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INTRODUCTION: We know little about the evolution of perihaematomal oedema (PHO) >24 h after ICH onset. We aimed to determine the trajectory of PHO after ICH onset and its association with outcome. METHODS: We did a prospective cohort study using a pre-specified scanning protocol in adults with first-ever spontaneous ICH and measured absolute PHO volumes on CT head scans at ICH diagnosis and 3 ± 2, 7 ± 2, and 14 ± 2 days after ICH onset. We used the largest ICH if ICHs were multiple. The primary outcomes were (a) the trajectory of PHO after ICH onset and (b) the association between PHO (absolute volume at the time when most repeat CT head scans were obtained, and change in PHO volume at this time compared with the first CT head scan) and poor functional outcome (modified Rankin scale 3-6 at 90 days). We pre-specified multivariable logistic regression models of this association adjusting analyses for potential confounders: age, GCS, infratentorial ICH location, and intraventricular extension. RESULTS: In 106 participants of whom 49 (46%) were female, with a median ICH volume 7 mL (interquartile range [IQR] 2-22 mL), the trajectory of median PHO volume increased from 14 mL (IQR: 7-26 mL) at diagnosis to 18 mL (IQR: 8-40 mL) at 3 ± 2 days (n = 87), 20 mL (IQR: 8-48 mL) at 7 ± 2 days (n = 93) and 21 mL (IQR: 10-54 mL) at 14 ± 2 days (n = 78) (p = <0.001). PHO volume at each time point was collinear with ICH volume at diagnosis (ârâ >0.7), but the change in PHO volume between diagnosis and each time point was not. Given collinearity, we used total lesion (i.e., ICH + PHO) volume instead of PHO volume in a logistic regression model of its association at each time point with outcome. Increasing total lesion (ICH + PHO) volume at day 7 ± 2 was associated with poor functional outcome (adjusted OR per mL 1.02, 95% CI: 1.00-1.03; p = 0.036), but the increase in PHO volume between diagnosis and day 7 ± 2 was not associated with poor functional outcome (adjusted OR per mL 1.03, 95% CI: 0.99-1.07; p = 0.132). CONCLUSION: PHO volume increases throughout the first 2 weeks after onset of mild to moderate ICH. Total lesion (ICH + PHO) volume at day 7 ± 2 was associated with poor functional outcome, but the change in PHO volume between diagnosis and day 7 ± 2 was not. Prospective cohort studies with larger sample sizes are needed to investigate these associations and their modifiers.
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OBJECTIVE: To describe a practical approach of when and how often to perform imaging, and when to stop imaging pituitary adenomas (PAs). METHODS: A literature review was carried out and recommendations provided are derived largely from personal experience. RESULTS: Magnetic resonance imaging is the mainstay imaging modality of choice in the assessment, treatment planning, and follow-up of PAs. These adenomas are discovered incidentally during imaging for a variety of unrelated conditions, because of clinical symptoms related to mass effects on the adjacent structures, or during workup for functional alterations of the adenoma. Imaging is also used in the preoperative and postoperative phases of assessment of PAs, for surgical and radiotherapy planning, for postoperative surveillance to assess for adenoma stability and detection of adenoma recurrence, and for surveillance to monitor for adenoma growth in unoperated PAs. Currently, because there are no evidence-based consensus recommendations, the optimal strategy for surveillance imaging of PAs is not clearly established. Younger age, initial adenoma size, extrasellar extension, mass effect, cavernous sinus invasion, functional status, histopathologic characteristics, cost considerations, imaging accessibility, patient preference, and patient contraindications (eg, implanted metallic devices and patient claustrophobia) are all important factors that influence the strategy for surveillance imaging. CONCLUSIONS: This review provides a practical approach of performing surveillance imaging strategies for PAs that should be individualized based on clinical presentation, history, adenoma morphology on imaging, and histopathologic characteristics.
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Adenoma , Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/patologia , Adenoma/diagnóstico por imagem , Adenoma/patologia , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease. METHODS: Integrated droplet- and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney. RESULTS: A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1, before transitioning to become Ccr2+ macrophages that accumulate in late injury. Conversely, a novel Mmp12+ macrophage subset acts during repair. CONCLUSIONS: Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.
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Nefropatias/etiologia , Nefropatias/patologia , Células Mieloides/fisiologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Nefropatias/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Análise de Célula Única , Obstrução Ureteral/etiologiaRESUMO
Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis-age-associated histologic changes in the kidneys. Recent studies have shown that the aged kidney undergoes a range of structural changes and has altered transcriptomic, hemodynamic, and physiologic behavior at rest and in response to renal insults. These changes impair the ability of the kidney to withstand and recover from injury, contributing to the high susceptibility of the aged population to AKI and their increased propensity to develop subsequent progressive CKD. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging in both experimental animal models and humans. We also discuss the potential for additional study to increase understanding of the aged kidney and lead to novel therapeutic strategies.
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Envelhecimento , Rim/fisiologia , Pesquisa Biomédica/tendências , Ciclo Celular , Hipóxia Celular , Previsões , Humanos , Rim/citologia , Rim/patologia , Rim/fisiopatologia , Masculino , Estresse Oxidativo , Insuficiência Renal Crônica/etiologia , Transdução de SinaisRESUMO
Many diabetic patients suffer from declining renal function without developing albuminuria. To identify alternative biomarkers for diabetic nephropathy (DN) we performed urinary peptidomic analysis in a rodent model in which hyperglycemia and hypertension synergize to promote renal pathologic changes consistent with human DN. We identified 297 increased and 15 decreased peptides in the urine of rats with DN compared with controls, including peptides derived from proteins associated with DN and novel candidate biomarkers. We confirmed by ELISA that one of the parent proteins, urinary epidermal growth factor (uEGF), was more than 2-fold reduced in rats with DN in comparison with controls. To assess the clinical utility of uEGF we examined renal outcomes in 642 participants from the Edinburgh Type 2 Diabetes Study who were normoalbuminuric and had preserved renal function at baseline. After adjustment for established renal risk factors, a lower uEGF to creatinine ratio was associated with new-onset estimated glomerular filtration rate less than 60 ml/min per 1.73m(2) (odds ratio 0.48; 95% confidence interval, 0.26-0.90), rapid (over 5% per annum) decline in renal function (odds ratio 0.44; 95% confidence interval, 0.27-0.72) or the composite of both outcomes (odds ratio 0.38; 95% confidence interval, 0.24-0.62). Thus, the utility of a low uEGF to creatinine ratio as a biomarker of progressive decline in renal function in normoalbuminuric patients should be assessed in additional populations.
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Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/urina , Receptores ErbB/urina , Proteinúria/urina , Proteômica , Receptor ErbB-2/urina , Idoso , Animais , Biomarcadores/urina , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Creatinina/urina , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Estimativa de Kaplan-Meier , Rim/fisiopatologia , Modelos Logísticos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Valor Preditivo dos Testes , Proteômica/métodos , Ratos Transgênicos , Fatores de Risco , Escócia , UrináliseRESUMO
Heat preconditioning induces heat-shock protein-70 upregulation and protects from renal ischemia/reperfusion injury. Kim et al. report that heat-shock protein-70 and regulatory T cells play a key role in protective heat preconditioning. This work reinforces the utility of inducing heat-shock protein-70 expression by pharmacological agents as a novel therapy for the prevention and treatment of ischemic kidney injury.
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Injúria Renal Aguda/imunologia , Proteínas de Choque Térmico HSP70/fisiologia , Traumatismo por Reperfusão/imunologia , Linfócitos T Reguladores/fisiologia , Animais , MasculinoRESUMO
The incidence of acute kidney injury due to ischaemia-reperfusion injury (IRI) is rising but effective treatments and preventative approaches are currently lacking. IRI is also an inevitable consequence of kidney transplantation and significantly contributes to delayed graft function. Heat-shock proteins (Hsps) are highly conserved and ubiquitously expressed molecular chaperones that help maintain and restore normal cellular function in the kidney following IRI. Hsp70 is one of the most frequently studied Hsps because of potential cytoprotective properties and attractiveness as a therapeutic target. However, the protective properties of Hsp70 in renal IRI are not fully understood and putative modes of protection include correction of protein conformation, cytoskeletal stabilisation, anti-inflammatory effects, requirement in autophagy, anti-apoptotic properties, influence over macrophage phenotype and stimulation of regulatory T cells. Significant clinical interest has been generated about the possibility of applying pharmacological agents to induce Hsp70 and prevent renal IRI, but prior to this, an increased mechanistic understanding of the protective nature of Hsp70 is needed. In particular, further investigation of Hsp expression on inflammatory cell behaviour is required as this could lead to the development of new therapeutic strategies for enhancing recovery following renal IRI and broaden the range of these therapies to a wider group of patients.
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Injúria Renal Aguda/metabolismo , Proteínas de Choque Térmico/biossíntese , Isquemia/metabolismo , Rim/irrigação sanguínea , Rim/metabolismo , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/terapia , Animais , Humanos , Isquemia/diagnóstico , Isquemia/terapia , Rim/patologiaRESUMO
BACKGROUND/AIMS: Acute kidney injury (AKI) following cardiac surgery is a complication associated with high rates of morbidity and mortality. We compared staging systems for the diagnosis of AKI after cardiac surgery, and assessed pre-operative factors predictive of post-operative AKI. METHODS: Clinical data, surgical risk scores, procedure and clinical outcome were obtained on all 4,651 patients undergoing cardiac surgery to the Royal Infirmary of Edinburgh between April 2006 and March 2011, of whom 4,572 had sufficient measurements of creatinine before and after surgery to permit inclusion and analysis. The presence of AKI was assessed using the AKIN and RIFLE criteria. RESULTS: By AKIN criteria, 12.4% of the studied population developed AKI versus 6.5% by RIFLE criteria. Any post-operation AKI was associated with increased mortality from 2.2 to 13.5% (relative risk 7.0, p < 0.001), and increased inpatient stay from a median of 7 (IQR 4) to 9 (IQR 11) days (p < 0.05). Patients identified by AKIN, but not RIFLE, had a mean peak creatinine rise of 34% from baseline and had a significantly lower mortality compared to RIFLE-'Risk' AKI (mortality 6.1 vs. 9.7%; p < 0.05). Pre-operative creatinine, diabetes, NYHA Class IV dyspnoea and EuroSCORE-1 (a surgical risk score) all predicted subsequent AKI on multivariate analysis. EuroSCORE-1 outperformed any single demographic factor in predicting post-operative AKI risk, equating to an 8% increase in relative risk for each additional point. CONCLUSION: AKI after cardiac surgery is associated with delayed discharge and high mortality rates. The AKIN and RIFLE criteria identify patients at a range of AKI severity levels suitable for trial recruitment. The utility of EuroSCORE as a risk stratification tool to identify high AKI-risk subjects for prospective intervention merits further study.
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Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Idoso , Feminino , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Risco , Índice de Gravidade de DoençaRESUMO
AIMS: Regression of albuminuria and renal fibrosis occurs in patients with diabetic nephropathy (DN) following tight control of blood glucose and blood pressure, however the pathways that promote regression remain poorly understood and we wished to characterize these using a rodent model. METHODS: Diabetes was induced with streptozotocin in Cyp1a1mRen2 rats and hypertension was generated by inducing renin transgene expression with dietary indole-3-carbinol (I-3-C) for 28 weeks. At this point an 'injury cohort' was culled, while in a 'reversal cohort' glycaemia was tightly controlled using insulin implants and blood pressure normalized by withdrawing dietary I-3-C for a further 8 weeks. Pathways activated during and following reversal of diabetes and hypertension were assessed by microarray profiling. RESULTS: Tight control of blood glucose and blood pressure reduced albuminuria and renal hypertrophy, but had no impact on renal fibrosis. 85 genes were up-regulated specifically during the injury phase, including genes encoding multiple myofibroblast and extracellular matrix (ECM) proteins. Conversely, 314 genes remained persistently elevated during reversal including genes linked to innate/adaptive immunity, phagocytosis, lysosomal processing and degradative metalloproteinases (MMPs). Despite increased MMP gene expression, MMP activity was suppressed during both injury and reversal, in association with up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) protein. Physical separation of the TIMP-1/MMP complexes during zymography of tissue homogenate restored MMP activity. CONCLUSION: Normalization of blood glucose and pressure ameliorates albuminuria and inhibits excess ECM production, however persistent TIMP-1 expression hinders attempts at ECM remodelling. Therapies which counteract the action of TIMPs may accelerate scar resolution.
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Glicemia/efeitos dos fármacos , Pressão Sanguínea , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Matriz Extracelular/metabolismo , Hipertensão/fisiopatologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Rim/efeitos dos fármacos , Albuminúria/metabolismo , Albuminúria/patologia , Albuminúria/fisiopatologia , Albuminúria/prevenção & controle , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Citocromo P-450 CYP1A1/genética , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Matriz Extracelular/genética , Fibrose , Perfilação da Expressão Gênica/métodos , Hipertensão/genética , Indóis , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Ratos Transgênicos , Renina/genética , Renina/metabolismo , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
Primary central nervous system post-transplant lymphoproliferative disease (PCNS-PTLD) is a rare subset of post-transplant lymphoproliferative disorder (PTLD) isolated to the CNS without nodal or extra-nodal organ involvement [1,2]. PCNS-PTLD occurs primarily in patients following either solid organ transplants or hematopoietic stem cell transplants and tends to be monomorphic DLBCL. The development of PCNS-PTLD is commonly associated with EBV infection [3]. Many intracranial pathologies can resemble the imaging appearance of PCNS-PTLD, including primary CNS lymphoma, glial tumors, metastatic disease, and intracranial abscesses. The purpose of this systematic review is to identify the most common imaging characteristics of PCNS-PTLD. Our review included 97 sources that describe the imaging appearance of PCNS-PTLD. Based on our review, PCNS-PTLD lesions are typically multifocal, ring-enhancing and diffusion-restricting. PCNS-PTLD lesions typically demonstrate focal FDG avidity. Despite advancement in medical imaging, PCNS-PTLD remains a diagnostic challenge due to its rare incidence. Limited data is available on advanced imaging with regards to PTLD, but techniques including DCE-MRI and fMRI demonstrate promising results that may help further delineate PCNS-PTLD.
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Prefixes and suffixes in pharmacy might suggest a drug class, generation, or mechanism of action. As pharmacy educators, we also use an alphabet soup of acronyms and abbreviations to describe board certifications or professional organizations and our affiliation to them. Although we may be experts in nomenclature and abbreviations related to health professions education, sometimes, we also have to remind ourselves to be humble and embrace a learning mindset relative to the abbreviations and naming conventions used more broadly in higher education and in other fields. This article discusses the use of abbreviations in minority-serving institutions as well as the financial, historical, and political implications surrounding their names and definitions. The need to appreciate institutional designations and what they represent is not unique to minority-serving institutions or solely the responsibility of personnel who lead diversity, equity, inclusion, and accessibility efforts. Appreciating what institution designations mean is a logical first step toward discovering and acting upon the possibilities to facilitate and support the success of all learners recruited into the pharmacy profession.
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OBJECTIVES: Referencing literature and professional experiences of multiple academic affairs deans in Doctor of Pharmacy degree granting programs, this commentary examines ways offices of academic affairs (OAA) play an integral part in the professional identity formation (PIF) of students, faculty, preceptors, and staff. Overlapping roles of academic affairs and other program and university offices are examined with a focus on approaches that impact student PIF. FINDINGS: While size, organizational structure, and roles or responsibilities can vary among OAA within pharmacy education, five focus areas are identified as opportunities where most, if not all, OAA can positively impact PIF for students. These five areas include 1) curriculum design, delivery, and operations, 2) leadership, 3) professional development, 4) student support and progression, and 5) accreditation. SUMMARY: OAA can help to shape PIF within pharmacy education in a variety of ways. Identifying and reflecting upon the five focus areas described in this paper may help individuals within OAA units recognize where PIF efforts may be developed, refined, or assessed within their program. By intentionally layering PIF strategies across these five focus areas, OAA personnel and those from other units within and outside of the university system may thoughtfully work together to develop graduates who have increased self-awareness, confidence, and ability to lead within the profession of pharmacy.
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Although "implicit bias" has been a major focus in diversity, equity, inclusion, and antiracism educational efforts, less attention has been directed to "stereotype threat." This commentary aimed to bring increased awareness to the pharmacy academy about stereotype threat phenomena as well as explore its impact in the areas of education, with a specific focus on health professions education. In addition, potential and practical strategies are discussed to mitigate its occurrence in pharmacy education.
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Educação em Farmácia , Humanos , Estereotipagem , EscolaridadeRESUMO
The notion of consumerism and that students are customers of pharmacy colleges was explored by proponents and opponents of the idea. First, a working definition of a "customer" in pharmacy education is pondered with respect to the roles and responsibilities of students and schools/colleges of pharmacy. Second, the pros and cons of "student-centered" education are considered in the light of students and their families being consumers of the educational experience. Third, the duality of student-centered education is discussed including student engagement/disengagement in their learning, professional/unprofessional behaviors, and shared/individual responsibilities. Lastly, learning and teaching environment dynamics are discerned when higher education becomes more student-centric and how that may affect the overall outcome of the student and the goals of pharmacy educational programs.
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Educação em Farmácia , Estudantes de Farmácia , Humanos , Comportamento do Consumidor , Faculdades de Farmácia , Aprendizagem , CurrículoRESUMO
A mouse model of kidney transplantation was first described in 1973 by Skoskiewicz et al. Although the mouse model is technically difficult, it is attractive for several reasons: the mouse genome has been characterized and in many aspects is similar to man and there is a greater diversity of experimental reagents and techniques available for mouse studies than other experimental models. We reviewed the literature on all studies of mouse kidney transplantation to report the donor and recipient strain combinations that have been investigated and the resultant survival and histological outcomes. Some models of kidney transplantation have used the transplanted kidney as a life-supporting organ, however, in many studies the recipient mouse's native kidney has been left in situ. Several different combinations of inbred mouse strains have been reported, with varying degrees of injury, survival or tolerance because of haplotype differences. This model has been exceptionally useful as an investigational tool to understand multiple aspects of transplantation including acute rejection, cellular and humoral rejection mechanisms and their treatment. Furthermore, this model has been used to investigate disease mechanisms beyond transplant rejection including intrinsic renal disease and infection-associated pathology.
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Transplante de Rim , Camundongos , Animais , Modelos Animais de Doenças , Rejeição de Enxerto/patologia , Rejeição de Enxerto/fisiopatologia , Rim/patologia , Camundongos Endogâmicos , Transplante HomólogoRESUMO
RATIONALE: Acute lung injury (ALI) is an important cause of morbidity and mortality, with no currently effective pharmacological therapies. Neutrophils have been specifically implicated in the pathogenesis of ALI, and there has been significant research into the mechanisms of early neutrophil recruitment, but those controlling the later phases of neutrophil emigration that characterize disease are poorly understood. OBJECTIVES: To determine the influence of peripheral blood monocytes (PBMs) in established ALI. METHODS: In a murine model of LPS-induced ALI, three separate models of conditional monocyte ablation were used: systemic liposomal clodronate (sLC), inducible depletion using CD11b diphtheria toxin receptor (CD11b DTR) transgenic mice, and antibody-dependent ablation of CCR2(hi) monocytes. MEASUREMENTS AND MAIN RESULTS: PBMs play a critical role in regulating neutrophil emigration in established murine LPS-induced lung injury. Gr1(hi) and Gr1(lo) PBM subpopulations contribute to this process. PBM depletion is associated with a significant reduction in measures of lung injury. The specificity of PBM depletion was demonstrated by replenishment studies in which the effects were reversed by systemic PBM infusion but not by systemic or local pulmonary infusion of mature macrophages or lymphocytes. CONCLUSIONS: These results suggest that PBMs, or the mechanisms by which they influence pulmonary neutrophil emigration, could represent therapeutic targets in established ALI.
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Lesão Pulmonar Aguda/patologia , Movimento Celular/imunologia , Macrófagos/citologia , Monócitos/citologia , Neutrófilos/citologia , Lesão Pulmonar Aguda/fisiopatologia , Análise de Variância , Animais , Líquido da Lavagem Broncoalveolar/citologia , Movimento Celular/fisiologia , Ácido Clodrônico/farmacologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/imunologia , Neutrófilos/fisiologia , Distribuição Aleatória , Estatísticas não ParamétricasRESUMO
The renal mononuclear phagocytic system, conventionally composed of macrophages (Mø) and dendritic cells (DCs), plays a central role in health and disease of the kidney. Overlapping definitions of renal DCs and Mø, stemming from historically separate research tracks and the lack of experimental tools to specifically study the roles of these cells in vivo, have generated confusion and controversy, however, regarding their immunologic function in the kidney. This brief review provides an appraisal of the current state of knowledge of the renal mononuclear phagocytic system interpreted from the perspective of immunologic function. Physical characteristics, ontogeny, and known functions of the main subsets of renal mononuclear phagocytes as they relate to homeostasis, surveillance against injury and infection, and immune-mediated inflammatory injury and repair within the kidney are described. Gaps and inconsistencies in current knowledge are used to create a roadmap of key questions to be answered in future research.
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Células Dendríticas/fisiologia , Rim/imunologia , Macrófagos/fisiologia , Fagócitos , Animais , Citoproteção , Humanos , Imunidade , Inflamação/etiologiaRESUMO
Rodent models exhibit only the earliest features of human diabetic nephropathy, which limits our ability to investigate new therapies. Hypertension is a prerequisite for advanced diabetic nephropathy in humans, so its rarity in typical rodent models may partly explain their resistance to nephropathy. Here, we used the Cyp1a1mRen2 rat, in which the murine renin-2 gene is incorporated under the Cytochrome P4501a1 promoter. In this transgenic strain, administration of low-dose dietary indole-3-carbinol induces moderate hypertension. In the absence of hypertension, streptozotocin-induced diabetes resulted in a 14-fold increase in albuminuria but only mild changes in histology and gene expression despite 28 weeks of marked hyperglycemia. In the presence of induced hypertension, hyperglycemia resulted in a 500-fold increase in albuminuria, marked glomerulosclerosis and tubulointerstitial fibrosis, and induction of many of the same pathways that are upregulated in the tubulointerstitium in human diabetic nephropathy. In conclusion, although induction of diabetes alone in rodents has limited utility to model human diabetic nephropathy, renin-dependent hypertension and hyperglycemia synergize to recapitulate many of the clinical, histological, and gene expression changes observed in humans.