Publications by authors named "Uyen Huynh-Do"

69 Publications

Fetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress.

Nat Commun 2021 01 22;12(1):549. Epub 2021 Jan 22.

Department of Nephrology and Hypertension, Bern University Hospital, Freiburgstrasse 15, 3010, Bern, Switzerland.

Intrauterine growth restriction (IUGR) is associated with reduced kidney size at birth, accelerated renal function decline, and increased risk for chronic kidney and cardiovascular diseases in adults. Precise mechanisms underlying fetal programming of adult diseases remain largely elusive and warrant extensive investigation. Setting up a mouse model of hypoxia-induced IUGR, fetal adaptations at mRNA, protein and cellular levels, and their long-term functional consequences are characterized, using the kidney as a readout. Here, we identify fetuin-A as an evolutionary conserved HIF target gene, and further investigate its role using fetuin-A KO animals and an adult model of ischemia-reperfusion injury. Beyond its role as systemic calcification inhibitor, fetuin-A emerges as a multifaceted protective factor that locally counteracts calcification, modulates macrophage polarization, and attenuates inflammation and fibrosis, thus preserving kidney function. Our study paves the way to therapeutic approaches mitigating mineral stress-induced inflammation and damage, principally applicable to all soft tissues.
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http://dx.doi.org/10.1038/s41467-020-20832-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822914PMC
January 2021

Pre-transplant Social Adaptability Index and clinical outcomes in renal transplantation: The Swiss Transplant Cohort study.

Clin Transplant 2021 Apr 6;35(4):e14218. Epub 2021 Mar 6.

Institute of Nursing Science, Department of Public Health, University of Basel, Basel, Switzerland.

Background: The impact of pre-transplant social determinants of health on post-transplant outcomes remains understudied. In the United States, poor clinical outcomes are associated with underprivileged status, as assessed by the Social Adaptability Index (SAI), a composite score of education, employment status, marital status, household income, and substance abuse. Using data from the Swiss Transplant Cohort Study (STCS), we determined the SAI's predictive value regarding two post-transplant outcomes: all-cause mortality and return to dialysis.

Methods: Between 2012 and 2018, we included adult renal transplant patients (aged ≥ 18 years) with pre-transplant assessment SAI scores, calculated from a STCS Psychosocial Questionnaire. Time to all-cause mortality and return to dialysis were predicted using Cox regression.

Results: Of 1238 included patients (mean age: 53.8 ± 13.2 years; 37.9% female; median follow-up time: 4.4 years [IQR: 2.7]), 93 (7.5%) died and 57 (4.6%) returned to dialysis. The SAI's hazard ratio was 0.94 (95%CI: 0.88-1.01; p = .09) for mortality and 0.93 (95%CI: 0.85-1.02; p = .15) for return to dialysis.

Conclusions: In contrast to most published studies on social deprivation, analysis of this Swiss sample detected no significant association between SAI score and mortality or return to dialysis.
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http://dx.doi.org/10.1111/ctr.14218DOI Listing
April 2021

Quality of Life in Autosomal Dominant Polycystic Kidney Disease Patients Treated With Tolvaptan.

Kidney Med 2020 Mar-Apr;2(2):162-171. Epub 2020 Feb 26.

Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Rationale & Objective: The impact of tolvaptan on health-related quality-of-life (HRQoL) in patients with autosomal dominant polycystic kidney disease (ADPKD) is unknown. To address this knowledge gap, we studied patient-reported HRQoL in patients enrolled in the Bern ADPKD registry.

Study Design: Prospective cohort study.

Settings & Participants: Inclusion criteria were age 18 years or older, clinical diagnosis of ADPKD, and informed consent. The main exclusion criterion was need for kidney replacement therapy.

Outcome: HRQoL was assessed using the standardized Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire at start of the study (baseline) and after 1 year (follow-up). The KDQOL-SF has 2 parts: a generic 36-Item Health Survey instrument with 8 subscores and 2 summary scores and a kidney disease-specific instrument to assess health concerns. Higher scores indicate better HRQoL. The influence of tolvaptan treatment on HRQoL and kidney-specific health concerns was analyzed using analysis of covariance, adjusting for HRQoL and health concerns before the start of the study, sex, and age.

Results: In 38 of 121 registry patients, tolvaptan treatment was initiated. Within the first 3 months, treatment had to be discontinued in 6 (16%) patients due to aquaretic side effects (n = 4; 11%) or elevated liver enzyme levels (n = 2; 5%), and a dose reduction was necessary in 8 (21%) patients. We included 98 patients (30 with and 68 without tolvaptan treatment) in the analysis for which baseline and 1-year follow-up data were available. At follow-up, and after adjusting for baseline scores, sex, and age, HRQoL and kidney-specific health concerns were not influenced by tolvaptan treatment, except for patient satisfaction, which was increased.

Limitations: Observational study design, monocentric study at tertiary referral hospital, almost exclusively white study population, grant support by Otsuka Pharmaceuticals.

Conclusions: Our results indicate that tolvaptan does not significantly affect HRQoL in patients with ADPKD who tolerate treatment beyond the first 3 months of therapy.
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http://dx.doi.org/10.1016/j.xkme.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487949PMC
February 2020

Urinary Lithogenic Risk Profile in ADPKD Patients Treated with Tolvaptan.

Clin J Am Soc Nephrol 2020 07 11;15(7):1007-1014. Epub 2020 Jun 11.

Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Background And Objectives: Nephrolithiasis is a common health problem in autosomal dominant polycystic kidney disease (ADPKD) and significantly contributes to patient morbidity. Recently, Tolvaptan has been introduced for the treatment of ADPKD, but whether it is associated with alterations of the urinary lithogenic risk profile remains unknown.

Design, Setting, Participants, & Measurements: We conducted an analysis of participants enrolled in the Bern ADPKD registry, a prospective observational cohort study. Twenty-four-hour urine analyses were performed at baseline and then at yearly follow-ups. Relative supersaturation ratios for calcium oxalate, brushite, and uric acid were calculated with the program EQUIL2. Unadjusted and multivariable mixed-effects linear regression models, adjusted for age, sex, body mass index, eGFR, net acid excretion, and height-adjusted total kidney volume, were used to assess the association of Tolvaptan with urinary parameters relevant for kidney stone formation. The maximum individual follow-up time was 3 years, median follow-up time 1.9 years, and cumulative follow-up time 169 years.

Results: In total, 125 participants (38 with and 87 without Tolvaptan treatment) were included in the analysis. In multivariable analysis, Tolvaptan treatment was associated [adjusted estimate of the difference between Tolvaptan and no Tolvaptan; 95% confidence interval (CI)] with lower urine relative supersaturation ratios for calcium oxalate (-0.56; 95% CI, -0.82 to -0.3; <0.001), brushite (-0.33; 95% CI, -0.54 to -0.11; =0.004), and uric acid (-0.62; 95% CI, -0.88 to -0.37; <0.001), and with higher urine citrate in mmol/mmol creatinine per day (0.25; 95% CI, 0.05 to 0.46; =0.02) and calcium in mmol/mmol creatinine per day (0.31; 95% CI, 0.09 to 0.53; =0.006) excretion. In addition, Tolvaptan treatment was associated with lower net acid excretion in mEq/mmol creatinine per day (-0.54; 95% CI, -0.90 to -0.17; =0.004) and higher net gastrointestinal alkali absorption in mEq/mmol creatinine per day (0.57; 95% CI, 0.26 to 0.88; <0.001).

Conclusions: Tolvaptan treatment is associated with a significantly improved urinary lithogenic risk profile in patients with ADPKD.
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http://dx.doi.org/10.2215/CJN.13861119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341771PMC
July 2020

Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1.

Kidney Int 2020 09 22;98(3):717-731. Epub 2020 May 22.

Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.
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http://dx.doi.org/10.1016/j.kint.2020.04.038DOI Listing
September 2020

Identification of highly active systemic lupus erythematosus by combined type I interferon and neutrophil gene scores vs classical serologic markers.

Rheumatology (Oxford) 2020 11;59(11):3468-3478

Division of Immunology and Allergy, University Hospital and School of Medicine, Geneva.

Objectives: In SLE, heterogeneous clinical expression and activity may reflect diverse pathogenic and/or effector mechanisms. We investigated SLE heterogeneity by assessing the expression of three gene sets representative of type I IFN (IFN-I), polymorphonuclear neutrophil (PMN) and plasmablast (PB) signatures in a well-characterized, multidisciplinary cohort of SLE patients. We further assessed whether individual gene products could be representative of these three signatures.

Methods: Whole blood, serum and clinical data were obtained from 140 SLE individuals. Gene expression was assessed by NanoString technology, using a panel of 37 probes to compute six IFN-I, one PMN and one PB scores. Protein levels were measured by ELISA.

Results: Depending on the score, 45-50% of SLE individuals showed high IFN-I gene expression. All six IFN-I scores were significantly associated with active skin involvement, and two of six were associated with arthritis. IFN-induced Mx1 protein (MX1) level was correlated with IFN-I score (P < 0.0001) and associated with a similar clinical phenotype. In all, 25% of SLE individuals showed high PMN gene expression, associated with SLE fever, serositis, leukopoenia and glucocorticoid use. PB gene expression was highly affected by immunosuppressant agents, with no association with SLE features. Combined IFN-I and PMN gene scores were significantly associated with high disease activity and outperformed anti-dsDNA and anti-C1q autoantibody and complement levels for predicting SLE activity.

Conclusion: IFN-I and PMN gene scores segregate with distinct SLE clinical features, and their combination may identify high disease activity. MX1 protein level performed similar to IFN-I gene expression.
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http://dx.doi.org/10.1093/rheumatology/keaa167DOI Listing
November 2020

Dialysis after graft loss: a Swiss experience.

Nephrol Dial Transplant 2020 12;35(12):2182-2190

Division of Nephrology, University Hospital Zürich, Zürich, Switzerland.

Background: Patients returning to dialysis after graft loss have high early morbidity and mortality.

Methods: We used data from the Swiss Transplant Cohort Study to describe the current practice and outcomes in Switzerland. All patients who received a renal allograft between May 2008 and December 2014 were included. The patients with graft loss were divided into two groups depending on whether the graft loss occurred within 1 year after transplantation (early graft loss group) or later (late graft loss group). Patients with primary non-function who never gained graft function were excluded.

Results: Seventy-seven out of 1502 patients lost their graft during follow-up, 40 within 1 year after transplantation. Eleven patients died within 30 days after allograft loss. Patient survival was 86, 81 and 74% at 30, 90 and 365 days after graft loss, respectively. About 92% started haemodialysis, 62% with definitive vascular access, which was associated with decreased mortality (hazard ratio = 0.28). At the time of graft loss, most patients were on triple immunosuppressive therapy with significant reduction after nephrectomy. One year after graft loss, 77.5% (31 of 40) of patients in the early and 43.2% (16 out of 37) in the late-loss group had undergone nephrectomy. Three years after graft loss, 36% of the patients with early and 12% with late graft loss received another allograft.

Conclusion: In summary, our data illustrate high mortality, and a high number of allograft nephrectomies and re-transplantations. Patients commencing haemodialysis with a catheter had significantly higher mortality than patients with definitive access. The role of immunosuppression reduction and allograft nephrectomy as interdependent factors for mortality and re-transplantation needs further evaluation.
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http://dx.doi.org/10.1093/ndt/gfaa037DOI Listing
December 2020

Anti-C1q Antibodies as Occurring in Systemic Lupus Erythematosus Could Be Induced by an Epstein-Barr Virus-Derived Antigenic Site.

Front Immunol 2019 7;10:2619. Epub 2019 Nov 7.

Clinical Immunology, Department of Biomedicine and Division of Internal Medicine, University and University Hospital Basel, Basel, Switzerland.

Previous infection with Epstein-Barr virus (EBV) is believed to trigger autoimmunity and to drive autoantibody generation as occurring in patients with systemic lupus erythematosus (SLE). Complement C1q and autoantibodies targeting it (anti-C1q) are also considered to be involved in the pathogenesis of SLE, independently of the impact of environmental insults. Still, the circumstances under which these autoantibodies arise remain elusive. By studying a major antigenic site of C1q targeted by anti-C1q (A08), we aimed to determine environmental factors and possible mechanisms leading to the development of anti-C1q. First, we determined antigenic residues of A08 that were critical for the binding of anti-C1q; importantly, we found the binding to depend on amino-acid-identity. Anti-C1q of SLE patients targeting these critical antigenic residues specifically cross-reacted with the EBV-related EBNA-1 (Epstein-Barr virus nuclear antigen 1)-derived peptide EBNA348. In a cohort of 180 SLE patients we confirmed that patients that were seropositive for EBV and recognized the EBNA348 peptide had increased levels of anti-A08 and anti-C1q, respectively. The correlation of anti-EBNA348 with anti-A08 levels was stronger in SLE patients than in matched healthy controls. Finally, EBNA348 peptide-immunization of C1q mice induced the generation of cross-reactive antibodies which recognized both the A08 epitope of C1q and intact C1q. These findings suggest that anti-C1q in SLE patients could be induced by an EBV-derived epitope through molecular mimicry, thereby further supporting the pathogenic role of EBV in the development of SLE. Considering the role of C1q and anti-C1q, modifying the anti-EBV response might be a promising strategy to improve the course of the disease.
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http://dx.doi.org/10.3389/fimmu.2019.02619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853867PMC
November 2020

Susceptibility of BAFF-var allele carriers to severe SLE with occurrence of lupus nephritis.

BMC Nephrol 2019 11 21;20(1):430. Epub 2019 Nov 21.

Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.

Background: Dysregulation of the B-cell activating factor (BAFF) system is involved in the pathogenesis of systemic lupus erythematosus (SLE). Increased serum concentrations of BAFF are related to lupus nephritis and disease activity among SLE patients. Recently, a variant of the BAFF-encoding gene, BAFF-var, was identified to be associated with autoimmune diseases, in particular SLE, and to promote the production of soluble BAFF. The present study aimed to assess the prevalence of BAFF-var in a cohort of 195 SLE patients and to analyze the association of the BAFF-var genotype (TNSF13B) with various manifestations of SLE.

Methods: A cohort of 195 SLE patients from Central Europe, including 153 patients from the Swiss SLE Cohort Study and 42 patients from the University Hospital Essen, Germany, underwent genotyping for detection of BAFF-var allele.

Results: Of the 195 patients, 18 (9.2%) tested positive for BAFF-var variant according to the minor allele frequency of 4.6%. The presence of BAFF-var was associated with the occurrence of lupus nephritis (p = 0.038) (p = 0.03 and p = 0.003). Among various organ manifestations of SLE, the presence of BAFF-var was associated with the occurrence of lupus nephritis (p = 0.038; odds ratio [OR], 2.4; 95% confidence interval [CI], 0.89-6.34) and renal activity markers such as proteinuria and hematuria (p = 0.03; OR, 2.4; 95% CI, 0.9-6.4 for proteinuria; p = 0.003; OR, 3.9; 95% CI, 1.43-10.76 for hematuria). SLE patients carrying the BAFF-var allele exhibited increased disease activity at study entry, as determined by the physician's global assessment (PGA: p = 0.002; OR, 4.8; 95% CI, 1.54-14.93) and the SLE Disease Activity Index (p = 0.012; OR, 3.5; 95% CI, 1.12-11.18). Consistent with that, the percentage of patients treated with immunosuppressive agents at study entry was higher among those carrying the BAFF-var allele than among those tested negative for BAFF-var (p = 0.006; OR, 3.7; 95% CI, 1.27-10.84).

Conclusions: Our results indicate an association between the BAFF-var genotype and increased severity of SLE. Determining the BAFF-var status of SLE patients may improve the risk stratification of patients for whom the development of lupus nephritis is more likely and thus may be helpful in the follow-up care and treatment of SLE patients.
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http://dx.doi.org/10.1186/s12882-019-1623-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873527PMC
November 2019

Imaging patterns of Pneumocystis jirovecii pneumonia in HIV-positive and renal transplant patients - a multicentre study.

Swiss Med Wkly 2019 Sep 3;149:w20130. Epub 2019 Oct 3.

Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Objectives: To investigate differences in chest computed tomography (CT) and chest radiographs (CXRs) of Pneumocystis jirovecii pneumonia (PJP) between renal transplant recipients (RTRs) and human immunodeficiency virus (HIV)-positive patients.

Methods: From 2005 to 2012, 84 patients with PJP (RTR n = 24; HIV n = 60) were included in this retrospective multicentre study. Written informed consent was obtained. CT scans and CXRs were recorded within 2 weeks after the onset of symptoms. PJP diagnosis was confirmed either by cytology/histology or successful empirical treatment. Two blinded radiologists analysed the conventional chest films and CT images, and recorded the radiological lung parenchyma patterns, lymph node enlargement and pleural pathologies (pneumothorax, effusion). The radiological features of the two subgroups were compared.

Results: Consolidations and solid nodules prevailed on CT in RTRs (91.7 ± 5.6% vs 58.3 ± 6.4% with HIV, p = 0.019 and 91.7 ± 5.6% vs 51.6 ± 6.5% with HIV, p = 0.005). HIV-positive patients with PJP showed more atelectasis (41.7 ± 6.4% vs 4.2 ± 4.1% in RTRs, p = 0.017) and hilar lymph node enlargement (23.3 ± 5.5% vs 0.0 ± 0.0% in RTRs, p = 0.088). Ground glass opacification was found in all cases. Pneumothorax was a rare complication, occurring in 3% of the HIV-positive patients; no pneumothorax was found in the RTRs. On CXR, the basal lungs were more affected in HIV-positive patients as compared with RTRs (p = 0.024).

Conclusions: PJP on CT differs substantially between RTRs and HIV-positive patients. Physicians should be aware of such differences in order not to delay treatment, particularly in renal transplant recipients.
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http://dx.doi.org/10.4414/smw.2019.20130DOI Listing
September 2019

Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.

J Inherit Metab Dis 2020 03 30;43(2):326-333. Epub 2019 Sep 30.

Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this article, we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and one patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual α-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations.
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http://dx.doi.org/10.1002/jimd.12167DOI Listing
March 2020

Anti-apolipoprotein A-1 autoantibodies correlate with disease activity in systemic lupus erythematosus.

Rheumatology (Oxford) 2020 03;59(3):534-544

Division of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland.

Objectives: Apolipoprotein A-1 (ApoA-1) is a protein fraction of the high-density lipoproteins with anti-inflammatory and antioxidant properties that play a major role in reverse cholesterol transport. The presence of anti-ApoA-1 IgG has been reported in SLE to be variably associated with disease activity or cardiovascular events (CVEs). We assessed the clinical performance of anti-ApoA-1 IgG and of antibodies directed against its immunodominant F3L1 peptide (F3L1 IgG) in a well-characterized Swiss SLE cohort study.

Methods: A total of 354 biological samples and interviews from 176 individuals were studied. SLEDAI, clinical characteristics, anamnestic CVEs and therapy details were recorded. Sera were tested for the presence of anti-ApoA-1 IgG, anti-F3L1 IgG, anti-dsDNA IgG and aPL.

Results: Anti-ApoA-1 and anti-F3L1 IgG positivity was associated with higher SLEDAI, mostly due to concomitant positivity of dsDNA IgG and low complement. Variations in time of anti-ApoA-1 IgG correlated positively with variations of anti-dsDNA IgG and inversely to variations of C3 levels. No cross-reactivity was found between anti-ApoA-1 and anti-dsDNA IgG. Positivity for anti-Apo-A1 IgG was more frequent in individuals receiving 10 mg/day or more of prednisone. We did not find any significant association between anti-ApoA-1 IgG positivity and CVEs.

Conclusion: Anti-ApoA-1 and anti-F3L1 IgG in SLE correlate strongly with laboratory markers of activity, particularly with the presence and titre of dsDNA IgG. These results confirm and extend previous findings and support the use of anti-ApoA1 IgG in the clinical setting. Their role in CVEs deserves further investigation.
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http://dx.doi.org/10.1093/rheumatology/kez306DOI Listing
March 2020

Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study.

Transplantation 2019 09;103(9):1953-1963

Department of Renal Medicine, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.

Background: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail.

Methods: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids.

Results: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA.

Conclusions: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.
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http://dx.doi.org/10.1097/TP.0000000000002626DOI Listing
September 2019

Autoantibodies Against Albumin in Patients With Systemic Lupus Erythematosus.

Front Immunol 2018 2;9:2090. Epub 2018 Oct 2.

Division of Internal Medicine and Clinical Immunology laboratory, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.

Autoantibodies and aberrant immune complexes are pathological hallmarks of systemic lupus erythematosus (SLE). This study aimed to determine the occurrence of IgG autoantibodies against human serum albumin (anti-HSA IgG) and their potential association with antibodies against bovine serum albumin (anti-BSA IgG) in patients with SLE. Sera of 180 SLE patients included to the Swiss SLE Cohort Study and 188 age- and sex-matched healthy controls were evaluated. Levels of anti-HSA IgG and anti-BSA IgG were quantified by ELISA. Selected samples were further characterized using serum fractions obtained by fast liquid chromatography (FPLC). SLE patients had increased levels of anti-HSA IgG ( = 0.002) but similar levels of anti-BSA IgG compared to matched healthy controls. Anti-HSA IgG levels correlated with the SLE Disease Activity Index (SLEDAI), which was more pronounced in patients with an physician's global assessment (PGA) of ≥ 1 ( = 0.309, = 0.0066). Anti-HSA IgG was partially complexed with serum albumin but also occurred as monomeric autoantibodies in highly positive SLE patients. A positive correlation between anti-HSA IgG and anti-BSA IgG was found that was stronger in SLE patients than in healthy controls ( = 0.3172, < 0.001 vs. = 0.2122, < 0.0035). Binding of anti-BSA IgG was inhibited partially in the presence of HSA in samples with double positivity for anti-HSA and anti-BSA (median inhibition 47.9%, range 0.9-100%) and vice versa. In SLE patients there is an increased prevalence of anti-HSA IgG antibodies that are associated with SLE disease activity.
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http://dx.doi.org/10.3389/fimmu.2018.02090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176020PMC
September 2019

Association of antibodies against myelin and neuronal antigens with neuroinflammation in systemic lupus erythematosus.

Rheumatology (Oxford) 2019 05;58(5):908-913

Neurologic Clinic and Policlinic, Department of Medicine, University Hospital Basel, Basel.

Objectives: To determine frequency and syndrome specificity of novel and known nervous system (NS)-directed antibodies in a large, unbiased cohort of SLE patients in the Swiss SLE Cohort Study.

Methods: This retrospective pilot study included 174 patients in a cross-sectional and 102 in a longitudinal study. Antibodies against 12 NS antigens [myelin oligodendrocyte glycoprotein (MOG), neurofascin 186 (NF186), aquaporin-4 (AQP4), N-methyl-D-aspartate receptor (subunit NR1) (NMDAR-NR1), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (subunits 1 and 2) (AMPAR1/2), gamma-aminobutyric acid B receptor (subunits B1 and B2) (GABABR1/2), glutamate decarboxylase 65 (GAD65), glycine receptor (GlyR), contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), metabotropic glutamate receptor 5 (mGluR5) and dipeptidyl-peptidase-like protein 6 (DPPX)] were screened with validated cell-based assays and correlated with clinical and diagnostic findings.

Results: Twenty-three of one hundred and seventy-four (13.2%) patients harboured antibodies against MOG (n = 14), NF186 (n = 6), GAD65 (n = 2), AQP4 and GlyR (n = 1). Anti-MOG antibodies were most frequently found in the cohort (8%). Thirteen of the anti-NS antibody-positive patients showed clinical symptoms of NS involvement, a subgroup of which (n = 8) resembled the syndrome associated with the antibody. Nine patients harboured antibodies without neurological symptoms and one patient was lost to follow-up. The frequency of NPSLE was significantly higher in the anti-NS antibody-positive patients (13/23, 56.5%: MOG 6/14, 42.9%; NF186 5/6, 83.3%; GAD65 2/2, 100%; AQP4/GlyR 0/1, 0%) compared with the antibody-negative cohort (21/151, 13.9%) (chi-square test, P < 0.0001).

Conclusion: Anti-NS antibodies, most prevalently anti-MOG antibodies, are significantly associated with NPSLE and manifest with the distinct neurological syndrome associated with the antibody in a subgroup. Follow-up studies in large, independent cohorts will reveal whether these anti-NS antibodies could serve as a diagnostic and prognostic biomarker for NPSLE and enable tailored treatment decisions in this challenging and diverse patient cohort.
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http://dx.doi.org/10.1093/rheumatology/key282DOI Listing
May 2019

Monitoring of cefepime in urine by micellar electrokinetic capillary chromatography with ultraviolet detection and liquid chromatography coupled to mass spectrometry.

J Sep Sci 2018 Nov 25;41(21):4067-4074. Epub 2018 Sep 25.

Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.

Cefepime monitoring in urine by micellar electrokinetic capillary chromatography with UV detection and liquid chromatography coupled to mass spectrometry via electrospray ionization is described. For micellar electrokinetic capillary chromatography, sample preparation comprised urine dilution and dodecyl-sulfate protein precipitation at pH 4.5, whereas diluted urines were analyzed in the other assay. Both approaches provided suitable conditions for cefepime analysis in urines of healthy volunteers that were spiked with cefepime. Cefepime monitoring by micellar electrokinetic capillary chromatography in samples from patients taking multiple drugs were prone to interferences, whereas liquid chromatography coupled to mass spectrometry provided clean chromatograms and thus selective detection of cefepime in all samples. The latter assay was used to measure urinary cefepime in a prospective pilot study and to assess cefepime stability in urines at 25, 4, -20 and -70°C. The data suggest that urinary cefepime is stable for at least 72 h at all tested temperatures.
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http://dx.doi.org/10.1002/jssc.201800763DOI Listing
November 2018

The effect of a previous created distal arteriovenous-fistula on radial bone DXA measurements in prevalent renal transplant recipients.

PLoS One 2018 26;13(7):e0200708. Epub 2018 Jul 26.

Department of Nephrology and Hypertension, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

Background: Accelerated bone loss occurs rapidly following renal transplantation due to intensive immunosuppression and persistent hyperparathyroidism. In renal transplant recipients (RTRs) due to the hyperparathyroidism the non-dominant forearm is often utilized as a peripheral measurement site for dual-energy x-ray absorptiometry (DXA) measurements. The forearm is also the site of previous created distal arteriovenous fistulas (AVF). Although AVF remain patent long after successful transplantation, there are no data available concerning their impact on radial bone DXA measurements.

Methods: In this cross-sectional study we performed DXA in 40 RTRs with preexisting distal AVF (RTRs-AVF) to assess areal bone mineral density (aBMD) differences between both forearms (three areas) and compared our findings to patients with chronic kidney disease (CKD, n = 40), pre-emptive RTRs (RTRs-pre, n = 15) and healthy volunteers (n = 20). In addition, we assessed relevant demographic, biochemical and clinical aspects.

Results: We found a marked radial asymmetry between the forearms in RTRs with preexisting AVF. The radial aBMD at the distal AVF forearm was lower compared to the contralateral forearm, resulting in significant differences for all three areas analyzed: the Rad-1/3: median (interquartile range) in g/cm2, Rad-1/3: 0.760 (0.641-0.804) vs. 0.742 (0.642, 0.794), p = 0.016; ultradistal radius, Rad-UD: 0.433 (0.392-0.507) vs. 0.420 (0.356, 0.475), p = 0.004; and total radius, Rad-total: 0.603 (0.518, 0.655) vs. 0.599 (0.504, 0.642), p = 0.001). No such asymmetries were observed in any other groups. Lower aBMD in AVF forearm subregions resulted in misclassification of osteoporosis.

Conclusions: In renal transplant recipients, a previously created distal fistula may exert a negative impact on the radial bone leading to significant site-to-site aBMD differences, which can result in diagnostic misclassifications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200708PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061984PMC
January 2019

Long-term Outcomes of Kidney Transplantation in Fabry Disease.

Transplantation 2018 Nov;102(11):1924-1933

Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene that obliterate or markedly reduce α-galactosidase A activity. This results in the systemic accumulation of its glycosphingolipid substrates in body fluids and organs, including the kidney. Fabry nephropathy can lead to end-stage renal disease requiring kidney transplantation. Little is known about its long-term outcomes and the overall patient survival after kidney transplantation.

Methods: Here, we report 17 Fabry patients (15 male and 2 female subjects) who received kidney transplants and their long-term treatment and follow-up at 4 specialized Fabry centers.

Results: The posttransplant follow-up ranged to 25 years, with a median of 11.5 (range, 0.8-25.5] years. Graft survival was similar, and death-censored graft survival was superior to matched controls. Fabry patients died with functioning kidneys, mostly from cardiac causes. In 2 male subjects 14 and 23 years posttransplant, the grafts had a few typical FD lamellar inclusions, presumably originating from invading host macrophages and vascular endothelial cells.

Conclusions: We conclude that kidney transplantation has an excellent long-term outcome in FD.
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http://dx.doi.org/10.1097/TP.0000000000002252DOI Listing
November 2018

Prevalence, persistence and clinical correlations of classic and novel antiphospholipid antibodies in systemic lupus erythematosus.

Rheumatology (Oxford) 2018 08;57(8):1350-1357

Clinical Immunology Unit, Department of Internal Medicine Specialties, University Hospital and School of Medicine, Geneva, Switzerland, Switzerland.

Objectives: aPL are frequently present in SLE. In a well characterized SLE cohort we aimed at investigating the prevalence of aPL and assessing their analytical performance and clinical association by testing criteria specificities including LA, aCL IgG and IgM, anti-β2-glycoprotein 1 (antiβ2GP1) IgG and IgM, as well as the non-criteria aPS-PT IgG and IgM and anti-β2GP1 domain 1 (aD1) IgG.

Methods: We included 178 patients satisfying the ACR SLE classification criteria, from whom 283 samples and thrombotic events were collected longitudinally. Each sample was tested for criteria and non-criteria aPL using validated techniques in a single centre.

Results: All assays provided highly reproducible results. Of the samples, 42.5% were positive for at least one criteria assay, 20.5% showed double positivity and 12.6% triple positivity. All criteria and non-criteria specificities persisted over time. Most antibody titres were only moderately correlated; however, strong correlation was observed on one hand between aD1 IgG, antiβ2GP1 IgG and aCL IgG, and on the other between aPS-PT IgG and LA. aD1 IgG titres were extremely elevated in triple-positive samples. aPS-PT IgG by itself, and jointly with LA, was associated with thrombosis, an association mostly driven by venous thrombotic events.

Conclusions: In this SLE cohort, the non-criteria aPL aD1 IgG and aPS-PT IgG performed differently. aD1 IgG was highly enriched in triple-positive samples, and aPS-PT IgG, jointly with LA, was associated with thrombotic events.
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http://dx.doi.org/10.1093/rheumatology/key095DOI Listing
August 2018

Serum calcification propensity is independently associated with disease activity in systemic lupus erythematosus.

PLoS One 2018 24;13(1):e0188695. Epub 2018 Jan 24.

Department of Nephrology and Hypertension lnselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Systemic lupus erythematosus (SLE) is associated with severe cardiovascular complications. The T50 score is a novel functional blood test quantifying calcification propensity in serum. High calcification propensity (or low T50) is a strong and independent determinant of all-cause mortality in various patient populations.

Methods: A total of 168 patients with ≥ 4 American College of Rheumatology (ACR) diagnostic criteria from the Swiss Systemic lupus erythematosus Cohort Study (SSCS) were included in this analysis. Serum calcification propensity was assessed using time-resolved nephelometry.

Results: The cohort mainly consisted of female (85%), middle-aged (43±14 years) Caucasians (77%). The major determinants of T50 levels included hemoglobin, serum creatinine and serum protein levels explaining 43% of the variation at baseline. Integrating disease activity (SELENA-SLEDAI) into this multivariate model revealed a significant association between disease activity and T50 levels. In a subgroup analysis considering only patients with active disease (SELENA-SLEDAI score ≥4) we found a negative association between T50 and SELENA-SLEDAI score at baseline (Spearman's rho -0.233, P = 0.02).

Conclusions: Disease activity and T50 are closely associated. Moreover, T50 levels identify a subgroup of SLE patients with ongoing systemic inflammation as mirrored by increased disease activity. T50 could be a promising biomarker reflecting SLE disease activity and might offer an earlier detection tool for high-risk patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188695PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783342PMC
February 2018

The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys.

Am J Transplant 2018 07 6;18(7):1636-1645. Epub 2018 Feb 6.

Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.

Calcineurin inhibitor toxicity (CNT) is a frequent occurrence in transplanted renal grafts and autochthone kidneys from patients undergoing long-term treatment with calcineurin inhibitors, notably cyclosporin A (CsA) and tacrolimus. Here, we show an indispensable role of the tumor necrosis factor superfamily (TNFS) molecule TNF-related weak inducer of apoptosis (TWEAK) (TNFSF12) in the pathogenesis of acute CNT lesions in mice. A deficiency in TWEAK resulted in limited tubulotoxicity after CsA exposure, which correlated with diminished expression of inflammatory cytokines and reduced intraparenchymal infiltration with immune cells. We further identified tubular epithelial cells of the kidney as major targets of CsA activity and found that Fn14 (tumor necrosis factor receptor superfamily 12A), the receptor for TWEAK, is a highly CsA-inducible gene in these cells. Correlating with this, CsA pretreatment sensitized tubular epithelial cells specifically to the pro-inflammatory activities of recombinant TWEAK in vitro. Moreover, injection of rTWEAK alone into mice induced moderate disease similar to CsA, and rTWEAK combined with CsA resulted in synergistic nephrotoxicity. These findings support the importance of tubular epithelial cells as cellular targets of CsA toxicity and introduce TWEAK as a critical contributor to CNT pathogenesis.
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http://dx.doi.org/10.1111/ajt.14632DOI Listing
July 2018

Change of sleep quality from pre- to 3 years post-solid organ transplantation: The Swiss Transplant Cohort Study.

PLoS One 2017 11;12(10):e0185036. Epub 2017 Oct 11.

Institute of Nursing Science, Department Public Health, University of Basel, Basel, Switzerland.

Background: Poor sleep quality (SQ) is common after solid organ transplantation; however, very little is known about its natural history. We assessed the changes in SQ from pre- to 3 years post-transplant in adult heart, kidney, liver and lung recipients included in the prospective nation-wide Swiss Transplant Cohort Study. We explored associations with selected variables in patients suffering persistent poor SQ compared to those with good or variable SQ.

Methods: Adult single organ transplant recipients enrolled in the Swiss Transplant Cohort Study with pre-transplant and at least 3 post-transplant SQ assessment data were included. SQ was self-reported pre-transplant (at listing), then at 6, 12, 24 and 36 months post-transplant. A single SQ item was used to identify poor (0-5) and good sleepers (6-10). Between organ groups, SQ was compared via logistic regression analysis with generalized estimating equations. Within the group reporting persistently poor SQ, we used logistic regression or Kaplan-Meier analysis as appropriate to check for differences in global quality of life and survival.

Results: In a sample of 1173 transplant patients (age: 52.1±13.2 years; 65% males; 66% kidney, 17% liver, 10% lung, 7% heart) transplanted between 2008 and 2012, pre- transplant poor SQ was highest in liver (50%) and heart (49%) recipients. Overall, poor SQ decreased significantly from pre-transplant (38%) to 24 months post-transplant (26%) and remained stable at 3 years (29%). Patients reporting persistently poor SQ had significantly more depressive symptomatology and lower global quality of life.

Conclusion: Because self-reported poor SQ is related to poorer global quality of life, these results emphasize the need for further studies to find suitable treatment options for poor SQ in transplant recipients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185036PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636098PMC
October 2017

Immune complexes containing serum B-cell activating factor and immunoglobulin G correlate with disease activity in systemic lupus erythematosus.

Nephrol Dial Transplant 2018 Jan;33(1):54-64

Division of Internal Medicine, University Hospital Basel, and Clinical Immunology Lab, Department of Biomedicine, University of Basel, Switzerland.

Methods: Levels of serum BAFF, IgG anti-BAFF and BAFF-IgG complexes were quantified by enzyme-linked immunosorbent assay. IgG anti-BAFF and BAFF-IgG complexes were further characterized using serum fractions obtained by fast protein liquid chromatography. To study the association of serum BAFF, IgG anti-BAFF and BAFF-IgG complex levels with SLE manifestations, 373 visits from 178 patients prospectively included in the Swiss SLE Cohort Study were analysed.

Results: While IgG anti-BAFF levels were not associated with clinical manifestations of SLE, serum BAFF levels correlated with disease activity and were higher in patients with renal involvement. Interestingly, we could also demonstrate the occurrence of BAFF-IgG complexes of different sizes in the sera of SLE patients, which were not due to treatment with belimumab and differed from complexes constructed in vitro. Most strikingly, the levels of these BAFF-IgG complexes were found to strongly correlate with overall disease activity, low complement levels and a history of lupus nephritis.

Conclusion: BAFF-IgG complexes strongly correlate with disease activity in SLE patients, suggesting a pathogenic role in SLE.
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http://dx.doi.org/10.1093/ndt/gfx220DOI Listing
January 2018

Early complications after living donor nephrectomy: analysis of the Swiss Organ Living Donor Health Registry.

Swiss Med Wkly 2017 25;147:w14497. Epub 2017 Aug 25.

Clinic for Transplant Immunology and Nephrology, University Hospital Basel, Switzerland; Swiss Organ Living Donor Health Registry, University Hospital of Basel, Switzerland.

Background: We evaluated the prospectively collected data about the incidence of early peri- and postoperative complications, and potential risk factors for adverse outcomes after living kidney donation in Switzerland.

Methods: Peri- and postoperative events were prospectively recorded on a questionnaire by the local transplant teams of all Swiss transplant centres and evaluated by the Swiss Organ Living Donor Health Registry. Complications were classified according to the Clavien grading system. A total of 1649 consecutive donors between 1998 and 2015 were included in the analysis.

Results: There was no perioperative mortality observed. The overall complication rate was 13.5%. Major complications defined as Clavien ≥3 occurred in 2.1% of donors. Obesity was not associated with any complications. Donor age >70years was associated with major complications (odds ratio [OR] 3.99) and genitourinary complications (urinary tract infection OR 5.85; urinary retention OR 6.61). There were more major complications observed in donors with laparoscopic surgery versus open surgery (p = 0.048), but an equal overall complication rate (p = 0.094).

Conclusion: We found a low rate of major and minor complications, independent of surgical technique, after living donor nephrectomy. There was no elevated complication rate in obese donors. In contrast, elderly donors >70 years had an elevated risk for perioperative complications.
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http://dx.doi.org/10.4414/smw.2017.14497DOI Listing
June 2018

Endoglin inhibition leads to intussusceptive angiogenesis via activation of factors related to COUP-TFII signaling pathway.

PLoS One 2017 31;12(8):e0182813. Epub 2017 Aug 31.

Institute of Anatomy, University of Bern, Bern, Switzerland.

Angiogenesis is a highly coordinated, extremely complex process orchestrated by multiple signaling molecules and blood flow conditions. While sprouting mode of angiogenesis is very well investigated, the molecular mechanisms underlying intussusception, the second mode of angiogenesis, remain largely unclear. In the current study two molecules involved in vascular growth and differentiation, namely endoglin (ENG/CD105) and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) were examined to unravel their specific roles in angiogenesis. Down- respectively up-regulation of both molecules tightly correlates with intussusceptive microvascular growth. Upon ENG inhibition in chicken embryo model, formation of irregular capillary meshwork accompanied by increased expression of COUP-TFII could be observed. This dynamic expression pattern of ENG and COUP-TFII during vascular development and remodeling correlated with formation of pillars and progression of intussusceptive angiogenesis. Similar findings could be observed in mammalian model of acute rat Thy1.1 glomerulonephritis, which was induced by intravenous injection of anti-Thy1 antibody and has shown upregulation of COUP-TFII in initial phase of intussusception, while ENG expression was not disturbed compared to the controls but decreased over the time of pillar formation. In this study, we have shown that ENG inhibition and at the same time up-regulation of COUP-TFII expression promotes intussusceptive angiogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578572PMC
October 2017

C-terminal fragment of agrin (CAF) levels predict acute kidney injury after acute myocardial infarction.

BMC Nephrol 2017 Jun 24;18(1):202. Epub 2017 Jun 24.

Cardiology Department, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.

Background: Patients with acute myocardial infarction are at high risk for acute kidney injury. Novel biomarkers that can predict acute kidney injury in AMI may allow timely interventions. C-terminal fragment of agrin (CAF), a proteoglycan of the glomerular and tubular basement membrane, have been recently associated with rapid renal function deterioration and proximal tubular dysfunction. It is unknown whether elevated CAF levels may serve as a novel AKI biomarker in patients presenting with AMI.

Methods: In 436 persons enrolled in a multicenter prospective observational cohort study of patients with acute myocardial infarction, we measured plasma and urine levels of several kidney injury biomarkers including CAF, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and cystatin-C.The relationship between biomarker levels at baseline and the development of AKI and long-term mortality were analyzed after adjustment for demographic and clinical variables.

Results: AKI incidence was up to 15% during hospitalization. The predictive accuracy for AKI of urinary CAF was similar to NGAL and superior to other tested kidney injury biomarkers. In a multivariate model that included all possible confounding variables only urinary CAF continued to be an independent marker for AKI (OR 1.35 95%CI 1.05 -1.74). During the 2 years follow-up, only plasma CAF levels remained a significant independent predictor of mortality (OR 2.5 95%CI 1.02-6.2; P = 0.04).

Conclusions: Elevated CAF levels are associated with AKI in patients with acute myocardial infarction. Our study provides preliminary evidence that CAF levels may predict AKI and mortality after AMI in low risk patients with relative preserved kidney function at baseline.
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http://dx.doi.org/10.1186/s12882-017-0611-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483277PMC
June 2017

Impact of disease activity on health-related quality of life in systemic lupus erythematosus - a cross-sectional analysis of the Swiss Systemic Lupus Erythematosus Cohort Study (SSCS).

BMC Immunol 2017 03 28;18(1):17. Epub 2017 Mar 28.

Clinical Immunology and Allergy, University Hospital Lausanne, Rue du Bugnon 46, Lausanne, 1011, Switzerland.

Background: To assess the impact of disease activity on health-related quality of life (HRQoL) in systemic lupus erythematosus (SLE).

Methods: Cross-sectional study of patients included in the Swiss SLE Cohort Study between April 2007 and June 2014. HRQoL outcomes were based on the Medical Outcome Study Short Form 36 (SF-36). Disease activity was assessed by the SLE Disease Activity Index score with the Safety of Estrogens in SLE National Assessment modification (SELENA-SLEDAI) and by the physican's global assessment (PGA).

Results: Of the 252 patients included, 207 (82%) were women. Median [interquartile range (IQR)] age was 43 [32-57] years. SLE was active in 125 patients (49.6%). Median [IQR] mental component summary (MCS) in active vs inactive SLE was 40.0 [30.2-51.0] compared to 47.3 [39.2-52.8] (p < 0.01) and median [IQR] physical component summary (PCS) 43.7 [37.0-52.8] compared to 49.1 [38.4-55.6], respectively (p < 0.05). Increase in SELENA-SLEDAI or increase in PGA were negatively correlated with PCS and/or MCS. After adjusting for gender, age and disease duration, disease activity impacted on both PCS and MCS and all subscales except general health. Active lupus nephritis and musculoskeletal involvement were associated with physical limitations and emotional problems, increased bodily pain and poor social functioning. Low complement and/or presence of anti-dsDNA antibodies were associated with increased fatigue and reduced mental health.

Conclusions: In patients with SLE, HRQoL is reduced in those with active disease. Impact of disease activity on HRQoL dimensions depends on SELENA-SLEDAI system components.
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http://dx.doi.org/10.1186/s12865-017-0200-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371245PMC
March 2017

Reduced β-catenin expression affects patterning of bone primordia, but not bone maturation.

Biol Open 2017 May 15;6(5):582-588. Epub 2017 May 15.

Department of Clinical Research, Department of Nephrology and Hypertension, Bern University Hospital, University of Bern, Freiburgstrasse 15, Bern CH-3010, Switzerland

Wnt/β-catenin signaling is involved in patterning of bone primordia, but also plays an important role in the differentiation of chondrocytes and osteoblasts. During these processes the level of β-catenin must be tightly regulated. Excess β-catenin leads to conditions with increased bone mass, whereas loss of β-catenin is associated with osteoporosis or, in extreme cases, the absence of limbs. In this study, we examined skeletogenesis in mice, which retain only 25% of β-catenin. These embryos showed severe morphological abnormalities of which the lack of hindlimbs and misshaped front paws were the most striking. Surprisingly however, calcification of bone primordia occurred normally. Moreover, the Wnt-dependent regulatory network of transcription factors driving the differentiation of cartilage and bone, as well as the expression of extracellular matrix components, were preserved. These findings show that 25% β-catenin is insufficient for the correct patterning of bone primordia, but sufficient for their mineralization. Our approach helps to identify bone morphogenetic processes that can proceed normally even at low β-catenin levels, in contrast to those that require high β-catenin dosages. This information could be exploited to improve the treatment of bone diseases by fine-tuning the individual β-catenin dosage requirements.
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http://dx.doi.org/10.1242/bio.023572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450319PMC
May 2017

Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease.

Kidney Blood Press Res 2017 28;42(1):1-15. Epub 2017 Feb 28.

Department of Pediatric Clinical Pharmacology, Pediatric Pharmacology and Pharmacometrics Research Center, University of Basel Children's Hospital (UKBB), Basel, Switzerland.

Background/aims: Fabry disease (FD) is a rare inherited lysosomal storage disease with common and serious kidney complications. Enzyme replacement therapies (ERT) with agalsidase-α and -β were investigated to characterize their therapeutic effect on kidney function in FD patients with Classic phenotype.

Methods: The prospective FD cohort consisted of 98 genetically confirmed patients (females, n = 61, males, n = 37). The median [interquartile range] follow-up time (time difference from first to last visit) was 9 [6, 12] years. The median age of ERT start was 36 [21 - 54] years for females and 39 [28 - 49] years for males.

Results: A disease progression model was developed to (i) characterize the time course of estimated glomerular filtration rate (eGFR) and (ii) evaluate therapeutic effects of ERT on kidney function. Change in eGFR over time was best described by the linear model. Females had stable kidney function with and without ERT (eGFR slopes of -0.07 ml/min/1.73m^2 per year and 0.52 ml/min/1.73m^2 per year, respectively). Males with ERT showed an eGFR decrease of -3.07 ml/min/1.73m^2 per year.

Conclusion: Mathematical disease progression modeling indicates that there is no clear therapeutic effect of ERT on kidney function in adult patients with Classic Phenotype of FD. Interpretation of these findings should take into account that the study is not randomized and lacks a placebo controlled group. Further investigations are warranted to clarify whether earlier ERT initiation before 18 years of age, higher ERT dose or more intensive therapies can preserve kidney function.
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http://dx.doi.org/10.1159/000464312DOI Listing
March 2018

Clinical Course, Radiological Manifestations, and Outcome of Pneumocystis jirovecii Pneumonia in HIV Patients and Renal Transplant Recipients.

PLoS One 2016 8;11(11):e0164320. Epub 2016 Nov 8.

Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Pneumocystis jirovecii pneumonia (PCP) is a frequent opportunistic infection in immunocompromised patients. In literature, presentation and outcome of PCP differs between patients with human immunodeficiency virus (HIV) infection and renal transplant recipients (RTRs).

Methods: We conducted a cross-sectional study of patients with PCP based on the HIV and renal transplant registries at our institution. Radiological and clinical data from all confirmed PCP cases between 2005 and 2012 were compared.

Results: Forty patients were included: 16 with HIV and 24 RTRs. Radiologically, HIV patients had significantly more areas of diffuse lung affection (81% HIV vs. 25% RTR; p = 0.02), more ground glass nodules 5-10 mm (69% vs. 4%; p = <0.001) and enlarged hilar lymph nodes were found only in HIV patients (44%). Cough and dyspnea were the most common clinical signs (>80%) in both groups. Duration from illness onset to hospital presentation was longer in the HIV patients (median of 18 vs. 10 days (p = 0.02)), implying a less fulminant clinical course. Sixty percent of PCP cases in RTRs occurred >12 months after transplantation. Lengths of hospitalization, admission rates to the intensive care unit, and requirements for mechanical ventilation were similar. Outcome in both groups was favourable.

Conclusions: While important differences in radiological presentation of PCP between HIV patients and RTRs were found, clinical presentation was similar. PCP only rarely presented with fulminant respiratory symptoms requiring ICU admission, with similar results and outcomes for HIV patients and RTRs. Early diagnosis and treatment is mandatory for clinical success.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164320PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100884PMC
June 2017