Healthcare reforms aim to change certain parts of the health system to improve quality of care, access, or financial sustainability. Traditionally, healthcare reform is understood as an action undertaken by a government at a national or local level. However, bottom-up changes can also lead to improvements in the health system. This paper describes the efforts of a coordinated multi-stakeholder advocacy group in Spain to promote a more cost-effective and patient-centred treatment for people receiving renal replacement therapy and assesses the outcomes of their advocacy for health system financing and patient satisfaction. It concludes that bottom-up initiatives do indeed have the power to change health policy and that policy makers should pay attention to their arguments.
[Abstract] Healthcare reforms aim to change certain parts of the health system to improve quality of care, access, or financial sustainability. Traditionally, healthcare reform is understood as an action undertaken by a government at a national or local level. However, bottom-up changes can also lead to improvements in the health system. This paper describes the efforts of a coordinated multi-stakeholder advocacy group in Spain to promote a more cost-effective and patient-centred treatment for people receiving renal replacement therapy and assesses the outcomes of their advocacy for health system financing and patient satisfaction. It concludes that bottom-up initiatives do indeed have the power to change health policy and that policy makers should pay attention to their arguments.
Chronic kidney disease (CKD) is emerging as an important health problem due to the increase number of CKD patients and the absence of an effective curative treatment. Gremlin has been proposed as a novel therapeutic target for renal inflammatory diseases, acting via Vascular Endothelial Growth Factor Receptor-2 (VEGFR2). Although many evidences suggest that Gremlin could regulate renal fibrosis, the receptor involved has not been yet clarified. Gremlin, as other TGF-β superfamily members, regulates tubular epithelial to mesenchymal transition (EMT) and, therefore, could contribute to renal fibrosis. In cultured tubular epithelial cells Gremlin binding to VEGFR2 is linked to proinflammatory responses. Now, we have found out that in these cells VEGFR2 is also involved in the profibrotic actions of Gremlin. VEGFR2 blockade by a pharmacological kinase inhibitor or gene silencing diminished Gremlin-mediated gene upregulation of profibrotic factors and restored changes in EMT-related genes. Moreover, VEGFR2 inhibition blocked EMT phenotypic changes and dampened the rate of wound healing in response to Gremlin. The role of VEGFR2 in experimental fibrosis was evaluated in experimental unilateral ureteral obstruction. VEFGR2 inhibition diminished the upregulation of profibrotic genes and EMT changes, as well as the accumulation of extracellular matrix proteins, such as fibronectin and collagens in the obstructed kidneys. Notch pathway activation participates in renal damage progression by regulating cell growth/proliferation, regeneration and inflammation. In cultured tubular epithelial cells, Notch inhibition markedly downregulated Gremlin-induced EMT changes and wound healing speed. These results show that Gremlin regulates the EMT process via VEGFR2 and Notch pathway activation, suggesting that the Gremlin/VEGFR2 axis could be a potential therapeutic target for CKD. ; This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI16/02057, PI17/00119, PI17/01495, and Red de Investigación Renal REDINREN: RD16/0009), Sociedad Española de Nefrologia, "NOVELREN-CM: Enfermedad renal crónica: nuevas Estrategias para la prevención, Diagnóstico y tratamiento"; B2017/BMD-3751, B2017/BMD-3686 CIFRA2-CM, PAI 82140017, and FONDECYT 1160465 (Chile) and Bayer HealthCare AG (Grants4Targets initiative, Berlin, Germany).
Chronic kidney disease (CKD) is emerging as an important health problem due to the increase number of CKD patients and the absence of an effective curative treatment. Gremlin has been proposed as a novel therapeutic target for renal inflammatory diseases, acting via Vascular Endothelial Growth Factor Receptor-2 (VEGFR2). Although many evidences suggest that Gremlin could regulate renal fibrosis, the receptor involved has not been yet clarified. Gremlin, as other TGF-β superfamily members, regulates tubular epithelial to mesenchymal transition (EMT) and, therefore, could contribute to renal fibrosis. In cultured tubular epithelial cells Gremlin binding to VEGFR2 is linked to proinflammatory responses. Now, we have found out that in these cells VEGFR2 is also involved in the profibrotic actions of Gremlin. VEGFR2 blockade by a pharmacological kinase inhibitor or gene silencing diminished Gremlin-mediated gene upregulation of profibrotic factors and restored changes in EMT-related genes. Moreover, VEGFR2 inhibition blocked EMT phenotypic changes and dampened the rate of wound healing in response to Gremlin. The role of VEGFR2 in experimental fibrosis was evaluated in experimental unilateral ureteral obstruction. VEFGR2 inhibition diminished the upregulation of profibrotic genes and EMT changes, as well as the accumulation of extracellular matrix proteins, such as fibronectin and collagens in the obstructed kidneys. Notch pathway activation participates in renal damage progression by regulating cell growth/proliferation, regeneration and inflammation. In cultured tubular epithelial cells, Notch inhibition markedly downregulated Gremlin-induced EMT changes and wound healing speed. These results show that Gremlin regulates the EMT process via VEGFR2 and Notch pathway activation, suggesting that the Gremlin/VEGFR2 axis could be a potential therapeutic target for CKD. ; This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI16/02057, PI17/00119, PI17/01495, and Red de Investigación Renal REDINREN: RD16/0009), Sociedad Española de Nefrologia, "NOVELREN-CM: Enfermedad renal crónica: nuevas Estrategias para la prevención, Diagnóstico y tratamiento"; B2017/BMD-3751, B2017/BMD-3686 CIFRA2-CM, PAI 82140017, and FONDECYT 1160465 (Chile) and Bayer HealthCare AG (Grants4Targets initiative, Berlin, Germany).
Fibrosis is a general complication in many diseases. It is the main complication during peritoneal dialysis (PD) treatment, a therapy for renal failure disease. Local inflammation and mesothelial to mesenchymal transition (MMT) are well known key phenomena in peritoneal damage during PD. New data suggest that, in the peritoneal cavity, inflammatory changes may be regulated at least in part by a delicate balance between T helper 17 and regulatory T cells. This paper briefly reviews the implication of the Th17/Tregaxis in fibrotic diseases. Moreover, it compares current evidences described in PD animal experimental models, indicating a loss of Th17/Treg balance (Th17 predominance) leading to peritoneal damage during PD. In addition, considering the new clinical and animal experimental data, new therapeutic strategies to reduce the Th17 response and increase the regulatory T response are proposed.Thus, future goals should be to develop newclinical biomarkers to reverse this immunemisbalance and reduce peritoneal fibrosis in PD. ; This work was supported in part by grants from Ministerio de EconomIa y competitividad SAF2010-21249 to Manuel López-Cabrera, Comunidad Autónoma de Madrid 2010- BMD2321 (FIBROTEAM) to Manuel López Cabrera, and Fondo de Investigaciones Santitarias RETICS 06/0016 and PI 09/0064 to Rafael Selgas and FIS 12/01175 to Abelardo Aguilera Peralta. Georgios Liappas is fully supported from European Union, Seventh Framework Program "EuTRiPD," under Grant Agreement PITN-GA-2011-287813.
Fibrosis is a general complication in many diseases. It is the main complication during peritoneal dialysis (PD) treatment, a therapy for renal failure disease. Local inflammation and mesothelial to mesenchymal transition (MMT) are well known key phenomena in peritoneal damage during PD. New data suggest that, in the peritoneal cavity, inflammatory changes may be regulated at least in part by a delicate balance between T helper 17 and regulatory T cells. This paper briefly reviews the implication of the Th17/Tregaxis in fibrotic diseases. Moreover, it compares current evidences described in PD animal experimental models, indicating a loss of Th17/Treg balance (Th17 predominance) leading to peritoneal damage during PD. In addition, considering the new clinical and animal experimental data, new therapeutic strategies to reduce the Th17 response and increase the regulatory T response are proposed. Thus, future goals should be to develop new clinical biomarkers to reverse this immune misbalance and reduce peritoneal fibrosis in PD. ; This work was supported in part by grants from Ministerio de Economia y competitividad SAF2010-21249 to Manuel Lopez-Cabrera, Comunidad Autonoma de Madrid 2010-BMD2321 (FIBROTEAM) to Manuel Lopez Cabrera, and Fondo de Investigaciones Santitarias RETICS 06/0016 and PI 09/0064 to Rafael Selgas and FIS 12/01175 to Abelardo Aguilera Peralta. Georgios Liappas is fully supported from European Union, Seventh Framework Program ``EuTRiPD,´´ under Grant Agreement PITN-GA-2011-287813. The authors would like to thank Juliette Siegfried and her team at ServingMed.com for editing the language of the paper. ; Sí
Peritoneal hyalinizing vasculopathy (PHV) represents the cornerstone of long-term peritoneal dialysis (PD), and especially characterizes patients associated with encapsulating peritoneal sclerosis. However, the mechanisms of PHV development remain unknown. A cross sectional study was performed in 100 non-selected peritoneal biopsies of PD patients. Clinical data were collected and lesions were evaluated by immunohistochemistry. In selected biopsies a microRNA (miRNA)-sequencing analysis was performed. Only fifteen patients (15%) showed PHV at different degrees. PHV prevalence was significantly lower among patients using PD fluids containing low glucose degradation products (GDP) (5.9% vs. 24.5%), angiotensin converting enzyme inhibitors (ACEIs) (7.5% vs. 23.4%), statins (6.5% vs. 22.6%) or presenting residual renal function, suggesting the existence of several PHV protective factors. Peritoneal biopsies from PHV samples showed loss of endothelial markers and induction of mesenchymal proteins, associated with collagen IV accumulation and wide reduplication of the basement membrane. Moreover, co-expression of endothelial and mesenchymal markers, as well as TGF-β1/Smad3 signaling activation were found in PHV biopsies. These findings suggest that an endothelial-to-mesenchymal transition (EndMT) process was taking place. Additionally, significantly higher levels of miR-7641 were observed in severe PHV compared to non-PHV peritoneal biopsies. Peritoneal damage by GDPs induce miRNA deregulation and an EndMT process in submesothelial vessels, which could contribute to collagen IV accumulation and PHV. ; Funding: This research was funded by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI15/00120 to R.S, PI18/00882 to M.A.B, PI17/00119 to M.R.-O. and Red de Investigación Renal (REDINREN): RD16/0009, to R.S and M.R-O); "Convocatoria Dinamización Europa Investigación 2019" MINECO (EIN2019-103294 to M.R.-O.); IMPROVE-PD project ("Identification and Management of Patients at Risk–Outcome and Vascular Events in Peritoneal Dialysis") funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 812699 to M.R.-O. and M.L-C. Spanish Ministry of Science and Innovation/Fondo Europeo de Desarrollo Regional (MICINN/FEDER) (PID2019-110132RB-I00) to M.L.-C.
Chronic kidney disease (CKD) is a health problem reaching epidemic proportions. There is no cure for CKD, and patients may progress to end-stage renal disease (ESRD). Peritoneal dialysis (PD) is a current replacement therapy option for ESRD patients until renal transplantation can be achieved. One important problem in long-term PD patients is peritoneal membrane failure. The mechanisms involved in peritoneal damage include activation of the inflammatory and immune responses, associated with submesothelial immune infiltrates, angiogenesis, loss of the mesothelial layer due to cell death and mesothelial to mesenchymal transition, and collagen accumulation in the submesothelial compact zone. These processes lead to fibrosis and loss of peritoneal membrane function. Peritoneal inflammation and membrane failure are strongly associated with additional problems in PD patients, mainly with a very high risk of cardiovascular disease. Among the inflammatory mediators involved in peritoneal damage, cytokine IL-17A has recently been proposed as a potential therapeutic target for chronic inflammatory diseases, including CKD. Although IL-17A is the hallmark cytokine of Th17 immune cells, many other cells can also produce or secrete IL-17A. In the peritoneum of PD patients, IL-17A-secreting cells comprise Th17 cells, gamma delta T cells, mast cells, and neutrophils. Experimental studies demonstrated that IL-17A blockade ameliorated peritoneal damage caused by exposure to PD fluids. This article provides a comprehensive review of recent advances on the role of IL-17A in peritoneal membrane injury during PD and other PD-associated complications. ; This research was funded by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI17/00119 to M.R.-O.; PI17/01495, DTS17/00203, and DTS19/00093 to J.E.; PI16/02057 and PI19/00815 to A.O.; PI 15/00120 to R.S; PI18/0610 to J.M.V.; and Red de Investigacion Renal (REDINREN): RD16/0009 to M.R.-O., A.O., R.S., and J.M.V.); by Comunidad de Madrid ("NOVELREN" B2017/BMD-3751 to M.R.-O. and B2017/BMD-3686 CIFRA2-CM to A.O.); by the "Juan de la Cierva Formacion" training program of the Ministerio de Economia, Industria y Competitividad (MINECO) supporting the salary of S.R.-M. (FJCI-2016-29050); by "Convocatoria Dinamizacion Europa Investigacion 2019" MINECO (EIN2019-103294 to M.R.-O. and S.R.-M.); by Sociedad Espanola de Nefrologia (S.E.N. to M.R.-O.); by ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071) and DTS18/00032 toA.O; by IMPROVE-PD project ("Identification and Management of Patients at Risk-Outcome and Vascular Events in Peritoneal Dialysis") with funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 812699 to M.R.O., M.L.-C., and D.F.; and by the Spanish Ministry of Science and Innovation/Fondo Europeo de Desarrollo Regional (MICINN/FEDER) (PID2019-110132RB-I00) to M.L.-C.
Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by cells of the immunesystem, predominantly Th17 and lymphocytes. In this paper, we review the role of IL-17A in the pathogenesis of hypertension and in target organ damage. Preclinical studiesin mice have shown that systemic adminstration of IL-17A increases blood pressure, prob-ably by acting on multiple levels. Furthermore, IL-17A plasma concentrations are alreadyelevated in patients with mild or moderate hypertension. Many studies in hypertensive mice models have detected IL-17A-producing cells in target organs such as the heart, vesselsand kidneys. Patients with hypertensive nephrosclerosis show kidney infiltration by Th17lymphocytes and lymphocytes that express IL-17A. In addition, in experimental models ofhypertension, the blockade of IL-17A by genetic strategies or using neutralizing antibodies,disminished blood pressure, probablyby acting on the small mesenteric arteries as well as inthe regulation of tubule sodium transport. Moreover, IL-17A inhibition reduces end-organsdamage. As a whole, the data presented in this review suggest that IL-17A participates in theregulation of blood pressure and in the genesis and maintenance of arterial hypertension,and may constitute a therapeutic target of hypertension-related pathologies in the future. ; La interleuquina 17A (IL-17A) es una citoquina proinflamatoria producida por células del sis-tema inmune, sobre todo por los linfocitos Th17 y los linfocitos . En este trabajo, revisamosel papel de IL-17A en la patogenia de la hipertensión y de la lesión en órganos diana. Estu-dios en ratones han demostrado que la IL-17A aumenta la presión arterial, probablementepor acciones a varios niveles. Además, las concentraciones plasmáticas de IL-17A están yaaumentadas en pacientes con hipertensión arterial ligera o moderada. Estudios preclíni-cos sobre hipertensión arterial han detectado células productoras de IL-17A en órganosdiana, como corazón, vasos y ri ̃nón. En pacientes con nefroesclerosis hipertensiva existeinfiltración del ri ̃nón por linfocitos Th17 y linfocitos que expresan IL-17A. Además, enmodelos experimentales de hipertensión el bloqueo de IL-17A, mediante estrategias génicas,o utilizando anticuerpos neutralizantes, disminuye la presión arterial por acciones sobre lapared vascular y el transporte tubular de sodio y disminuye la lesión en órganos diana. Enconjunto, los datos presentados en esta revisión sugieren que la IL-17A participa en la reg-ulación de la presión arterial y en la génesis y mantenimiento de la hipertensión arterial,pudiendo constituir una diana terapéutica en el futuro. ; This work has been funded by the Spanish Society of Nephrology and by grants from the Carlos III Health Institute (ISCIII) and FEDER European Union Funds (PI17/00119 and PI20/00140 and Renal Research Network (REDINREN): RD16/0009, to MR-O, RS, PI17/01495 to JE), Community of Madrid («NOVELREN» B2017/BMD3751 to MR-O); the José Castillejo grant (CAS19/00133 to RRR-D); «Juan de la Cierva Incorporacion» of the Ministry of Economy, Industry and Competitiveness (MINECO) for SR-M (IJC2018-035187-I); "Call for Dynamization Europe Research 2019" MINECO (EIN2019-103294 to MR-O and SR-M); IMPROVE-PD project («Identification and Management of Patients at Risk – Outcome and Vascular Events in Peritoneal Dialysis») of Horizon 2020 MarieSkłodowska-Curie Grant Agreement No. 812699 to MRO, and Fondecyt Chile 1160465
