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1.  A Peritoneal Dialysis Regimen Low in Glucose and Glucose Degradation Products Results in Increased Cancer Antigen 125 and Peritoneal Activation 
♦ Background: Glucose and glucose degradation products (GDPs) in peritoneal dialysis fluids (PDFs) are both thought to mediate progressive peritoneal worsening.
♦ Methods: In a multicenter, prospective, randomized crossover study, incident continuous ambulatory peritoneal dialysis patients were treated either with conventional lactate-buffered PDF (sPD regimen) or with a regimen low in glucose and GDPs: Nutrineal×1, Extraneal×1, and Physioneal×2 (NEPP regimen; all solutions: Baxter Healthcare, Utrecht, Netherlands). After 6 months, patients were switched to the alternative regimen for another 6 months. After 6 weeks of run-in, before the switch, and at the end of the study, 4-hour peritoneal equilibration tests were performed, and overnight effluents were analyzed for cells and biomarkers. Differences between the regimens were assessed by multivariate analysis corrected for time and regimen sequence.
♦ Results: The 45 patients who completed the study were equally distributed over both groups. During NEPP treatment, D4/D0 glucose was lower (p < 0.01) and D/P creatinine was higher (p = 0.04). In NEPP overnight effluent, mesothelial cells (p < 0.0001), cancer antigen 125 (p < 0.0001), hyaluronan (p < 0.0001), leukocytes (p < 0.001), interleukins 6 (p = 0.001) and 8 (p = 0.0001), and vascular endothelial growth factor (VEGF, p < 0.0001) were increased by a factor of 2 – 3 compared with levels in sPD effluent. The NEPP regimen was associated with higher transport parameters, but that association disappeared after the addition of VEGF to the model. The association between NEPP and higher effluent levels of VEGF could not be attributed to glucose and GDP loads.
♦ Conclusions: Study results indicate preservation of the mesothelium and increased peritoneal activation during NEPP treatment. Whether the increase in VEGF reflects an increase in mesothelial cell mass or whether it points to another, undesirable mechanism cannot be determined from the present study. Longitudinal studies are needed to finally evaluate the usefulness of the NEPP regimen for further clinical use.
doi:10.3747/pdi.2010.00115
PMCID: PMC3525441  PMID: 22045100
Biocompatibility; CA125; CAPD; clinical trial; glucose; glucose degradation products; mesothelial regeneration; icodextrin; amino acids
2.  Urinary Vitamin D Binding Protein: A Potential Novel Marker of Renal Interstitial Inflammation and Fibrosis 
PLoS ONE  2013;8(2):e55887.
Non-invasive tubulointerstitial damage markers may allow better titration and monitoring of renoprotective therapy. We investigated the value of urinary vitamin D binding protein excretion (uVDBP) as a tubulointerstitial inflammation and fibrosis marker in adriamycin rats, and tested whether uVDBP parallels renal damage and responds to therapy intensification in humans. In adriamycin (ADR) rats, uVDBP was strongly elevated vs controls (CON) already 6 wks after nephrosis induction (ADR: 727±674 [mean±SD] vs CON: 9±12 µg/d, p<0.01), i.e. before onset of pre-fibrotic and inflammatory tubulointerstitial damage, and at all following 6-wk time points until end of follow up at 30 wks (ADR: 1403±1026 vs CON: 206±132 µg/d, p<0.01). In multivariate regression analysis, uVDBP was associated with tubulointerstitial macrophage accumulation (standardized beta = 0.47, p = 0.01) and collagen III expression (standardized beta = 0.44, p = 0.02) independently of albuminuria. In humans, uVDBP was increased in 100 microalbuminuric subjects (44±93 µg/d) and in 47 CKD patients with overt proteinuria (9.2±13.0 mg/d) compared to 100 normoalbuminuric subjects (12±12 µg/d, p<0.001). In CKD patients, uVDBP responded to intensification of renoprotective therapy (ACEi+liberal sodium: 9.2±13.0 mg/d vs dual RAAS blockade+low sodium: 2747±4013, p<0.001), but remained still >100-fold increased during maximal therapy vs normoalbuminurics (p<0.001), consistent with persisting tubulointerstitial damage. UVDBP was associated with tubular and inflammatory damage markers KIM-1 (standardized beta = 0.52, p<0.001), beta-2-microglobuline (st.beta = 0.45, p<0.001), cystatin C (st.beta = 0.40, p<0.001), MCP-1 (st.beta = 0.31, p<0.001) and NGAL (st.beta = 0.20, p = 0.005), independently of albuminuria. UVDBP may be a novel urinary biomarker of tubulointerstitial damage. Prospectively designed studies are required to validate our findings and confirm its relevance in the clinical setting.
doi:10.1371/journal.pone.0055887
PMCID: PMC3569442  PMID: 23409077
3.  Proteinuria Triggers Renal Lymphangiogenesis Prior to the Development of Interstitial Fibrosis 
PLoS ONE  2012;7(11):e50209.
Proteinuria is an important cause of progressive tubulo-interstitial damage. Whether proteinuria could trigger a renal lymphangiogenic response has not been established. Moreover, the temporal relationship between development of fibrosis, inflammation and lymphangiogenesis in chronic progressive kidney disease is not clear yet. Therefore, we evaluated the time course of lymph vessel (LV) formation in relation to proteinuria and interstitial damage in a rat model of chronic unilateral adriamycin nephrosis. Proteinuria and kidneys were evaluated up to 30 weeks after induction of nephrosis. LVs were identified by podoplanin/VEGFR3 double staining. After 6 weeks proteinuria was well-established, without influx of interstitial macrophages and myofibroblasts, collagen deposition, osteopontin expression (tubular activation) or LV formation. At 12 weeks, a ∼3-fold increase in cortical LV density was found (p<0.001), gradually increasing over time. This corresponded with a significant increase in tubular osteopontin expression (p<0.01) and interstitial myofibroblast numbers (p<0.05), whereas collagen deposition and macrophage numbers were not yet increased. VEGF-C was mostly expressed by tubular cells rather than interstitial cells. Cultured tubular cells stimulated with FCS showed a dose-dependent increase in mRNA and protein expression of VEGF-C which was not observed by human albumin stimulation. We conclude that chronic proteinuria provoked lymphangiogenesis in temporal conjunction with tubular osteopontin expression and influx of myofibroblasts, that preceded interstitial fibrosis.
doi:10.1371/journal.pone.0050209
PMCID: PMC3506584  PMID: 23189189
4.  UMOD as a susceptibility gene for end-stage renal disease 
BMC Medical Genetics  2012;13:78.
Background
In recent genetic association studies, common variants including rs12917707 in the UMOD locus have shown strong evidence of association with eGFR, prevalent and incident chronic kidney disease and uromodulin urinary concentration in general population cohorts. The association of rs12917707 with end-stage renal disease (ESRD) in a recent case-control study was only nominally significant.
Methods
To investigate whether rs12917707 associates with ESRD, graft failure (GF) and urinary uromodulin levels in an independent cohort, we genotyped 1142 ESRD patients receiving a renal transplantation and 1184 kidney donors as controls. After transplantation, 1066 renal transplant recipients were followed up for GF. Urinary uromodulin concentration was measured at median [IQR] 4.2 [2.2-6.1] yrs after kidney transplantation.
Results
The rs12917707 minor allele showed association with lower risk of ESRD (OR 0.89 [0.76-1.03], p = 0.04) consistent in effect size and direction with the previous report (Böger et al, PLoS Genet 2011). Meta-analysis of these findings showed significant association of rs12917707 with ESRD (OR 0.91 [0.85-98], p = 0.008). In contrast, rs12917707 was not associated with incidence of GF. Urinary uromodulin concentration was lower in recipients-carriers of the donor rs12917707 minor allele as compared to non-carriers, again consistent with previous observations in general population cohorts.
Conclusions
Our study thus corroborates earlier evidence and independently confirms the association between UMOD and ESRD.
doi:10.1186/1471-2350-13-78
PMCID: PMC3495046  PMID: 22947327
UMOD; Uromodulin; Polymorphisms; SNP; End-stage renal disease; Kidney transplantation
5.  CUBN as a Novel Locus for End-Stage Renal Disease: Insights from Renal Transplantation 
PLoS ONE  2012;7(5):e36512.
Chronic kidney disease (CKD) is a complex disorder. As genome-wide association studies identified cubilin gene CUBN as a locus for albuminuria, and urinary protein loss is a risk factor for progressive CKD, we tested the hypothesis that common genetic variants in CUBN are associated with end-stage renal disease (ESRD) and proteinuria. First, a total of 1142 patients with ESRD, admitted for renal transplantation, and 1186 donors were genotyped for SNPs rs7918972 and rs1801239 (case-control study). The rs7918972 minor allele frequency (MAF) was higher in ESRD patients comparing to kidney donors, implicating an increased risk for ESRD (OR 1.39, p = 0.0004) in native kidneys. Second, after transplantation recipients were followed for 5.8 [3.8–9.2] years (longitudinal study) documenting ESRD in transplanted kidneys – graft failure (GF). During post-transplant follow-up 92 (9.6%) cases of death-censored GF occurred. Donor rs7918972 MAF, representing genotype of the transplanted kidney, was 16.3% in GF vs 10.7% in cases with functioning graft. Consistently, a multivariate Cox regression analysis showed that donor rs7918972 is a predictor of GF, although statistical significance was not reached (HR 1.53, p = 0.055). There was no association of recipient rs7918972 with GF. Rs1801239 was not associated with ESRD or GF. In line with an association with the outcome, donor rs7918972 was associated with elevated proteinuria levels cross-sectionally at 1 year after transplantation. Thus, we identified CUBN rs7918972 as a novel risk variant for renal function loss in two independent settings: ESRD in native kidneys and GF in transplanted kidneys.
doi:10.1371/journal.pone.0036512
PMCID: PMC3344899  PMID: 22574174
6.  N-Glycosylation of Carnosinase Influences Protein Secretion and Enzyme Activity 
Diabetes  2010;59(8):1984-1990.
OBJECTIVE
The (CTG)n polymorphism in the serum carnosinase (CN-1) gene affects CN-1 secretion. Since CN-1 is heavily glycosylated and glycosylation might influence protein secretion as well, we tested the role of N-glycosylation for CN-1 secretion and enzyme activity. We also tested whether CN-1 secretion is changed under hyperglycemic conditions.
RESULTS
N-glycosylation of CN-1 was either inhibited by tunicamycin in pCSII-CN-1–transfected Cos-7 cells or by stepwise deletion of its three putative N-glycosylation sites. CN-1 protein expression, N-glycosylation, and enzyme activity were assessed in cell extracts and supernatants. The influence of hyperglycemia on CN-1 enzyme activity in human serum was tested in homozygous (CTG)5 diabetic patients and healthy control subjects.
Tunicamycin completely inhibited CN-1 secretion. Deletion of all N-glycosylation sites was required to reduce CN-1 secretion efficiency. Enzyme activity was already diminished when two sites were deleted. In pCSII-CN-1–transfected Cos-7 cells cultured in medium containing 25 mmol/l d-glucose, the immature 61 kilodaltons (kDa) CN-1 immune reactive band was not detected. This was paralleled by an increased GlcNAc expression in cell lysates and CN-1 expression in the supernatants. Homozygous (CTG)5 diabetic patients had significantly higher serum CN-1 activity compared with genotype-matched, healthy control subjects.
CONCLUSIONS
We conclude that apart from the (CTG)n polymorphism in the signal peptide of CN-1, N-glycosylation is essential for appropriate secretion and enzyme activity. Since hyperglycemia enhances CN-1 secretion and enzyme activity, our data suggest that poor blood glucose control in diabetic patients might result in an increased CN-1 secretion even in the presence of the (CTG)5 allele.
doi:10.2337/db09-0868
PMCID: PMC2911063  PMID: 20460427
7.  Differential Expression of Proteoglycans in Tissue Remodeling and Lymphangiogenesis after Experimental Renal Transplantation in Rats 
PLoS ONE  2010;5(2):e9095.
Background
Chronic transplant dysfunction explains the majority of late renal allograft loss and is accompanied by extensive tissue remodeling leading to transplant vasculopathy, glomerulosclerosis and interstitial fibrosis. Matrix proteoglycans mediate cell-cell and cell-matrix interactions and play key roles in tissue remodeling. The aim of this study was to characterize differential heparan sulfate proteoglycan and chondroitin sulfate proteoglycan expression in transplant vasculopathy, glomerulosclerosis and interstitial fibrosis in renal allografts with chronic transplant dysfunction.
Methods
Renal allografts were transplanted in the Dark Agouti-to-Wistar Furth rat strain combination. Dark Agouti-to-Dark Agouti isografts and non-transplanted Dark Agouti kidneys served as controls. Allograft and isograft recipients were sacrificed 66 and 81 days (mean) after transplantation, respectively. Heparan sulfate proteoglycan (collXVIII, perlecan and agrin) and chondroitin sulfate proteoglycan (versican) expression, as well as CD31 and LYVE-1 (vascular and lymphatic endothelium, respectively) expression were (semi-) quantitatively analyzed using immunofluorescence.
Findings
Arteries with transplant vasculopathy and sclerotic glomeruli in allografts displayed pronounced neo-expression of collXVIII and perlecan. In contrast, in interstitial fibrosis expression of the chondroitin sulfate proteoglycan versican dominated. In the cortical tubular basement membranes in both iso- and allografts, induction of collXVIII was detected. Allografts presented extensive lymphangiogenesis (p<0.01 compared to isografts and non-transplanted controls), which was associated with induced perlecan expression underneath the lymphatic endothelium (p<0.05 and p<0.01 compared to isografts and non-transplanted controls, respectively). Both the magnitude of lymphangiogenesis and perlecan expression correlated with severity of interstitial fibrosis and impaired graft function.
Interpretation
Our results reveal that changes in the extent of expression and the type of proteoglycans being expressed are tightly associated with tissue remodeling after renal transplantation. Therefore, proteoglycans might be potential targets for clinical intervention in renal chronic transplant dysfunction.
doi:10.1371/journal.pone.0009095
PMCID: PMC2816722  PMID: 20140097

Results 1-7 (7)