTR) with that of high-sensitivity C-reactive protein (hsCRP), an established marker of systemic chronic low-grade inflammation.

Methods: We included 575 RTR with functioning grafts for more than or equal to 1 year at a median (interquartile range) time of 6.1 (2.9-11.7) years posttransplant. PCT was determined using an ultrasensitive immunoluminometric assay and hsCRP using high-sensitivity enzyme-linked immunosorbent assay.

Results: Median (interquartile range) plasma PCT and hsCRP concentrations were 0.023 (0.017-0.036) ng/mL and 2.1 (0.8-4.9) mg/L, respectively. After a median (interquartile range) of 5.2 (4.5-5.7) years of follow-up, incidence of graft failure was 0.5%, 2.6%, and 18.5% according to increasing PCT tertiles (P<0.001 by log-rank test). Area under the curve of receiver operating characteristic analysis of PCT for prediction of graft failure was significantly higher than that of hsCRP (0.84 vs. 0.56, P<0.001). After adjustment for potential confounders, PCT remained an independent predictor of graft failure (hazard ratio=2.3 [95% confidence interval 1.4-3.7] per doubling PCT, P=0.0004), whereas this was not the case for hsCRP.

Conclusion: We identified plasma PCT as a strong and an independent predictor of graft failure in RTR. These data suggest that PCT in RTR reflects ongoing inflammation in parenchyma of transplanted kidneys. Further studies are required to investigate whether PCT could be of use as an early biomarker for chronic transplant dysfunction.
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http://dx.doi.org/10.1097/TP.0b013e3181ac9ea0DOI Listing
July 2009

N-terminal pro-B-type natriuretic peptide and mortality in renal transplant recipients versus the general population.

Transplantation 2009 May;87(10):1562-70

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Mortality rates are higher in renal transplant recipients (RTR) than in the general population (GP). It is unknown what risk factors account for this difference.

Methods: We prospectively followed a cohort of 606 RTR for 3026 person-years, during which 95 died. A GP cohort of 3234 subjects was followed for 24,940 person-years, during which 130 died.

Results: All investigated risk factors, except ethnicity, body mass index, and total cholesterol, differed significantly between cohorts, with an adverse risk profile in the RTR. The age-adjusted and gender-adjusted hazard ratio for mortality in RTR was 6.2 (95% confidence interval [CI] 4.6-8.3) compared with GP, which was reduced to 2.4 (95% CI 1.6-3.6), 4.3 (95% CI 3.0-6.1), and 5.0 (95% CI 3.5-7.3) after additional adjustment for differences in N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine clearance, and need for antihypertensive medication, respectively (all P<0.001), whereas adjustment for variables more related to atherosclerosis, including history of cardiovascular disease, diabetes, and high-density lipoprotein cholesterol, did not affect the difference in mortality between RTR and GP. Associations of NT-proBNP, creatinine clearance, and the use of antihypertensive medication with mortality were significantly steeper in RTR than in GP. Risk for mortality was similar for RTR and GP with low NT-proBNP (<100 pg/mL).

Conclusions: Elevated NT-proBNP, low creatinine clearance, and need for antihypertensive medication are stronger risk factors for mortality in RTR than in GP. The increased mortality seen in the RTR population may well be related to cardiac failure rather than "accelerated atherosclerosis."
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http://dx.doi.org/10.1097/TP.0b013e3181a4bb80DOI Listing
May 2009
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