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1.  Mortality in chronic kidney disease and renal replacement therapy: a population-based cohort study 
BMJ Open  2014;4(2):e004251.
Objective
To compare mortality in chronic kidney disease (CKD) stages 4 and 5 (estimated glomerular filtration rate <30 mL/min/1.73 m2), peritoneal dialysis, haemodialysis and transplanted patients.
Design
Population-based cohort study.
Setting
Swedish national healthcare system.
Participants
Swedish adult patients with CKD stages 4 and 5 (n=3040; mean age 66 years), peritoneal dialysis (n=725; 60 years), haemodialysis (n=1791; 62 years) and renal transplantation (n=606; 48 years) were identified in Stockholm County clinical quality registers for renal disease between 1999 and 2010. Five general population controls were matched to each patient by age, sex and index year.
Exposure
CKD status (stage 4 or 5/peritoneal dialysis/haemodialysis/transplanted).
Primary outcome
All-cause mortality was ascertained from the Swedish Causes of Death Register. Mortality HRs were estimated using Cox regression conditioned on age, sex, diabetes status, education level and index year.
Results
During 6553 person-years, 766 patients with CKD stages 4 and 5 died (deaths/100 person-years 12, 95% CI 11 to 13) compared with 186 deaths during 1113 person-years in peritoneal dialysis (17, 95% CI 15 to 19), 924 deaths during 3680 person-years in haemodialysis (25, 95% CI 23 to 27) and 53 deaths during 2935 person-years in transplanted patients (1.8, 95% CI 1.4 to 2.4). Against matched general population controls, the mortality HR was 3.6 (95% CI 3.2 to 4.0) for CKD, 5.6 (95% CI 3.5 to 8.9) for transplanted patients, 9.2 (95% CI 6.6 to 12.7) for peritoneal dialysis and 12.6 (95% CI 10.8 to 14.6) for haemodialysis. In direct comparison versus CKD, the mortality HR was 1.7 (95% CI 1.4 to 2.1) for peritoneal dialysis, 2.6 (95% CI 2.3 to 2.9) for haemodialysis and 0.5 (95% CI 0.3 to 0.7) for transplanted patients.
Conclusions
We did not find support for mortality in CKD to be similar to dialysis mortality. The patients with CKD stages 4 and 5 had considerably lower mortality risk than dialysis patients, and considerably higher risk than transplanted patients and matched general population controls.
doi:10.1136/bmjopen-2013-004251
PMCID: PMC3931988  PMID: 24549162
chronic kidney disease; mortality; renal replacement therapy; transplantation
2.  Hemoglobin A1c Levels and Mortality in the Diabetic Hemodialysis Population 
Diabetes Care  2012;35(12):2527-2532.
OBJECTIVE
Lowering hemoglobin A1c to <7% reduces the risk of microvascular complications of diabetes, but the importance of maintaining this target in diabetes patients with kidney failure is unclear. We evaluated the relationship between A1c levels and mortality in an international prospective cohort study of hemodialysis patients.
RESEARCH DESIGN AND METHODS
Included were 9,201 hemodialysis patients from 12 countries (Dialysis Outcomes and Practice Patterns Study 3 and 4, 2006–2010) with type 1 or type 2 diabetes and at least one A1c measurement during the first 8 months after study entry. Associations between A1c and mortality were assessed with Cox regression, adjusting for potential confounders.
RESULTS
The association between A1c and mortality was U-shaped. Compared with an A1c of 7–7.9%, the hazard ratios (95% CI) for A1c levels were 1.35 (1.09–1.67) for <5%, 1.18 (1.01–1.37) for 5–5.9%, 1.21 (1.05–1.41) for 6–6.9%, 1.16 (0.94–1.43) for 8–8.9%, and 1.38 (1.11–1.71) for ≥9.0%, after adjustment for age, sex, race, BMI, serum albumin, years of dialysis, serum creatinine, 12 comorbid conditions, insulin use, hemoglobin, LDL cholesterol, country, and study phase. Diabetes medications were prescribed for 35% of patients with A1c <6% and not prescribed for 29% of those with A1c ≥9%.
CONCLUSIONS
A1c levels strongly predicted mortality in hemodialysis patients with type 1 or type 2 diabetes. Mortality increased as A1c moved further from 7–7.9%; thus, target A1c in hemodialysis patients may encompass values higher than those recommended by current guidelines. Modifying glucose-lowering medicines for dialysis patients to target A1c levels within this range may be a modifiable practice to improve outcomes.
doi:10.2337/dc12-0573
PMCID: PMC3507600  PMID: 22912431
3.  Leukocyte Proliferation and Immune Modulator Production in Patients with Chronic Kidney Disease 
PLoS ONE  2013;8(8):e73141.
Introduction
In Chronic Kidney Disease (CKD), immune cells are affected by uremic retention toxins. Given this effect, we analyzed lymphocyte proliferative response and immune modulators production following in vitro stimulation.
Methods
Whole blood was drawn from healthy controls, patients with eGFR <20 ml/min/1.73 m2 (Pre-dialysis, CKD stages 4 and 5) and hemodialysis patients (stage 5D). Peripheral cells were incubated for six days with pokeweed mitogen, concanavalin A, Staphylococcus enterotoxin A or influenza A vaccine. Peripheral lymphocyte proliferation was then analyzed by the “Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood” (FASCIA) method, and cytokine profile in the cell supernatants was analyzed by the Milliplex multi-array method.
Results
The absolute number of lymphoblasts in response to mitogenic stimulation and the number of cells in each CD4+ and CD8+ subpopulation were similar comparing the three groups, except for a single decline in number of lymphoblasts after stimulation with Staphylococcus enterotoxin A, comparing dialysis patients with healthy controls. Levels of interleukin (IL)-2 (p=0.026), -10 (p=0.019) and -15 (p=0.027) in the Staphylococcus enterotoxin A-stimulated supernatant were lower in hemodialysis patients compared to healthy controls. Levels of IL-15 (p=0.017) from pre-dialysis patients and levels of IL-5 (p=0.019) from hemodialysis patients in influenza A vaccine-stimulated supernatants were also lower compared to controls. In pokeweed mitogen–stimulated supernatant, IL-2 levels (p=0.013) were lower in hemodialysis patients compared to pre-dialysis patients. TNF-α, IL-10, IL-12, IL-15, IL-8, MCP-1, IP-10, IFN-α2, IL-1α and eotaxin levels were all significantly higher in plasma obtained from CKD patients.
Conclusion
Our results suggest that T-cells from CKD patients have similar proliferative response to stimulation compared with healthy individuals. Moreover, however the immune cells show inability to produce selected cytokines, most likely due to the uremic milieu or dialysis procedure.
doi:10.1371/journal.pone.0073141
PMCID: PMC3739766  PMID: 23951343
4.  Serum phosphorus reduction in dialysis patients treated with cinacalcet for secondary hyperparathyroidism results mainly from parathyroid hormone reduction 
Clinical Kidney Journal  2013;6(3):287-294.
Background
The calcimimetic cinacalcet lowers parathyroid hormone (PTH), calcium (Ca) and phosphorus (P) in dialysis patients with secondary hyperparathyroidism (SHPT). We explored serum P changes in dialysis patients treated with cinacalcet, while controlling for vitamin D sterol and phosphate binder (PB) changes, based on data from the pan-European observational study ECHO.
Methods
Patients were categorized by serum P change (decreased/unchanged/increased) at 12 months after starting cinacalcet and subcategorized by vitamin D sterol and PB dose changes (decreased/unchanged/increased). The impact of PTH, Ca and P, and vitamin D sterol, PB and cinacalcet doses (absolute values and/or change) was evaluated. Predictors of P change were explored using univariate and multivariate general linear models (GLM) and logistic regression analysis.
Results
At Month 12, 661 (41%) of 1607 patients had decreased, 61 (4%) unchanged and 400 (25%) increased serum P, while 485 patients had missing data. In 45% of the patients with serum P reduction, vitamin D was either increased or unchanged and P binders decreased or unchanged. PTH was a key predictor of serum P reduction, with an estimated 3% decrease in P per 10% reduction in PTH. Changes in vitamin D sterol and PB doses were not generally significant factors in GLM and regression analyses.
Conclusions
The serum P reduction observed in a significant proportion of dialysis patients after adding cinacalcet to an existing therapeutic regimen for SHPT appears to result mainly from PTH reduction, rather than from changes in vitamin D sterol or PB doses. Financial support for the ECHO study was provided by Amgen.
doi:10.1093/ckj/sft026
PMCID: PMC3665312  PMID: 23717787
chronic kidney disease; cinacalcet; secondary hyperparathyroidism; serum phosphorus
5.  Genetic Risk Factors in Lupus Nephritis and IgA Nephropathy – No Support of an Overlap 
PLoS ONE  2010;5(5):e10559.
Background
IgA nephropathy (IgAN) and nephritis in Systemic Lupus Erythematosus (SLE) are two common forms of glomerulonephritis in which genetic findings are of importance for disease development. We have recently reported an association of IgAN with variants of TGFB1. In several autoimmune diseases, particularly in SLE, IRF5, STAT4 genes and TRAF1-C5 locus have been shown to be important candidate genes. The aim of this study was to compare genetic variants from the TGFB1, IRF5, STAT4 genes and TRAF1-C5 locus with susceptibility to IgAN and lupus nephritis in two Swedish cohorts.
Patients and Methods
We genotyped 13 single nucleotide polymorphisms (SNPs) in four genetic loci in 1252 DNA samples from patients with biopsy proven IgAN or with SLE (with and without nephritis) and healthy age- and sex-matched controls from the same population in Sweden.
Results
Genotype and allelic frequencies for SNPs from selected genes did not differ significantly between lupus nephritis patients and SLE patients without nephritis. In addition, haplotype analysis for seven selected SNPs did not reveal a difference for the SLE patient groups with and without nephritis. Moreover, none of these SPNs showed a significant difference between IgAN patients and healthy controls. IRF5 and STAT4 variants remained significantly different between SLE cases and healthy controls. In addition, the data did not show an association of TRAF1-C5 polymorphism with susceptibility to SLE in this Swedish population.
Conclusion
Our data do not support an overlap in genetic susceptibility between patients with IgAN or SLE and reveal no specific importance of SLE associated SNPs for the presence of lupus nephritis.
doi:10.1371/journal.pone.0010559
PMCID: PMC2866667  PMID: 20479942
6.  Genetic variation in the transforming growth factor-β1 gene is associated with susceptibility to IgA nephropathy 
Nephrology Dialysis Transplantation  2009;24(10):3061-3067.
Background. There is growing evidence of genetic risk for susceptibility to IgA nephropathy. Among several candidate genes related to immunological regulation in renal tissue, TGFB1 is known to be a contributor to proliferation and the development of fibrosis.
Methods. We analysed several SNPs in a region of this gene using 212 DNA samples from biopsy-proven IgA nephropathy patients, 146 men and 66 women and 477 healthy age-matched controls (321 men and 156 women) from the same population in Sweden.
Results. Frequencies of four out of five selected SNPs (rs6957, rs2241715, rs1800471, rs1982073 and rs1800469) were found to significantly differ between male patients and male controls in a co-dominant model (corrected P ≤ 0.05) and of two SNPs (rs1982073 and rs1800469) in the allelic model (P ≤ 0.05 in 100 000 permutation test). Haplotype analysis for five selected SNPs revealed a significant association of TGGCG with protective effect (P = 0.0012, empirical P = 0.006, 100 000 permutations) and of CTGTA with susceptibility effect (P = 0.0018, empirical P = 0.008, 100 000 permutations). In our study, no association with TGFB1 variations was found when comparing female patients and female controls. No association was found for TGFB1 markers with disease progression for selected individuals from the patient's group. In addition, meta-analysis performed for SNP rs1982073 for combined patients and controls from our study together with published data from two independent studies showed a significant association.
Conclusions. Our experimental data together with the meta-analysis suggest TGFB1 as an important candidate gene for further biological studies of IgA nephropathy and as a possible target for therapy. Our data also indicate a possibility of a gender effect in the genetic background of IgA nephropathy.
doi:10.1093/ndt/gfp079
PMCID: PMC2747497  PMID: 19258388
IgA nephropathy; polymorphism; SNP; TGFB1
7.  Activation of Wnt/β-Catenin Pathway in Monocytes Derived from Chronic Kidney Disease Patients 
PLoS ONE  2013;8(7):e68937.
Patients with chronic kidney disease (CKD) have significantly increased morbidity and mortality resulting from infections and cardiovascular diseases. Since monocytes play an essential role in host immunity, this study was directed to explore the gene expression profile in order to identify differences in activated pathways in monocytes relevant to the pathophysiology of atherosclerosis and increased susceptibility to infections. Monocytes from CKD patients (stages 4 and 5, estimated GFR <20 ml/min/1.73 m2) and healthy donors were collected from peripheral blood. Microarray gene expression profile was performed and data were interpreted by GeneSpring software and by PANTHER tool. Western blot was done to validate the pathway members. The results demonstrated that 600 and 272 genes were differentially up- and down regulated respectively in the patient group. Pathways involved in the inflammatory response were highly expressed and the Wnt/β-catenin signaling pathway was the most significant pathway expressed in the patient group. Since this pathway has been attributed to a variety of inflammatory manifestations, the current findings may contribute to dysfunctional monocytes in CKD patients. Strategies to interfere with this pathway may improve host immunity and prevent cardiovascular complications in CKD patients.
doi:10.1371/journal.pone.0068937
PMCID: PMC3720736  PMID: 23935909
8.  Uropathogenic Escherichia coli Modulates Immune Responses and Its Curli Fimbriae Interact with the Antimicrobial Peptide LL-37 
PLoS Pathogens  2010;6(7):e1001010.
Bacterial growth in multicellular communities, or biofilms, offers many potential advantages over single-cell growth, including resistance to antimicrobial factors. Here we describe the interaction between the biofilm-promoting components curli fimbriae and cellulose of uropathogenic E. coli and the endogenous antimicrobial defense in the urinary tract. We also demonstrate the impact of this interplay on the pathogenesis of urinary tract infections. Our results suggest that curli and cellulose exhibit differential and complementary functions. Both of these biofilm components were expressed by a high proportion of clinical E. coli isolates. Curli promoted adherence to epithelial cells and resistance against the human antimicrobial peptide LL-37, but also increased the induction of the proinflammatory cytokine IL-8. Cellulose production, on the other hand, reduced immune induction and hence delayed bacterial elimination from the kidneys. Interestingly, LL-37 inhibited curli formation by preventing the polymerization of the major curli subunit, CsgA. Thus, even relatively low concentrations of LL-37 inhibited curli-mediated biofilm formation in vitro. Taken together, our data demonstrate that biofilm components are involved in the pathogenesis of urinary tract infections by E. coli and can be a target of local immune defense mechanisms.
Author Summary
Most infections of the urinary tract are caused by uropathogenic E. coli. On abiotic surfaces, these bacteria are able to form biofilms, which protect them from various adverse environmental conditions. In this study, we sought to investigate whether two E. coli biofilm components, curli fimbriae and cellulose, provide a similar protection against innate immune defense mechanisms of the urinary tract. We put special emphasis on the interaction with the human antimicrobial peptide LL-37, which plays a crucial role in the protection against uropathogenic E. coli. We demonstrate that curli expression specifically reduces bacterial sensitivity to LL-37 by binding the peptide before reaching the bacterial cell membrane and exhibiting its bactericidal activity. A more general protection is mediated by cellulose, possibly by hiding immunogenic surface structures of the bacterium. In addition to providing protection, curli are also targeted by the immune system. The formation of new curli fibers is inhibited in the presence of LL-37. Moreover, curliated bacteria show higher immunogenicity than their non-curliated counterparts. Cellulose expression, on the other hand, appears to impair initial host colonization. In conclusion, our findings demonstrate an example of the tight interplay between bacterial virulence factors and the host immune defense.
doi:10.1371/journal.ppat.1001010
PMCID: PMC2908543  PMID: 20661475

Results 1-8 (8)