Publications by authors named "Stephan Segerer"

134 Publications

Admission kidney function is a strong predictor for the response to nutritional support in patients at nutritional risk.

Clin Nutr 2021 Mar 15;40(5):2762-2771. Epub 2021 Mar 15.

Medical University Department, Division of General Internal and Emergency Medicine, Kantonsspital Aarau, Aarau, Switzerland; Medical Faculty of the University of Basel, Switzerland. Electronic address:

Background: Patients with chronic kidney disease (CKD) are at substantial risk of malnutrition, which negatively affects clinical outcomes. We investigated the association of kidney function assessed at hospital admission and effectiveness of nutritional support in hospitalized medical patients at risk of malnutrition.

Methods: This is a secondary analysis of an investigator-initiated, randomized-controlled, Swiss multicenter trial (EFFORT) that compared individualised nutritional support with usual hospital food on clinical outcomes. We compared effects of nutritional support on mortality in subgroups of patients stratified according to kidney function at the time of hospital admission (estimated glomerular filtration rates [eGFR] <15, 15-29, 30-59, 60-89 and ≥ 90 ml/min/1.73 m).

Results: We included 1943 of 2028 patients (96%) from the original trial with known admission creatinine levels. Admission eGFR was a strong predictor for the beneficial effects of nutritional support in regard to lowering of 30-day mortality. Patients with an eGFR <15, 15-29 and 30-59 had the strongest mortality benefit (odds ratios [95%CI] of 0.24 [0.05 to 1.25], 0.37 [0.14 to 0.95] and 0.39 [0.21 to 0.75], respectively), while patients with less severe impairment in kidney function had a less pronounced mortality benefits (p for interaction 0.001). A similar stepwise association of kidney function and response to nutritional support was found also for other secondary outcomes.

Conclusion: In medical inpatients at nutritional risk, admission kidney function was a strong predictor for the response to nutritional therapy. Initial kidney function may help to individualize nutritional support in the future by identification of patients with most clinical benefit.

Clinical Trial Registration: Registered under ClinicalTrials.gov Identifier no. NCT02517476.
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http://dx.doi.org/10.1016/j.clnu.2021.03.013DOI Listing
March 2021

Body Surface Area, Creatinine Excretion Rate, and Total Body Water: Reference Data for Adults in the United States.

Kidney Med 2021 Mar-Apr;3(2):312-313. Epub 2021 Jan 12.

Division of Nephrology, Dialysis and Transplantation, Kantonsspital Aarau, Aarau, Switzerland.

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http://dx.doi.org/10.1016/j.xkme.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039403PMC
January 2021

Increased Insulin Concentrations During Growth Hormone Treatment in Girls With Turner Syndrome Are Ameliorated by Hormone Replacement Therapy.

Front Endocrinol (Lausanne) 2020 14;11:586055. Epub 2020 Dec 14.

Department of Endocrinology, Centre for Infertility, Prenatal Medicine, Endocrinology and Osteology, Amedes Hamburg, Hamburg, Germany.

Objective: Turner syndrome (TS) is characterized by complete or partial loss of one sex chromosome and is commonly associated with short stature, metabolic changes (such as central obesity, abnormal glucose tolerance and high triglycerides) and premature ovarian insufficiency (POI). Primary management of TS during childhood and adolescence comprises treatment with human growth hormone (hGH) and, in cases with early loss of ovarian function, hormone replacement therapy (HRT). Given that metabolic parameters are altered when HRT is applied during menopause, we analyzed whether metabolic changes might be positively or negatively affected within 10 years after HRT and/or hGH in girls with TS.

Design: Observational study.

Methods: Data were collected from the medical records of 31 girls with TS attending two endocrinologic centers in Germany between 2000 and 2020. Descriptive statistics are reported as the mean ± SEM or percentages.

Results: The mean age at first presentation was 99.06 ± 8.07 months, the mean height was 115.8 ± 3.94 cm, and the mean BMI 19.0 ± 0.99 was kg/m. Treatment with hGH was given to 96.8% of the girls, starting at an average age of 99.06 ± 8.70 months, and was continued for 67.53 ± 6.28 months. HRT was administered to 80.6% of all patients and was started at a mean age of 164.4 ± 4.54 months. During the follow-up, we did not observe any significant absolute changes in lipid parameters, but we detected beneficial effects of childhood hGH: significantly lower cholesterol (-0.206/month; p = 0.006), lower low density lipoprotein cholesterol (-0.216/month; p = 0.004), and higher high density lipoprotein cholesterol (+0.095/month; p = 0.048). Insulin concentrations, showed a significant increase attributable to hGH treatment (+0.206/month; p = 0.003), which was ameliorated by concomitant or subsequent HRT (-0.143/month; p = 0.039).

Conclusion: Treatment with hGH and HRT is provided to most girls with TS. Metabolic effects are associated with both modalities. Monitoring of metabolic changes appears to be important to detect unfavorable effects, and could guide treatment adjustment and duration.
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http://dx.doi.org/10.3389/fendo.2020.586055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767985PMC
December 2020

Hyperoxia in portal vein causes enhanced vasoconstriction in arterial vascular bed.

Sci Rep 2020 12 1;10(1):20966. Epub 2020 Dec 1.

Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.

Long-term perfusion of liver grafts outside of the body may enable repair of poor-quality livers that are currently declined for transplantation, mitigating the global shortage of donor livers. In current ex vivo liver perfusion protocols, hyperoxic blood (arterial blood) is commonly delivered in the portal vein (PV). We perfused porcine livers for one week and investigated the effect of and mechanisms behind hyperoxia in the PV on hepatic arterial resistance. Applying PV hyperoxia in porcine livers (n = 5, arterial PV group), we observed an increased need for vasodilator Nitroprussiat (285 ± 162 ml/week) to maintain the reference hepatic artery flow of 0.25 l/min during ex vivo perfusion. With physiologic oxygenation (venous blood) in the PV the need for vasodilator could be reduced to 41 ± 34 ml/week (p = 0.011; n = 5, venous PV group). This phenomenon has not been reported previously, owing to the fact that such experiments are not feasible practically in vivo. We investigated the mechanism of the variation in HA resistance in response to blood oxygen saturation with a focus on the release of vasoactive substances, such as Endothelin 1 (ET-1) and nitric oxide (NO), at the protein and mRNA levels. However, no difference was found between groups for ET-1 and NO release. We propose direct oxygen sensing of endothelial cells and/or increased NO break down rate with hyperoxia as possible explanations for enhanced HA resistance.
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http://dx.doi.org/10.1038/s41598-020-77915-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708838PMC
December 2020

Amelioration of Murine Autoimmune Pancreatitis by Targeted LTβR Inhibition and Anti-CD20 Treatment.

Immunohorizons 2020 11 5;4(11):688-700. Epub 2020 Nov 5.

Swiss Hepato-Pancreato-Biliary Centre, Visceral and Transplantation Surgery, University Hospital Zurich, 8091 Zurich, Switzerland;

Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis, for which treatment options, especially the long-term management, are limited. The only therapy that has been established and accepted so far is corticosteroids, but the relapse rate is significant. In the current study, we discern the effector mechanisms of targeted LTβR pathway inhibition using LTβR-Ig. Furthermore, the efficacy of LTβR-Ig therapy is compared with the depletion of immune cell subsets (CD4 and CD20), which are suggested to play a pathological role in AIP development. Three well-established mouse models of AIP were used to examine treatment efficacies and mechanisms. (Ela1-Lta,b) mice represent a genetic model, in which AIP develops spontaneously. In MRL/Mp and IL-10 mice, AIP is induced by repeated polyinosinic:polycytidylic acid injection. Mice with AIP were treated with anti-CD20, anti-CD4 mAbs, or targeted LTβR-Ig. LTβR-Ig and anti-CD20 treatment led to significant improvement of AIP, including a decrease in autoantibody production and pancreatic inflammation in (Ela1-Lta,b) and IL-10 mice. The molecular mechanism of this beneficial effect possibly involves the downregulation of Stat3 and noncanonical NF-κb activation. Anti-CD4 treatment reduced Th1 and Th2 signature but did not alleviate AIP. Additionally, in contrast to anti-CD20 or anti-CD4 treatments, blocking LTβR signaling disrupted tertiary lymphoid organs in all three models. We demonstrate that treatment with LTβR-Ig or anti-CD20 Ab alleviated murine AIP. LTβR-Ig treatment for AIP was effective in both lymphotoxin-dependent and lymphotoxin-independent AIP models, possibly because of its dual anti-inflammatory and antiautoimmune mechanisms.
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http://dx.doi.org/10.4049/immunohorizons.2000079DOI Listing
November 2020

Estimated glomerular filtration rate predicts 30-day mortality in medical emergency departments: Results of a prospective multi-national observational study.

PLoS One 2020 6;15(4):e0230998. Epub 2020 Apr 6.

Division of Nephrology, Dialysis and Transplantation, University Department of Medicine, Kantonsspital Aarau, Aarau, Switzerland.

Background: Renal failure is common in patients seeking help in medical emergency departments. Decreased renal function is associated with increased mortality in patients with heart failure or sepsis. In this study, the association between renal function (reflected by estimated glomerular filtration rate (eGFR) at the time of admission) and clinical outcome was evaluated.

Methods/objectives: Data was used from a prospective, multi-national, observational cohort of patients treated in three medical emergency departments of tertiary care centers. The eGFR was calculated from the creatinine at the time of admission (using the Chronic Kidney Disease-Epidemiology Collaboration equation,CKD-EPI). Uni- and multivariate regression models were used for eGFR and 30-day mortality, in hospital mortality, length of stay and intensive care unit admission rate.

Results: 6983 patients were included. The 30-day mortality was 1.8%, 3.5%, 6.9%, 11.1%, 13.6%, and 14.2% in patients with eGFR of above 90, 60-89, 45-59, 30-44, 15-29, and <15 ml/min/1.73m2, respectively. Using multivariate regression, the adjusted odds ratio (OR) was 2.31 (for 15-29 ml/min/1.73m2, 95% confidence interval 1.36 to 3.90, p = 0.002) and 3.73 (for eGFR <15ml/min/1.73m2 as compared to >90 ml/min/1.73m2, 95% CI 2.04 to 6.84, p<0.001). For 10 ml/min/1.73m2 decrease in eGFR the OR for the 30-day mortality was 1.15 (95% CI1.09 to 1.22, p<0.001).The eGFR was also significantly associated with in-hospital mortality, the percentage of ICU-admissions, and with a longer hospital stay. No association was found with hospital readmission within 30 days. As limitations, only eGFR at admission was available and the number of patients on hemodialysis was unknown.

Conclusion: Reduced eGFR at the time of admission is a strong and independent predictor for adverse outcome in this large population of patients admitted to medical emergency departments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230998PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135226PMC
July 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

Vascular endothelial growth factor D is a biomarker of fluid overload in haemodialysis patients.

Nephrol Dial Transplant 2021 02;36(3):529-536

Division of Nephrology, Regional Hospital of Lugano, Lugano, Switzerland.

Background: Improved understanding and assessment of the complex physiology of volume regulation in haemodialysis (HD) patients are required to improve patient care and reduce mortality associated with fluid overload (FO).

Methods: We searched for FO-related biomarkers among 184 peptides associated with cardiovascular disease in a cohort of 30 HD patients. First, we assessed the direct impact of HD on the peptides of interest by comparing plasma concentrations before and after treatment. Then, we compared cardiovascular peptide profiles between patients with and without FO as defined by bioimpedance analysis (BIA). The plasma concentration of selected candidate biomarkers for FO was determined by enzyme-linked immunosorbent assay (ELISA) and correlated with previously described FO-related clinical and laboratory parameters. For validation, results were confirmed in an independent cohort of 144 HD patients.

Results: We found seven peptides positively [NT-proBNP, B-type natriuretic peptide (BNP), vascular endothelial growth factor D (VEGFD), tumour necrosis factor-related apoptosis-inducing ligand receptor 2, growth differentiation factor 15, tumour necrosis factor ligand superfamily member 13B, chitinase-3-like protein 1] and five negatively (leptin, renin, epidermal growth factor receptor, interleukin-1 receptor antagonist, myeloblastin) correlated to FO. In addition to natriuretic peptides, VEGFD emerged as third peptide highly correlated with BIA (ρ = 0.619, P < 0.0001). In line with this, VEGFD concentration verified by ELISA correlated with BIA, BNP and soluble CD146 but not with vascular endothelial growth factor C (VEGFC). Notably, levels of VEGFD were unrelated to cardiac systolic function (P = 0.63), contrary to BNP (P = 0.0003). Finally, we observed that 1-year all-cause mortality was higher in patients with high BNP (P = 0.0002), FO (defined by BIA, P = 0.04) and high VEGFD (P = 0.02), but not with high VEGFC (P = 0.48).

Conclusion: VEGFD is a novel FO-related biomarker with unique diagnostic and prognostic properties.
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http://dx.doi.org/10.1093/ndt/gfz281DOI Listing
February 2021

Monitoring Urine Flow to Prevent Overcorrection of Hyponatremia: Derivation of a Safe Upper Limit Based on the Edelman Equation.

Am J Kidney Dis 2019 01 16;73(1):143-145. Epub 2018 Aug 16.

Division of Nephrology, Dialysis & Transplantation, Kantonsspital Aarau, Switzerland.

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http://dx.doi.org/10.1053/j.ajkd.2018.05.017DOI Listing
January 2019

-A Rare Cause of Peritoneal Dialysis-Related Peritonitis.

Perit Dial Int 2018 May-Jun;38(3):231-232

Division of Nephrology, University Hospital Zurich, Switzerland.

We present the first report of a patient with peritoneal dialysis (PD)-related peritonitis due to , an anaerobe bacterium that is commonly found in normal fecal flora. On rare occasions, it can be pathogenic in immunocompromised individuals. species, including , should be included in the differential diagnosis of PD-related peritonitis.
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http://dx.doi.org/10.3747/pdi.2017.00153DOI Listing
December 2018

High accuracy of proximity extension assay technology for the quantification of plasma brain natriuretic peptide.

J Clin Lab Anal 2018 Oct 23;32(8):e22574. Epub 2018 May 23.

INSERM, UMR-S 942, Paris, France.

Background: Novel multiplex assays allow the simultaneous identification of a large number of plasma proteins. While these new technologies have been shown to be highly sensitive and accurate for the identification of plasma proteins, the use of this technology to quantify those proteins has not been properly investigated. In this pilot study, we tested the accuracy of the proximity extension assay (PEA) for the quantification of the cardiac biomarker brain natriuretic peptide (BNP) compared to a standard clinically approved method.

Methods: Concentrations of BNP were assessed in 120 plasma samples from 30 patients with PEA and compared to chemiluminescent microparticle immunoassay (CMIA). Venous blood samples were collected from in tubes containing ethylenediaminetetraacetic acid, centrifuged within 6 hours at 3,500 rpm for 15 minutes at 4°C, frozen and stored at -80°C until analyzed. Correlation between the CMIA and PEA techniques was tested using the Spearman's rank correlation coefficient (rho) and the agreement was described with a Bland-Altman plot.

Results: Brain natriuretic peptide values obtained by CMIA and PEA were highly correlated (Spearman's rho = 0.865, P < .0001). In two patients, PEA consistently overestimated resp. underestimated BNP values compared to CMIA. After removal of those two patients, a very high correlation between the two techniques was shown (rho = 0.966, P < .0001). A high agreement between the two techniques over the whole range of tested concentrations was shown.

Conclusion: This pilot study showed for the first time an excellent correlation between a clinically approved method and the PEA-based approach for quantification of circulating plasma BNP.
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http://dx.doi.org/10.1002/jcla.22574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817038PMC
October 2018

Soluble CD146 and B-type natriuretic peptide dissect overhydration into functional components of prognostic relevance in haemodialysis patients.

Nephrol Dial Transplant 2018 11;33(11):2035-2042

Department of Nephrology, University Hospital Zurich, Zurich, Switzerland.

Background: Accurate volume status evaluation and differentiation of cardiac and non-cardiac components of overhydration (OH) are fundaments of optimal haemodialysis (HD) management.

Methods: This study, by combining bioimpedance measurements, cardiovascular biomarkers and echocardiography, aimed at dissecting OH into its major functional components, and prospectively tested the association between cardiac and non-cardiac components of OH with mortality. In the first part, we validated soluble CD146 (sCD146) as a non-cardiac biomarker of systemic congestion in a cohort of 30 HD patients. In the second part, we performed a prospective 1-year follow-up study in an independent cohort of 144 HD patients.

Results: sCD146 incrementally increased after the short and long intervals after HD (+53 ng/mL, P = 0.006 and  +91 ng/mL, P < 0.001), correlated with OH as determined by bioimpedance and well-diagnosed OH (area under the receiver operating characteristics curve 0.72, P = 0.005). The prevalence of OH was lower for low-sCD146 and low-BNP patients (B-type natriuretic peptide, 29%) compared with subjects with either one or both biomarkers elevated (65-74%, P < 0.001). Notably, most low-BNP but high-sCD146 subjects were overhydrated. Systolic dysfunction was 2- to 3-fold more prevalent among high-BNP compared with low-BNP patients (44-68% versus 21-23%, chi-square P < 0.001), regardless of sCD146. One-year all-cause mortality was markedly higher in patients with high-BNP (P = 0.001) but not with high-sCD146. In multivariate analysis, systolic dysfunction and BNP, but not OH, were associated with lower survival.

Conclusions: The combination of BNP and sCD146 dissects OH into functional components of prognostic value. OH in HD patients is associated with higher mortality only if resulting from cardiac dysfunction.
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http://dx.doi.org/10.1093/ndt/gfy113DOI Listing
November 2018

Lymphotoxin expression in human and murine renal allografts.

PLoS One 2018 4;13(1):e0189396. Epub 2018 Jan 4.

Division of Nephrology, University Hospital, Zuerich, Switzerland.

The kidney is the most frequently transplanted solid organ. Recruitment of inflammatory cells, ranging from diffuse to nodular accumulations with defined microarchitecture, is a hallmark of acute and chronic renal allograft injury. Lymphotoxins (LTs) mediate the communication of lymphocytes and stromal cells and play a pivotal role in chronic inflammation and formation of lymphoid tissue. The aim of this study was to assess the expression of members of the LT system in acute rejection (AR) and chronic renal allograft injury such as transplant glomerulopathy (TG) and interstitial fibrosis/tubular atrophy (IFTA). We investigated differentially regulated components in transcriptomes of human renal allograft biopsies. By microarray analysis, we found the upregulation of LTβ, LIGHT, HVEM and TNF receptors 1 and 2 in AR and IFTA in human renal allograft biopsies. In addition, there was clear evidence for the activation of the NFκB pathway, most likely a consequence of LTβ receptor stimulation. In human renal allograft biopsies with transplant glomerulopathy (TG) two distinct transcriptional patterns of LT activation were revealed. By quantitative RT-PCR robust upregulation of LTα, LTβ and LIGHT was shown in biopsies with borderline lesions and AR. Immunohistochemistry revealed expression of LTβ in tubular epithelial cells and inflammatory infiltrates in transplant biopsies with AR and IFTA. Finally, activation of LT signaling was reproduced in a murine model of renal transplantation with AR. In summary, our results indicate a potential role of the LT system in acute renal allograft rejection and chronic transplant injury. Activation of the LT system in allograft rejection in rodents indicates a species independent mechanism. The functional role of the LT system in acute renal allograft rejection and chronic injury remains to be determined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189396PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754061PMC
January 2018

Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation.

Gut 2018 09 3;67(9):1663-1673. Epub 2017 Aug 3.

Department of Visceral and Transplantation Surgery, Swiss HPB Centre, University Hospital Zurich, Zurich, Switzerland.

Objective: Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21-a member of cyclin-dependent kinase inhibitors-can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP.

Design: We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))-a model to study AIP development-with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens.

Results: p21 deficiency in LT mice (LTp21) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T-B cell infiltration. Interestingly, LT and LTp21 mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-κB pathway activation remained impaired in LTp21 pancreata.

Conclusions: Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.
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http://dx.doi.org/10.1136/gutjnl-2016-313458DOI Listing
September 2018

CD147 expression in peritoneal injury.

Clin Exp Nephrol 2017 Dec 27;21(6):1097-1104. Epub 2017 May 27.

Division of Nephrology, University Hospital, Rämistr. 100, 8091, Zurich, Switzerland.

Background: Peritoneal injury is an important cause of technical failure of long-term peritoneal dialysis (PD). Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term PD with potentially life threatening consequences. CD147 is a glycoprotein with diverse functions including modulation of extracellular matrix via induction of matrix metalloproteinases, cell adhesion, and regulation of immune reactions. We hypothesized that CD 147 plays a role in the peritoneal cavity.

Methods: In this retrospective study, we localized CD147 by immunohistochemistry in peritoneal biopsies from uremic patients not on PD (n = 8), on PD without signs of EPS (n = 7), and in biopsies in patients with the diagnosis of EPS (n = 7). Double immunofluorescence was used to co-localize α-smooth-muscle actin (α-SMA) and CD147 in selected biopsies from each group. Expression was scored semi-quantitatively.

Results: In biopsies from uremic controls, CD147 was prominently expressed in mesothelial cells, focally between fat cells and by some perivascular cells. In patients on PD, a similar distribution was present (although mesothelium was rarely conserved), with some focal accentuation. In EPS, layers of fibroblastic cells were positive for CD147. EPS biopsies demonstrated a significantly higher score in a blinded evaluation, compared to uremic patients. Cells expressing CD147 were α-SMA positive myofibroblasts as demonstrated by double immunofluorescence. Mean CD147 scores did not differ between patients with different transporter status.

Conclusions: This is the first study demonstrating CD147 on a major part of fibroblastic cells in EPS. Future studies need to address the role of these cells in this severe complication of long-term PD.
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http://dx.doi.org/10.1007/s10157-017-1390-0DOI Listing
December 2017

Alteration of membrane complement regulators is associated with transporter status in patients on peritoneal dialysis.

PLoS One 2017 19;12(5):e0177487. Epub 2017 May 19.

Department of Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany.

Introduction: A growing body of evidence from animal models and cell culture studies indicate an important role of a local regulatory complement system (CS) in peritoneal injury during peritoneal dialysis (PD). We investigated the expression of the local regulatory CS (reflected by CD46,CD55,CD59) in the peritoneal tissue of patients with different membrane function characteristics.

Patients And Methods: Biopsies from the parietal peritoneum were taken from 24 patients on PD, 22 uremic patients prior to PD. PD patients were grouped according to the dialysate-to-plasma ratio of creatinine (D/P Cre) and ratio of dialysate glucose at 4 hours versus dialysate glucose at time zero (D/D0 glucose) into low or low-average peritoneal transport status (L/LA) and high-average or high-transport status (HA/H) groups. CD46, CD55, and CD59 RNA expression were analyzed by real-time polymerase chain reaction (RT-PCR). Further localization of membrane complement regulators (CRegs) and semiquantitatively analysis was done by immunohistochemistry (IHC).

Results: CD46 and CD59 expression were similar in all groups. CD55 expression was significantly decreased in the HA/H group compared to the L/LA group and to uremic controls (p < 0.05 and p = 0.05, respectively). No statistically significant differences in CD46, CD55, and CD55 expression were detected when considering the history of peritonitis. There was no statistically significant correlation between PD duration and the expressions of CD46, CD55, and CD59. IHC revealed strong CD46, CD55, and CD59 expression in mesothelial cells. CD55 and CD59 were additionally detected in the vasculature. Using IHC, CD46 was lower in PD patients compared to uremic controls (p>0.05), but there was no difference between the L/LA compared to the H/HA group. Moreover IHC confirmed decreased expression of CD55 in the HA/H group compared to the L/LA group and uremic controls (p<0.0001 and p = 0.0001, respectively).

Conclusion: CD55 expression is decreased in patients with fast transporter membrane function, whereas peritonitis and PD duration do not appear to alter CReg expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177487PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438122PMC
September 2017

Gender-Specific Differences in Peritoneal Dialysis.

Kidney Blood Press Res 2017 25;42(2):276-283. Epub 2017 May 25.

Department of Internal Medicine, Division of General Medicine and Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany.

Background/aims: Gender-specific differences between patients on renal replacement therapy have so far rarely been investigated. In the present study we aimed to describe gender-specific differences in a large cohort of peritoneal dialysis (PD) patients.

Methods: Clinical information for all patients who started PD at our center has been collected since the start of the PD-program in 1979. We used Cox regression to examine associations between technique failure and gender. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs).

Results: A total of 745 patients (315 women and 430 men with a median age of 57 years; IQR 43-67) started PD between 1979 and 2015 in our center. Women were significantly younger at PD start 54 (40-65) years vs. 58 (47-68) years, p<0.001. Within the last almost 15 years, more man than women started PD, but technical survival rates were significantly better in female compared to men (HR=0.662, CI 95% (0.496-0.885) P=0.005). Cardiovascular events were the main cause of death over the study period in both sexes, but decreased over time. Additionally, death due to PD-associated peritonitis decreased significantly over the three decades in both sexes.

Conclusions: Our data suggest that technical survival rates were significantly better in female compared to men over three decades and death due to cardiovascular events and PD-associated peritonitis decreased significantly over the three decades in both sexes.
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http://dx.doi.org/10.1159/000477449DOI Listing
April 2018

The number of patients with severe encapsulating peritoneal sclerosis is decreasing in a large referral center in Germany.

Int J Nephrol Renovasc Dis 2016 5;9:183-6. Epub 2016 Aug 5.

Division of General Medicine and Nephrology, Department of Internal Medicine, Robert-Bosch-Hospital, Stuttgart, Germany.

Background: Encapsulating peritoneal sclerosis (EPS) is the most severe complication associated with long-term peritoneal dialysis (PD). Previous studies noticed a sharp decline in new patients with severe EPS. We investigated the number of severe EPS patients in our large referral center over almost 20 years.

Methods: All late-stage EPS patients who underwent major surgery due to extensive symptoms caused by bowel obstruction (vomiting, abdominal pain, and weight loss) between March 1997 and end of December 2015 in our hospital were included in the present study. An index was calculated between the number of patients with severe EPS and the implanted PD catheters in our center.

Results: Between 1979 and 2015, a total of 745 PD catheters were implanted in our center, with a steady increase in the numbers between 2003 and 2015. First patient with severe EPS was treated in 1998, then a rise in the number of patients with EPS was present in 2005. The number of patients with EPS peaked in the period of 2010-2012 (15 patients within 3 years). Afterward, both the absolute numbers and the index between the number of patients with severe EPS and the implanted catheters demonstrated a prominent reduction in the next 3-year period from 2013 to 2015.

Conclusion: Our data support the hypothesis that there seems to be a decrease of late-stage EPS incidence over the last years, but data about milder or asymptomatic patients are lacking. This should be kept in mind while giving the patients information about different renal replacement therapies at start of dialysis.
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http://dx.doi.org/10.2147/IJNRD.S108529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981167PMC
August 2016

Smoking Is a Risk Factor for Severe Acute Kidney Injury in Hantavirus-Induced Nephropathia Epidemica.

Nephron 2016 8;134(2):89-94. Epub 2016 Jul 8.

Department of Internal Medicine, Division of Nephrology, Robert-Bosch Hospital, Stuttgart, Germany.

Background/aims: Hantaviruses are zoonotic pathogens causing emerging diseases worldwide. Patients typically present with fever, acute kidney injury (AKI) and thrombocytopenia. Puumala virus (PUUV) that causes nephropathia epidemica (NE) is common in Germany. Recently, a study from Finland revealed an association between nicotine consumption and the severity of AKI in NE. Differences between individuals in Finland and Germany might modulate the effect; therefore, the aim of our study was to prove that smoking is a risk factor for a severe course of NE in Germany.

Methods: A cross-sectional prospective survey of 485 patients with hantavirus infections was performed. Clinical and laboratory data during the acute course of the disease were obtained from medical reports and files, while follow-up (including smoking status) data were collected prospectively.

Results: Smoking information was available for 298 out of 485 patients (61%). Male was the predominant gender (67%), median age at the time of diagnosis was 50 (interquartile range, IQR 41-60) years and 34% of patients were current smokers during the phase of acute NE. Patients in the smoking group were significantly younger than in the non-smoking group (p < 0.0001). Peak serum creatinine levels were significantly higher in the smoking group than in the non-smoking patients (median 301 (IQR 186-469 μmol/l) vs. median 240 (IQR 137-469 μmol/l), p < 0.05). In addition, severe AKI (stages 2 and 3 using KDIGO criteria) was more common in current smokers (80%) than in the non-smokers (68%, p < 0.05).

Conclusion: Current smoking is a risk factor for severity of AKI in patients with acute PUUV infection in Germany. Therefore, information about smoking habits needs to be an integral part of the documentation in patients with suspected acute PUUV infection, and increased monitoring of kidney function should be done in NE patients who are current smokers.
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http://dx.doi.org/10.1159/000447783DOI Listing
July 2017

Electrocardiographic abnormalities and relative bradycardia in patients with hantavirus-induced nephropathia epidemica.

Eur J Intern Med 2016 Sep 11;33:67-73. Epub 2016 Jun 11.

Department of Internal Medicine, Division of General Medicine and Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany. Electronic address:

Background: Nephropathia epidemica (NE), caused by Puumala virus (PUUV), is characterized by acute kidney injury (AKI) and thrombocytopenia. Cardiac involvement with electrocardiographic (ECG) abnormalities has been previously reported in NE; however, its prognostic value is unknown. Relative bradycardia is an important clinical sign in various infectious diseases, and previous smaller studies have described pulse-temperature deficit in patients with PUUV infection.

Methods: We performed a cross-sectional survey of 471 adult patients with serologically confirmed NE. Data were collected retrospectively from medical records and prospectively at follow-up visits. Patients for whom ECGs were recorded during the acute phase of disease were enrolled retrospectively (n=263). Three patients were excluded because of documented pre-existing ECG abnormalities prior to NE. All patients with ECG abnormalities during the acute phase underwent follow-up.

Results: A total of 46 patients had ECG abnormalities at the time of admission to hospital (18%). T-wave inversion was the most frequent ECG abnormality (n=31 patients), followed by ST segment changes (nine patients with elevation and six with depression). No major adverse cardiac events occurred during follow-up (median 37months; range 34-63months). Of note, ECG abnormalities reverted to normal in the majority of the patients during follow-up. During the acute phase of NE, 149 of 186 patients had relative bradycardia, without implications for disease course.

Conclusions: Transient ECG abnormalities were detected in 18% of patients during acute NE but were not associated with negative cardiovascular outcome. Relative bradycardia was identified in 80% of the patients with acute NE.
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http://dx.doi.org/10.1016/j.ejim.2016.06.001DOI Listing
September 2016

The Authors Reply.

Kidney Int 2016 May;89(5):1161-1162

Zurich Center for Integrative Human Physiology, Zurich, Switzerland; Institute of Anatomy, University of Zurich, Zurich, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2015.10.020DOI Listing
May 2016

Vertebral and internal mammary artery steal syndrome in patients with hemodialysis access.

Vasa 2016 ;45(2):163-8

1 Clinic for Angiology, University Hospital Zürich and University of Zürich, Switzerland.

Background: Increased flow in the subclavian artery feeding a vascular access for hemodialysis can induce steal phenomena in the vertebral (VA) and internal mammary artery (IMA). The aim of this study was to describe the hemodynamic effects of access flow on the VA and IMA in patients with native fistulas and grafts.

Patients And Methods: Peak systolic (PSV) and end diastolic (EDV) velocity measurements of the VA, IMA and carotid arteries, as well as flow volume measurements of the subclavian artery, were performed. Flow measurements at the side of the vascular access were compared with the contralateral side. Fifty-five patients were consecutively included, most with a radio-cephalic fistula on the left arm with a mean shunt volume of 1156 ml/min.

Results: Pathologic flow patterns were observed in the ipsilateral VA in four patients (7.3 %); contralateral VA flow was normal in all patients. Peak systolic velocity of the VA was significantly decreased at the side of the shunt arm with a PSV of 42.6 ± 11.8 cm/s compared to 48.4 ± 15.6 cm/s contralateral (p < 0.05). The IMA flow pattern were normal in all patients. The PSV of the IMA was significantly decreased (p < 0.01) at the side of the shunt arm (87.5 ± 29.1 cm/s) compared to the non-shunt arm (95.9 ± 27.4 cm/s).

Conclusion: We describe significant hemodynamic effects of fistulas to the vertebral and internal mammary arteries. Doppler spectral analysis of the vertebral and internal mammary arteries should be integrated in ultrasound, especially in patients with cerebrovascular or cardiac symptoms.
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http://dx.doi.org/10.1024/0301-1526/a000511DOI Listing
June 2016

The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation.

PLoS One 2016 3;11(2):e0147951. Epub 2016 Feb 3.

Institute of Physiology, University of Zurich, Zurich, Switzerland.

DNAX accessory protein-1 (DNAM-1, CD226) is a co-stimulatory and adhesion molecule expressed mainly by natural killer cells and T cells. DNAM-1 and its two ligands CD112 and CD155 are important in graft-versus-host disease, but their role in solid organ transplantation is largely unknown. We investigated the relevance of this pathway in a mouse kidney transplantation model. CD112 and CD155 are constitutively expressed on renal tubular cells and strongly upregulated in acutely rejected renal allografts. In vitro DNAM-1 blockade during allogeneic priming reduced the allospecific T cell response but not the allospecific cytotoxicity against renal tubular epithelial cells. Accordingly, absence of DNAM-1 in recipient mice or absence of CD112 or CD155 in the kidney allograft did not significantly influence renal function and severity of rejection after transplantation, but led to a higher incidence of infarcts in CD112 and CD155 deficient kidney allografts. Thus, DNAM-1 blockade is not effective in preventing transplant rejection. Despite of being highly expressed, CD112 and CD155 do not appear to play a major immunogenic role in kidney transplantation. Considering the high incidence of renal infarcts in CD112 and CD155 deficient grafts, blocking these molecules might be detrimental.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147951PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739582PMC
July 2016

Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease.

PLoS One 2016 11;11(1):e0146654. Epub 2016 Jan 11.

Nephrology, Institute of Physiology, University of Zurich, Zurich, Switzerland.

Dysregulated signaling cascades alter energy metabolism and promote cell proliferation and cyst expansion in polycystic kidney disease (PKD). Here we tested whether metabolic reprogramming towards aerobic glycolysis ("Warburg effect") plays a pathogenic role in male heterozygous Han:SPRD rats (Cy/+), a chronic progressive model of PKD. Using microarray analysis and qPCR, we found an upregulation of genes involved in glycolysis (Hk1, Hk2, Ldha) and a downregulation of genes involved in gluconeogenesis (G6pc, Lbp1) in cystic kidneys of Cy/+ rats compared with wild-type (+/+) rats. We then tested the effect of inhibiting glycolysis with 2-deoxyglucose (2DG) on renal functional loss and cyst progression in 5-week-old male Cy/+ rats. Treatment with 2DG (500 mg/kg/day) for 5 weeks resulted in significantly lower kidney weights (-27%) and 2-kidney/total-body-weight ratios (-20%) and decreased renal cyst index (-48%) compared with vehicle treatment. Cy/+ rats treated with 2DG also showed higher clearances of creatinine (1.98±0.67 vs 1.41±0.37 ml/min), BUN (0.69±0.26 vs 0.40±0.10 ml/min) and uric acid (0.38±0.20 vs 0.21±0.10 ml/min), and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-α, a negative regulator of mTOR, and restoration of ERK signaling. Assessment of Ki-67 staining indicated that 2DG limits cyst progression through inhibition of epithelial cell proliferation. Taken together, our results show that targeting the glycolytic pathway may represent a promising therapeutic strategy to control cyst growth in PKD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146654PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708993PMC
July 2016

Inhibition of Sodium-Glucose Cotransporter 2 with Dapagliflozin in Han: SPRD Rats with Polycystic Kidney Disease.

Kidney Blood Press Res 2015 19;40(6):638-47. Epub 2015 Dec 19.

Division of Nephrology, University Hospital, Zx00FC;rich, Switzerland.

Background/aims: Dapagliflozin (DAPA) is a selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2) which induces glucosuria and osmotic diuresis. The therapeutic effect of DAPA in progressing stages of polycystic kidney disease (PKD) has not been studied.

Methods: We examined the effect of DAPA in the Han: SPRD rat model of PKD. DAPA (10 mg/kg/day) or vehicle (VEH) was administered orally via gavage to 5 week old male Han: SPRD (Cy/+) or control (+/+) rats (n = 8-9 per group) for 5 weeks. Blood and urine were collected at baseline and after 2.5 and 5 weeks of treatment to assess renal function and albuminuria. At the end of the treatment, rats were sacrificed and kidneys were excised for histological analysis.

Results: After 5 weeks of treatment, DAPA-treated Cy/+ and +/+ rats exhibited significantly higher glucosuria, water intake and urine output than VEH-treated rats. DAPA-treated Cy/+ rats also exhibited significantly higher clearances for creatinine and BUN and less albuminuria than VEH-treated Cy/+ rats. DAPA treatment for 5 weeks resulted in a significant increase of the kidney weight in Cy/+ rats but no change in cyst growth. The degree of tubular epithelial cell proliferation, macrophage infiltration and interstitial fibrosis was also similar in DAPA-and VEH-treated Cy/+ rats.

Conclusion: The induction of glucosuria with the SGLT2-specific inhibitor DAPA was associated with improved renal function and decreased albuminuria, but had no effect on cyst growth in Cy/+ rats. Overall the beneficial effects of DAPA in this PKD model were weaker than the previously described effects of the combined SGLT1/2 inhibitor phlorizin.
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http://dx.doi.org/10.1159/000368540DOI Listing
September 2016

Human proximal tubule cells form functional microtissues.

Pflugers Arch 2016 Apr 17;468(4):739-50. Epub 2015 Dec 17.

Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.

The epithelial cells lining the proximal tubules of the kidney mediate complex transport processes and are particularly vulnerable to drug toxicity. Drug toxicity studies are classically based on two-dimensional cultures of immortalized proximal tubular cells. Such immortalized cells are dedifferentiated, and lose transport properties (including saturable endocytic uptake) encountered in vivo. Generating differentiated, organotypic human microtissues would potentially alleviate these limitations and facilitate drug toxicity studies. Here, we describe the generation and characterization of kidney microtissues from immortalized (HK-2) and primary (HRPTEpiC) human renal proximal tubular epithelial cells under well-defined conditions. Microtissue cultures were done in hanging drop GravityPLUS™ culture plates and were characterized for morphology, proliferation and differentiation markers, and by monitoring the endocytic uptake of albumin. Kidney microtissues were successfully obtained by co-culturing HK-2 or HRPTEpiC cells with fibroblasts. The HK-2 microtissues formed highly proliferative, but dedifferentiated microtissues within 10 days of culture, while co-culture with fibroblasts yielded spherical structures already after 2 days. Low passage HRPTEpiC microtissues (mono- and co-culture) were less proliferative and expressed tissue-specific differentiation markers. Electron microscopy evidenced epithelial differentiation markers including microvilli, tight junctions, endosomes, and lysosomes in the co-cultured HRPTEpiC microtissues. The co-cultured HRPTEpiC microtissues showed specific uptake of albumin that could be inhibited by cadmium and gentamycin. In conclusion, we established a reliable hanging drop protocol to obtain functional kidney microtissues with proximal tubular epithelial cell lines. These microtissues could be used for high-throughput drug and toxicology screenings, with endocytosis as a functional readout.
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http://dx.doi.org/10.1007/s00424-015-1771-8DOI Listing
April 2016

Puumala Hantavirus-Induced Hemorrhagic Fever with Renal Syndrome Must Be Considered across the Borders of Nephrology to Avoid Unnecessary Diagnostic Procedures.

PLoS One 2015 9;10(12):e0144622. Epub 2015 Dec 9.

Department of Internal Medicine, Division of General Medicine and Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany.

Background: Nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome, is caused by Puumala virus and is characterized by acute kidney injury and thrombocytopenia.

Methods: A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed.

Results: Of the 456 investigated patients, 335 had received inpatient treatment. At time of admission to hospital, 72% of the patients had still an AKI and thrombocytopenia was present in 64% of the patients. The 335 patients were treated in 29 different hospitals and 6 of which had nephrology departments. 10 out of 335 patients received treatment in university hospitals and 63% of patients admitted themselves to hospital. Initially, the patients were admitted to 12 different clinical departments (29% of the patients were referred to a nephrology department) and during the course of the disease, 8% of the patients were transferred to another department in the same hospital and 3% were transferred to a nephrology department at another hospital. Regarding diagnostic procedures, in 28% of the inpatients computed tomography to exclude pulmonary embolism or due to severe gastrointestinal symptoms, lumbar puncture to exclude meningitis, magnetic resonance tomography of the brain owing to suspected stroke because of visual disorders, gastroscopy, or colonoscopy due to gastrointestinal symptoms was performed at time of admission to hospital.

Conclusions: NE must be considered by physicians across the borders of nephrology to avoid unnecessary diagnostic procedures especially in areas where NE is endemic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144622PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674130PMC
April 2017

The potential role of NFAT5 and osmolarity in peritoneal injury.

Biomed Res Int 2015 30;2015:578453. Epub 2015 Sep 30.

Division of Nephrology, University Hospital Zurich, 8091 Zurich, Switzerland ; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland.

A rise in osmotic concentration (osmolarity) activates the transcription factor Nuclear Factor of Activated T Cells 5 (NFAT5, also known as Tonicity-responsive Enhancer Binding Protein, TonEBP). This is part of a regulatory mechanism of cells adjusting to environments of high osmolarity. Under physiological conditions these are particularly important in the kidney. Activation of NFAT5 results in the modulation of various genes including some which promote inflammation. The osmolarity increases in patients with renal failure. Additionally, in peritoneal dialysis the cells of the peritoneal cavity are repeatedly exposed to a rise and fall in osmotic concentrations. Here we review the current information about NFAT5 activation in uremic patients and patients on peritoneal dialysis. We suggest that high osmolarity promotes injury in the "uremic" milieu, which results in inflammation locally in the peritoneal membrane, but most likely also in the systemic circulation.
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http://dx.doi.org/10.1155/2015/578453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4606082PMC
August 2016

The lymphotoxin β receptor is a potential therapeutic target in renal inflammation.

Kidney Int 2016 Jan 4;89(1):113-26. Epub 2016 Jan 4.

Division of Nephrology, University Hospital, Zurich, Switzerland; Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland. Electronic address:

Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTβ ligands, as well as LTβR. The LTβR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTβ was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTβ mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTβR signaling. Importantly, in a murine lupus model, LTβR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTβR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases.
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http://dx.doi.org/10.1038/ki.2015.280DOI Listing
January 2016