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1.
Blood Press ; : 1-5, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32543915

RESUMO

Purpose: Hypertension is the most important risk factor for disease and premature death. Treatment strategies adjusted for cardiovascular risk have been proposed in guidelines, but real-life treatment strategies for patients with newly diagnosed hypertension in Germany are largely unknown. The aim of the study was to analyse initial drug treatment strategies and associated risk status in patients with newly diagnosed hypertension.Material and methods: In the representative research database of the public health insurance system in Germany (2077899 individuals) we identified patients with newly diagnosed hypertension in 2012 and analysed co-existing cardiovascular co-morbidities and hypertension-mediated organ damage by ICD-codes as qualifiers for high risk. Health insurance billing datasets for redeemed prescriptions were analysed at several time points using ATC-codes.Results: The incidence of hypertension was 2.6%, 33.6% of the patients were at high risk at diagnosis, mainly due to cardiovascular co-morbidities. Most patients initially received monotherapy (55.4%), of which ACE inhibitors (43.8%) or beta-blockers (32.4%) were the leading drug classes, while 21.7% of patients received no drug therapy during the first year. The treatment strategies of low and high-risk patients resembled each other - high-risk patients also received mostly monotherapy during the first year after diagnosis (53.4%), while 13.7% remained without drug therapy. Combination therapy was the most frequent treatment strategy one year after hypertension diagnosis (40.6%) and in the long term (68.4%).Conclusion: Initial treatment strategies may not always be stratified according to cardiovascular risk. The majority of patients with hypertension receives initial monotherapy independent of their individual risk. However, combination therapy represents the major form of therapy in the long-term.

2.
Diabetes Obes Metab ; 2020 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-32363737

RESUMO

AIMS: To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. METHODS: Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD-free status. RESULTS: Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD-free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all-cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75-2.33) and HR 2.05 (95% CI 1.82-2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all-cause mortality risk: HRs 3.91 (95% CI 3.02-5.07) and 3.14 (95% CI 2.90-3.40), respectively. CONCLUSION: In a large multinational study of >750 000 CVRD-free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.

3.
Blood Press ; : 1-9, 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32279529

RESUMO

Purpose: Most guidelines for treatment of hypertension in the setting of diabetes recommend a blood pressure (BP) target of <130/80 mmHg. However, uncertainty exists about the extent, effectiveness and safety of lowering BP in diabetics. To expand the evidence on this issue, we analysed data from the Randomised Olmesartan and Diabetes MicroAlbuminuria Prevention (ROADMAP) study population.Material: Substudy with blood pressure readings.Methods: The response after initiation of therapy and adequacy of BP control across patients with different BP levels at baseline were analysed.Results: BP at randomisation was 136.2(15.3)/80.6(9.5) [mean (SD)] mmHg with a range of 87-213/37-123 mmHg. At 1 year, mean BP was 127 (11.9)/75 (8.1) mmHg and the overall control rate (<130/80 mmHg) exceeded 61% in this population. The mean reductions in systolic [-9.4 (15.4) mmHg] and diastolic BP [-5.4 (9.5) mmHg] were highly dependent on the BP stage at Visit 1. At 1 year, treatment decreased the prevalence of patients with baseline BP levels of >160/100 from 9 to 2%[[mean BP change -31 (15.7)/ -14 (9.8) mmHg]] and of 140-159/90-99 mmHg from 32 to 11% [[mean BP change -16(12.7)/ -8.9 (8.7) mmHg]], with corresponding increases in the prevalence of patients with baseline BP levels of 120-139/80-99 from 48 to 65% [[mean BP change -4.1 (10.6)/ -3.1 (7.8) mmHg]]and of <120/80 from 11 to 22% [[mean BP change +5.9 (11.8)/+2.5 (8.6) mmHg]]. These effects did not change significantly thereafter and were maintained throughout follow-up.Conclusion: Blood pressure control is feasible in patients with diabetes without nephropathy, independent of baseline BP values. Asymmetric BP-lowering in the first year after starting therapy represents a true antihypertensive effect with sustainable shifts in BP severity.

4.
Transpl Immunol ; 61: 101291, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32330566

RESUMO

Belatacept, Nulojix®, inhibits the interaction of CD28 on naïve T cells with B7.1/B7.2 (CD80/86) on antigen presenting cells, leading to T cell hyporesponsiveness and anergy and is approved as immunosuppressive drug in kidney transplantation. Due to its specificity for B7.1/2 molecules, side effects are reduced compared to other immunosuppressive drugs like calcineurin- and mTOR-inhibitors. Kidney transplant recipients under Belatacept-based immunosuppression presented with superior renal function and similar graft survival seven years after transplantation compared to cyclosporine treatment. However, de novo Belatacept-based immunosuppression was associated with increased risk of early rejections and viral (EBV) infections in clinical trials, especially in EBV-naïve patients. Since there is no vaccination against EBV infection available, EBV-derived virus like particles (EBV-VLPs) are currently developed as vaccine strategy. Here, we investigated the immunosuppressive effects of Belatacept compared to calcineurin- and mTOR inhibitors on allo- versus virus-specific T cells and the potency of EBV-VLPs to induce virus-specific T cell responses in vitro. Using PBMC of kidney recipients and healthy donors, we could demonstrate selective inhibition of allo-specific de novo T cell responses but not virus-specific memory T cell responses by Belatacept, as measured by IFN-γ production. In contrast, calcineurin inhibitors suppressed IFN-γ production of virus-specific memory CD8+ T cells completely. These results experimentally confirm the concept that Belatacept blocks CD28-mediated costimulation in newly primed naïve T cells but does not interfere with memory T cell responses being already independent from CD28-mediated costimulation. Additionally, we could show that EBV-VLPs induce a significant though weak IFN-γ-mediated T cell response in vitro in both kidney recipients and healthy donors. In summary, we demonstrated that immunosuppression of kidney recipients by Belatacept may primarily suppress de novo allo-specific T cell responses sparing virus-specific memory T cells. Moreover, EBV-VLPs could represent a novel strategy for vaccination of immunocompromised renal transplant recipients to prevent EBV reactivation especially under Belatacept-based immunosuppression.

5.
Kidney Int ; 97(6): 1287-1296, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32299680

RESUMO

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome.

6.
J Am Soc Nephrol ; 31(5): 983-995, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32209589

RESUMO

BACKGROUND: Expression of SerpinB2, a regulator of inflammatory processes, has been described in the context of macrophage activation and cellular senescence. Given that mechanisms for these processes interact and can shape kidney disease, it seems plausible that SerpinB2 might play a role in renal aging, injury, and repair. METHODS: We subjected SerpinB2 knockout mice to ischemia-reperfusion injury or unilateral ureteral obstruction. We performed phagocyte depletion to study SerpinB2's role beyond the effects of macrophages and transplanted bone marrow from knockout mice to wild-type mice and vice versa to dissect cell type-dependent effects. Primary tubular cells and macrophages from SerpinB2 knockout and wild-type mice were used for functional studies and transcriptional profiling. RESULTS: Cultured senescent tubular cells, kidneys of aged mice, and renal stress models exhibited upregulation of SerpinB2 expression. Functionally, lack of SerpinB2 in aged knockout mice had no effect on the magnitude of senescence markers but associated with enhanced kidney damage and fibrosis. In stress models, inflammatory cell infiltration was initially lower in knockout mice but later increased, leading to an accumulation of significantly more macrophages. SerpinB2 knockout tubular cells showed significantly reduced expression of the chemokine CCL2. Macrophages from knockout mice exhibited reduced phagocytosis and enhanced migration. Macrophage depletion and bone marrow transplantation experiments validated the functional relevance of these cell type-specific functions of SerpinB2. CONCLUSIONS: SerpinB2 influences tubule-macrophage crosstalk by supporting tubular CCL2 expression and regulating macrophage phagocytosis and migration. In mice, SerpinB2 expression seems to be needed for coordination and timely resolution of inflammation, successful repair, and kidney homeostasis during aging. Implications of SerpinB2 in human kidney disease deserve further exploration.

7.
Crit Care ; 24(1): 71, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32122366

RESUMO

BACKGROUND: A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock. METHODS: We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4 µg/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma. RESULTS: Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41-61) vs. 63% (48-70), p = 0.029; protein C, 47% (38-60) vs. 62% (54-69), p = 0.029). Median ADAMTS13 activity was increased by TPE from 27 (21-42) % before to 47 (38-62) % after TPE (p < 0.001). In contrast, vWF:Ag was elevated and could be reduced by TPE (353 (206-492) IU/dL vs. 170 (117-232) IU/dL, p < 0.001). Regression analysis yielded a correlation between ADAMTS13 activity and platelet count (p = 0.001, R2 = 0.316). CONCLUSIONS: Septic shock was associated with activation of pro-coagulant pathways and simultaneous depletion of anti-coagulant factors. TPE partially attenuated this dysbalance by removing pro- and by replacing anti-coagulant factors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065751. Retrospectively registered on 28 February 2017.

8.
Clin Res Cardiol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32002632

RESUMO

BACKGROUND: Dialysis patients are at increased risk of HF. However, diagnostic utility of NT-proBNP as a biomarker is decreased in patients on dialysis. GDF-15 and cNEP are biomarkers of distinct mechanisms that may contribute to HF pathophysiology in such cohorts. The aim of this study was to determine whether growth differentiation factor-15 (GDF-15) and circulating neprilysin (cNEP) improve the diagnosis of congestive heart failure (HF) in patients on dialysis. METHODS AND RESULTS: We compared circulating concentrations of NT-proBNP, GDF-15, and cNEP along with cNEP activity in patients on chronic dialysis without (n = 80) and with HF (n = 73), as diagnosed by clinical parameters and post-dialysis echocardiography. We used correlation, linear and logistic regression as well as receiver operating characteristic (ROC) analyses. Compared to controls, patients with HF had higher median values of NT-proBNP (16,216 [interquartile range, IQR = 27739] vs. 2883 [5866] pg/mL, p < 0.001), GDF-15 (7512 [7084] vs. 6005 [4892] pg/mL, p = 0.014), but not cNEP (315 [107] vs. 318 [124] pg/mL, p = 0.818). Median cNEP activity was significantly lower in HF vs. controls (0.189 [0.223] vs. 0.257 [0.166] nmol/mL/min, p < 0.001). In ROC analyses, a multi-marker model combining clinical covariates, NT-proBNP, GDF-15, and cNEP activity demonstrated best discrimination of HF from controls (AUC = 0.902, 95% CI 0.857-0.947, p < 0.001 vs. base model AUC = 0.785). CONCLUSION: We present novel comparative data on physiologically distinct circulating biomarkers for HF in patients on dialysis. cNEP activity but not concentration and GDF-15 provided incremental diagnostic information over clinical covariates and NT-proBNP and may aid in diagnosing HF in dialysis patients.

9.
BMC Nephrol ; 21(1): 53, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070317

RESUMO

BACKGROUND: Surgical correction of hyperparathyroidism after kidney transplantation has been associated with significant graft function decline. We examined the effects of parathyroidectomy on short- and long-term graft function and its potential predictors. METHODS: For this retrospective, monocentric study we identified 48 (5.5%) out of 892 patients from our protocol biopsy program who received renal transplantation between 2000 and 2007, with parathyroidectomy after transplantation. Data from up to three years after parathyroidectomy was collected and analyzed with multivariable linear regression analyses. RESULTS: Main indications for parathyroidectomy were hypercalcemia and graft calcifications. Parathyroidectomy was successful in 47 patients, with a median drop in serum intact parathormone (iPTH) from 394 to 21 pg/ml. Mean estimated glomerular fitration rate (eGFR) before parathyroidectomy was 60 ± 26 ml/min. At three months after parathyroidectomy, the eGFR was 46 ± 18 ml/min (p < 0.001) but remained stable at one and three years (50 ± 20; 49 ± 20 ml/min). The median annual eGFR change was - 0.5 ml/min before and + 1.0 ml/min after parathyroidectomy. Multivariable modeling identified high iPTH levels and higher eGFR before parathyroidectomy as predictors of the eGFR drop after parathyroidectomy. Lower graft function twelve months after parathyroidectomy was predicted by the eGFR before and the iPTH drop after surgery. CONCLUSIONS: These results indicate that the extent of parathyroidectomy is critical and too much lowering of iPTH should be avoided by timely parathyroidectomy, before reaching extreme high iPTH values. In view of the observed loss of eGFR, parathyroidectomy can be considered safe in patients with an eGFR above 30 ml/min.

10.
PLoS One ; 15(1): e0218494, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935212

RESUMO

Inhibiting vascular endothelial growth factor (VEGF) is a therapeutic option in diabetic microangiopathy. However, VEGF is needed at physiological concentrations to maintain glomerular integrity; complete VEGF blockade has deleterious effects on glomerular structure and function. Anti-VEGF therapy in diabetes raises the challenge of reducing VEGF-induced pathology without accelerating endothelial cell injury. Heparan sulfate (HS) act as a co-receptor for VEGF. Calcium dobesilate (CaD) is a small molecule with vasoprotective properties that has been used for the treatment of diabetic microangiopathy. Preliminary evidence suggests that CaD interferes with HS binding sites of fibroblast growth factor. We therefore tested the hypotheses that (1) CaD inhibits VEGF signaling in endothelial cells, (2) that this effect is mediated via interference between CaD and HS, and (3) that CaD ameliorates diabetic nephropathy in a streptozotocin-induced diabetic mouse model by VEGF inhibition. We found that CaD significantly inhibited VEGF165-induced endothelial cell migration, proliferation, and permeability. CaD significantly inhibited VEGF165-induced phosphorylation of VEGFR-2 and suppressed the activity of VEGFR-2 mediated signaling cascades. The effects of CaD in vitro were abrogated by heparin, suggesting the involvement of heparin-like domain in the interaction with CaD. In addition, VEGF121, an isoform which does not bind to heparin, was not inhibited by CaD. Using the proximity ligation approach, we detected inhibition of interaction in situ between HS and VEGF and between VEGF and VEGFR-2. Moreover, CaD reduced VEGF signaling in mice diabetic kidneys and ameliorated diabetic nephropathy and neuropathy, suggesting CaD as a VEGF inhibitor without the negative effects of complete VEGF blockade and therefore could be useful as a strategy in treating diabetic nephropathy.


Assuntos
Dobesilato de Cálcio/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Sítios de Ligação/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Células Endoteliais/efeitos dos fármacos , Heparitina Sulfato/metabolismo , Humanos , Cinética , Camundongos , Camundongos Endogâmicos NOD/genética , Camundongos Endogâmicos NOD/crescimento & desenvolvimento , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
11.
Kidney Int ; 97(1): 89-94, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31718844

RESUMO

Renal allograft rejection can be prevented by immunological tolerance, which may be associated with de novo formed lymphatic vessels in the donor kidney after transplantation in man. A suitable mouse model of renal allograft rejection in which lymphangiogenesis can be deliberately induced in the graft is critical for elucidating the mechanisms responsible for the association between attenuated transplant rejection and abundance of lymphatic vessels. Here we describe the development of a novel mouse model of rapid renal transplant rejection in which transgenic induction of lymphangiogenesis in the immune-incompatible graft greatly extends its survival time. Thus, our novel approach may facilitate exploitation of lymphangiogenesis in the grafted organ.

12.
J Vasc Res ; 57(1): 34-45, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31726451

RESUMO

BACKGROUND: Sepsis is a pathological host response to infection leading to vascular barrier breakdown due to elevated levels of angiopoietin-2 (Angpt-2) and vascular endothelial growth factor-A (VEGF-A). Here, we tested a novel heterodimeric bispecific monoclonal IgG1-cross antibody of Angpt-2 and VEGF - termed "A2V." METHODS: Cecal ligation and puncture was used to induce murine polymicrobial sepsis. Organs and blood were harvested for fluorescence immunohistochemistry and RT-PCR, and survival was recorded. In vitro endothelial cells were stimulated with plasma from septic shock patients costimulated with A2V or IgG antibody followed by immunocytochemistry and real-time transendothelial electrical resistance. RESULTS: Septic mice treated with A2V had a reduced induction of the endothelial adhesion molecule ICAM-1, leading to a trend towards less transmigration of inflammatory cells (A2V: 42.2 ± 1.0 vs. IgG 48.5 ± 1.7 Gr-1+ cells/HPF, p = 0.08) and reduced tissue levels of inflammatory cytokines (e.g., IL-6 mRNA: A2V 9.4 ± 3.2 vs. IgG 83.9 ± 36.7-fold over control, p = 0.03). Endothelial permeability was improved in vivo and in vitro in stimulated endothelial cells with septic plasma. Survival was improved by 38% (p = 0.02). CONCLUSION: Dual inhibition of Angpt-2 and VEGF-A improves murine sepsis morbidity and mortality, making it a potential therapeutic against vascular barrier breakdown.

13.
Transpl Int ; 33(4): 376-390, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31705694

RESUMO

Among factors determining long-term kidney allograft outcome, pretransplant renal replacement therapy (RRT) is the most easily modifiable. Previous studies analysing RRT modality impact on patient and graft survival are conflicting. Studies on allograft function are scarce, lack sufficient size and follow-up. We retrospectively studied patient and allograft survival together with allograft function and its decline in 2277 allograft recipients during 2000-2014. Pretransplant RRT modality ≥60 days as grouped into "no RRT" (n = 136), "haemodialysis (HD)" (n = 1847), "peritoneal dialysis (PD)" (n = 159), and "HD + PD" (n = 135) was evaluated. Kaplan-Meier analysis demonstrated superior 5-/10-/15-year patient (93.0/81.8/73.1% vs. 86.2/71.6/49.8%), death-censored graft (90.8/85.4/71.5% vs. 84.4/75.2/63.2%), and 1-year rejection-free graft survival (73.8% vs. 63.8%) in PD versus HD patients. Adjusted Cox regression revealed 34.5% [1.5-56.5%] lower hazards of death, whereas death-censored graft loss was similar [HR = 0.707 (0.469-1.064)], and rejection was less frequent [HR = 0.700 (0.508-0.965)]. Allografts showed higher 1-/3-/5-year estimated glomerular filtration rate (eGFR) in "PD" versus "HD" groups. Living donation benefit for allograft function was most pronounced in groups "no RRT" and "PD". Functional allograft decline (eGFR slope) was lowest for "PD". Allograft recipients on pretransplant PD versus HD demonstrated superior all-cause patient and rejection-free graft survival along with better allograft function (eGFR).

14.
Hypertension ; 75(1): 257-264, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786986

RESUMO

Arterial baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of resistant hypertension. Previous studies suggested that the peripheral chemoreflex is tonically active in hypertensive patients and may inhibit baroreflex responses. We hypothesized that peripheral chemoreflex activation attenuates baroreflex efficacy evoked by electrical carotid sinus stimulation. We screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients with consistent acute depressor response were selected (7 men/4 women, age: 67±8 years, body mass index: 31.6±5.2 kg/m2, 6±2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO2: 79.0±1.5%), and hyperoxia (40% end-tidal O2 fraction) by measuring heart rate, blood pressure, ventilation, oxygen saturation, end-tidal CO2 and O2 fractions, and muscle sympathetic nerve activity. During normoxia, baroreflex activation reduced systolic blood pressure from 164±27 to 151±25 mm Hg (mean±SD, P<0.001), heart rate from 64±13 to 61±13 bpm (P=0.002), and muscle sympathetic nerve activity from 42±12 to 36±12 bursts/min (P=0.004). Hypoxia increased systolic blood pressure 8±12 mm Hg (P=0.057), heart rate 10±6 bpm (P<0.001), muscle sympathetic nerve activity 7±7 bursts/min (P=0.031), and ventilation 10±7 L/min (P=0.002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions: systolic blood pressure: -15±7 versus -14±8 mm Hg (P=0.938), heart rate: -2±3 versus -2±2 bpm (P=0.701), and muscle sympathetic nerve activity: -6±4 versus -4±3 bursts/min (P=0.531). We conclude that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy in patients with resistant hypertension. These patients provided insight into human baroreflex-chemoreflex interactions that could not be gained otherwise.

15.
PLoS Med ; 16(12): e1002983, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31815931

RESUMO

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI). METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53-0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66-0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10-1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33-0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I-III). CONCLUSIONS: SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/induzido quimicamente , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
16.
Kidney Int Rep ; 4(10): 1373-1386, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31701047

RESUMO

Aim: The aim of the case-control study was to investigate if serum biomarkers indicative of vascular inflammation and endothelial dysfunction can predict the development of microalbuminuria in patients with diabetes mellitus type 2. Methods: Among participants enrolled in the ROADMAP (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention) and observational follow-up (OFU) studies, a panel of 15 serum biomarkers was quantified from samples obtained at initiation of the study and tested for associations with the development of new-onset microalbuminuria during follow-up. A case-control study was conducted with inclusion of 172 patients with microalbuminuria and 188 matched controls. Nonparametric inferential, nonlinear regression, mediation, and bootstrapping statistical methods were used for the analysis. Results: The median follow-up time was 37 months. At baseline, mean concentrations of C-X-C motif chemokine ligand 16 (CXCL-16), transforming growth factor (TGF)-ß1 and angiopoietin-2 were higher in patients with subsequent microalbuminuria. In the multivariate analysis, after adjustment for age, sex, body mass index, glycated hemoglobin, duration of diabetes, low-density lipoprotein (LDL), smoking status, blood pressure, baseline urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), time of follow-up and cardiovascular disease, CXCL-16 (odds ratio [OR] 2.60, 95% confidence interval [CI] 1.71-3.96), angiopoietin-2 (OR 1.50, 95% CI 1.14-1.98) and TGF-ß1 (OR 1.03, 95% CI 1.01-1.04) remained significant predictors of new-onset microalbuminuria (P < 0.001). Inclusion of these biomarkers in conventional clinical risk models for prediction of microalbuminuria increased the area under the curve (AUC) from 0.638 to 0.760 (P < 0.001). Conclusion: In patients with type 2 diabetes, elevated plasma levels of CXCL-16, angiopoietin-2, and TGF-ß1 are independently predictive of microalbuminuria. Thus, these serum markers improve renal risk models beyond established clinical risk factors.

17.
Open Forum Infect Dis ; 6(10): ofz381, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31660345

RESUMO

Background: The impact of immunosuppression on outcomes in influenza is insufficiently understood. We analyzed the morbidity and mortality of immunocompetent (IC) vs immunosuppressed (IS) patients with influenza A and B in the 2017/2018 season. Methods: Patients with proven influenza in a German tertiary care hospital were analyzed for hospitalization, intensive care unit (ICU) admission, and mortality. Causes for IS were organ and bone marrow transplantation, AIDS, chemotherapy, and medical immunosuppression. Results: In total, 227 patients were included in this analysis (IC, n = 118 [52%]; IS, n = 109 [48%]). Hospitalization (71% vs 91%; P < .001) and ICU admission (7% vs 23%; P = .001) were less frequent in the IS compared with the IC group. IC patients had a higher need for invasive ventilation (20% vs 5%; P = .001), vasopressors (19% vs 4%; P < .001), and renal replacement therapy (15% vs 3%; P = .002). Influenza-associated cardiomyopathy was found in 18% of IC vs 2% of IS patients (P < .001). The 30-day in-hospital mortality was 6.6%, 10.2% in the IC group and 2.8% in the IS group (hazard ratio IS group, 0.259; 95% confidence interval [CI], 0.113-0.855; P = .023). Immunosuppression was associated with reduced mortality (odds ratio, 0.25; 95% CI, 0.07-0.91; P = .036). Conclusions: We observed that IS was not associated with a worse outcome in this influenza cohort. Due to the presence of both confounding and referral and selection bias, the conclusion that immunosuppression reduces mortality cannot be drawn. Prospective studies investigating the influence of baseline immunosuppression on severity of influenza infection are desirable.

18.
Sci Rep ; 9(1): 13591, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537875

RESUMO

The endothelial glycocalyx and its regulated shedding are important to vascular health. Endo-ß-D-glucuronidase heparanase-1 (HPSE1) is the only enzyme that can shed heparan sulfate. However, the mechanisms are not well understood. We show that HPSE1 activity aggravated Toll-like receptor 4 (TLR4)-mediated response of endothelial cells to LPS. On the contrary, overexpression of its endogenous inhibitor, heparanase-2 (HPSE2) was protective. The microfluidic chip flow model confirmed that HPSE2 prevented heparan sulfate shedding by HPSE1. Furthermore, heparan sulfate did not interfere with cluster of differentiation-14 (CD14)-dependent LPS binding, but instead reduced the presentation of the LPS to TLR4. HPSE2 reduced LPS-mediated TLR4 activation, subsequent cell signalling, and cytokine expression. HPSE2-overexpressing endothelial cells remained protected against LPS-mediated loss of cell-cell contacts. In vivo, expression of HPSE2 in plasma and kidney medullary capillaries was decreased in mouse sepsis model. We next applied purified HPSE2 in mice and observed decreases in TNFα and IL-6 plasma concentrations after intravenous LPS injections. Our data demonstrate the important role of heparan sulfate and the glycocalyx in endothelial cell activation and suggest a protective role of HPSE2 in microvascular inflammation. HPSE2 offers new options for protection against HPSE1-mediated endothelial damage and preventing microvascular disease.

19.
Am J Nephrol ; 50(4): 281-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31473739

RESUMO

BACKGROUND: Tolvaptan can slow down renal function decline in autosomal dominant polycystic kidney disease (-ADPKD). While there is consensus across international recommendations that the drug should only be used in patients with high risk of rapid progression, identification criteria for rapid progression vary. Here, we investigated different assessment strategies using a real-life ADPKD cohort. METHODS: Observational retrospective cohort analysis. The study included 131 ADPKD patients aged 19-78 years who were referred to the Hannover Medical School outpatient clinic for evaluation of tolvaptan treatment. Six different assessment strategies for tolvaptan eligibility were tested for each patient. Comparative analysis for different assessments was performed in the total study population, the subpopulation with available computed tomography/magnetic resonance imaging data, and the genotyped subpopulation. RESULTS: Comparing 6 assessment strategies revealed strong variations in the individual selection processes resulting in treatment recommendations for 14.5-64.9% of patients. The highest patient number was selected by the Scottish and the lowest by the Japanese approach. Few patients had positive recommendations by all 6 systems, but strong congruency was observed between the Scottish, U.K. and Canadian patient selection. The lowest number of overlapping patients was found between the Japanese and the ERA-EDTA selection. Important discrepancies were also found between the ERA-EDTA and the U.S. system due to different emphases on parameters of kidney function versus kidney volume. Limitations of the study included the restricted sample size, heterogeneity in parameter availability and lack of outcome data. CONCLUSIONS: The study draws attention to important discrepancies between different decision algorithms for tolvaptan eligibility in ADPKD patients.

20.
Biomed Res Int ; 2019: 4508048, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428635

RESUMO

The 6-O-endosulfatases (sulfs) are important enzymatic components involved in the regulation of heparan sulfate by altering the sulfatation pattern. Specifically in the kidney, sulfs have been implicated in the glomerular podocyte-endothelial cell crosstalk and in the preservation of the glomerular filtration barrier (GFB) in different mouse models. Since it has been shown that in zebrafish larvae, Sulf1, Sulf2a, and Sulf2b are expressed in the pronephric kidney we set out to establish if a reduction in sulf expression leads to GFB dysfunction. Here, we show that a reduced sulf expression following morpholino (MO) induced knockdown in zebrafish larvae promotes damage to the GFB leading to renal plasma protein loss from the circulation. Moreover, a combined knockdown of Sulf1, Sulf2a, and Sulf2b is associated with severe morphologic changes including narrowing of the fenestration between glomerular endothelial cells as well as thickening of the glomerular basement membrane and podocyte foot process effacement, suggesting that glomerular damage is an underlying cause of the circulatory protein loss observed after MO injection. Additionally, we show that a decrease in sulf expression reduces the bioavailability of VegfA in the glomerulus of the pronephros, which may contribute to the structural changes observed in the glomeruli of morphant fish. Furthermore, consistent with previous results, knockdown of the sulfs is associated with arteriovenous malformations in particular in the tail region of the larvae. Overall, taken together our results suggest that 6-O-endosulfatases are important in the preservation of GFB integrity and a reduction in their expression levels induces phenotypic changes that are indicative of renal protein loss.


Assuntos
Membrana Basal Glomerular/embriologia , Podócitos/enzimologia , Sulfatases/biossíntese , Proteínas de Peixe-Zebra/biossíntese , Peixe-Zebra/embriologia , Animais , Células Endoteliais/enzimologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Morfolinos/farmacologia , Sulfatases/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
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