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PURPOSE Infusing continuity of care into medical student clerkships may accelerate professional development, preserve patient-centered attitudes, and improve primary care training. However, prospective, randomized studies of longitudinal curricula are lacking. METHOD All entering Northwestern University Feinberg School of Medicine students in 2015 and 2016 were randomized to the Education Centered Medical Home (ECMH), a 4-year, team-based primary care clerkship; or a mentored individual preceptorship (IP) for 2 years followed by a traditional 4-week primary care clerkship. Students were surveyed 4 times (baseline, M1, M2, and M3 year [through 2018]); surveys included the Maslach Burnout Inventory (MBI); the Communication, Curriculum, and Culture (C3) survey assessing the hidden curriculum; and the Attitudes Toward Health Care Teams (ATHCT) scale. The authors analyzed results using an intent-to-treat approach. RESULTS Three hundred twenty-nine students were randomized; 316 (96%) participated in surveys. Seventy percent of all respondents would recommend the ECMH to incoming first-year students. ECMH students reported a more positive learning environment (overall quality, 4.4 ECMH vs 4.0 IP, P < .001), greater team-centered attitudes (ATHCT scale, 3.2 vs 3.0, P = .007), less exposure to negative aspects of the hidden curriculum (C3 scale, 4.6 vs 4.3, P < .001), and comparable medical knowledge acquisition. ECMH students established more continuity relationships with patients (2.2 vs 0.3, P < .001) and reported significantly higher professional efficacy (MBI-PE, 4.1 vs 3.9, P = .02). CONCLUSIONS In this randomized medical education trial, the ECMH provided superior primary care training across multiple outcomes compared with a traditional clerkship-based model, including improved professional efficacy.

The mechanisms by which angiotensin II (Ang II) promotes renal fibrosis remain incompletely understood. Ang II both stimulates TGFβ signaling and activates the EGF receptor (EGFR), but the relative contribution of these pathways to renal fibrogenesis is unknown. Using a murine model with EGFR-deficient proximal tubules, we demonstrate that upstream activation of EGFR-dependent ERK signaling is critical for mediating sustained TGFβ expression in renal fibrosis. Persistent activation of the Ang II receptor stimulated ROS-dependent phosphorylation of Src, leading to sustained EGFR-dependent signaling for TGFβ expression. Either genetic or pharmacologic inhibition of EGFR significantly decreased TGFβ-mediated fibrogenesis. We conclude that TGFβ-mediated tissue fibrosis relies on a persistent feed-forward mechanism of EGFR/ERK activation through an unexpected signaling pathway, highlighting EGFR as a potential therapeutic target for modulating tissue fibrogenesis.

The Journal of the American Society of Nephrology (JASN) gives authors submitting original research the option of suggesting qualified reviewers or those they wish to exclude. This historical habit often leaves us wondering whether author preferences correlate with reviewer recommendations and whether differences related to reviewer selection affect decisions by editors. In a self-study presented here, we found that author-suggested reviewers, as a group, make more positive recommendations than editor-suggested reviewers (P = 0.01), although the difference disappears when recommendations are compared with those of editor-suggested reviewers of the same manuscript (P = 0.081). The distribution of recommendations by author-excluded reviewers, as a group, did not differ from those by editor-suggested reviewers; however, author-excluded reviewers impart significantly more negative recommendations than other reviewers of the same manuscript (P = 0.029). We further explored whether such differences result from individual reviewer tendencies to give generally more positive or more negative recommendations than editor-suggested reviewers and found no such tendency. Finally, editorial decisions on manuscripts reviewed by author-suggested or author-excluded reviewers do not differ from those decisions on manuscripts assigned but not reviewed by them. JASN's policy of editors making decisions independent from individual reviewer recommendations minimizes the effect of selection bias on publication decisions.

The pathologic paradigm for renal progression is advancing tubulointerstitial fibrosis. Whereas mechanisms underlying fibrogenesis have grown in scope and understanding in recent decades, effective human treatment to directly halt or even reverse fibrosis remains elusive. Here, we examine key features mediating the molecular and cellular basis of tubulointerstitial fibrosis and highlight new insights that may lead to novel therapies. How to prevent chronic kidney disease from progressing to renal failure awaits even deeper biochemical understanding.

Background and objectives: α- and β-dystroglycan (DG), which link the actin cytoskeleton of the podocyte to the glomerular basement membrane, are maintained in FSGS but decreased in minimal change disease (MCD). Fibrosis has been linked to increased fibroblast-specific protein-1 (FSP1) and epithelial–mesenchymal transition. We studied DG, FSP1, and podocyte differentiation in FSGS variants and cases of suspected FSGS. Design, setting, participants, & measurements: We studied renal biopsies with FSGS, not otherwise specified (NOS), tip lesion, or collapsing variants (COLL), versus secondary FSGS or cases without segmental sclerotic lesions where a diagnosis of MCD versus FSGS could not be established (undefined [UNDEF]) and compared the expression of DG, FSP1, and podocyte Wilms9 tumor antigen (WT1). Results: WT1 is markedly decreased in NOS versus normal and correlates with the extent of sclerosis. α- and β-DG are maintained in most primary and secondary FSGS cases. In contrast, α-DG is significantly decreased in UNDEF, supporting a diagnosis of MCD. Furthermore, follow-up shows remission or decreased proteinuria in four of six of these UNDEF cases in response to therapy. Interstitial FSP1 is numerically highest in COLL but is only rarely found in tubules or podocytes in any other forms of FSGS. Conclusions: We conclude that increased FSP1 may be a marker of the aggressive course of collapsing FSGS. Furthermore, DG staining is a useful adjunct to assist in distinction of FSGS versus MCD in biopsies without defining lesions.

Once in a while, we should compulse over well-established paradigms, and I have been thinking about the terminality of differentiated epithelial cells. There are many believers in terminal differentiation, but if the concept encourages a sense of immutability, then does it cripple new ideas

For determination of the molecular mechanisms underlying the induction of epithelial cell hypertrophy by angiotensin II (Ang II), a well-characterized porcine renal proximal tubular cell line LLCPKcl4, which does not express endogenous Ang II receptor subtypes, was transfected with cDNA encoding Ang II subtype 1 receptor (AT1R/Cl4). Ang II transactivated the EGF receptor (EGFR) in these AT1R/Cl4 cells, which was blocked by the selective AT1R antagonist losartan but not by the selective AT2R antagonist PD123319. Ang II did not transactivate EGFR in empty vector-transfected LLCPKcl4 cells (Vector/Cl4). Ang II elicited release of soluble heparin-binding EGF-like growth factor (HB-EGF) from AT1R/Cl4 cells, and Ang II-induced EGFR activation was prevented by pretreatment with the specific HB-EGF inhibitor CRM197 or the metalloproteinase inhibitors batimastat or phenanthroline, none of which had any effect on EGFR activation by exogenously administered EGF. Ang II stimulated protein synthesis and cell hypertrophy in AT1R/Cl4 cells without increasing cell number, and signaling studies revealed that Ang II stimulated phosphorylation of the 40S ribosomal protein S6 and the eukaryotic translation initiation factor 4E-binding protein 1, the two downstream target proteins of the mammalian target of rapamycin, which is a central regulator of protein synthesis and cell size. Ang II-induced mammalian target of rapamycin activation, [3H]leucine incorporation, and cellular hypertrophy were inhibited by pretreatment with either batimastat or CRM197 or by pretreatment with rapamycin or the EGFR tyrosine kinase inhibitor AG1478. Ang II also stimulated Smad 2/3 phosphorylation, which was blocked by a selective TGF-beta receptor I kinase inhibitor but not by CRM197. With blockade of TGF-beta receptor, Ang II-mediated hypertrophy was converted into cell proliferation, which was blocked by CRM197. In summary, this is the first demonstration that HB-EGF shedding-dependent EGFR transactivation, along with activation of TGF-beta signaling pathways, mediates Ang II-induced renal tubular epithelial cell hypertrophy.

Loss of functioning nephrons stimulates the growth of residual kidney tissue to augment work capacity and maintain normal renal function. This growth largely occurs by hypertrophy rather than from hyperplasia of the remaining nephrons. The signaling mechanisms that increase RNA and protein synthesis during compensatory renal hypertrophy are unknown. This study found that the remaining kidney hypertrophied 42% by 16 d after unilateral nephrectomy (UNX) in DBA/2 mice. Immunoblotting analysis revealed increased phosphorylation of the 40S ribosomal protein S6 (rpS6) and the eukaryotic translation initiation factor (eIF) 4E-binding protein 1 (4E-BP1), the two downstream effectors of the mammalian target of rapamycin (mTOR). The highly specific mTOR inhibitor rapamycin blocked UNX-increased phosphorylation of both rpS6 and 4E-BP1. UNX increased the content of not only 40S and 60S ribosomal subunits but also 80S monosomes and polysomes in the remaining kidney. Administration of rapamycin decreased UNX-induced polysome formation and shifted the polysome profile in the direction of monosomes and ribosomal subunits. Pretreatment of the mice with rapamycin inhibited UNX-induced hypertrophy. These studies demonstrate that activation of the mTOR signaling pathway in the remaining kidney after UNX plays an essential role in modulating RNA and protein synthesis during development of compensatory renal hypertrophy.

Purpose of review Tubulointerstitial fibrosis is the final common pathway to end-stage renal disease. Understanding the mechanisms of tubulointerstitial fibrosis is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive kidney diseases. The present review focuses on a newly proposed mechanism of tubulointerstitial fibrosis, one that emphasizes the roles of epithelial-mesenchymal transition and cellular activation. Recent findings Among the cells that accumulate in the renal interstitium, fibroblasts are the principal effectors mediating tubulointerstitial fibrosis. By contrast, the phagocytosis of extracellular matrix and apoptotic cells by macrophages may actually exert a beneficial effect. Interstitial fibroblasts are more heterogeneous than expected, and during renal fibrosis new fibroblasts are derived mainly through epithelial-mesenchymal transition. The intracellular signaling pathways leading to initiation of epithelial-mesenchymal transition remain largely unknown, though recent studies have identified beta-catenin and Smad3 activation of lymphoid enhancer factor, integrin-linked kinase, and small GTPases and mitogen-activated protein kinases as key components. Transforming growth factor-beta is believed to be a critical fibrogenic factor, but recent studies have also focused on transforming growth factor-beta independent pathways as mechanisms of tubulointerstitial fibrosis. As the mechanisms underlying tubulointerstitial fibrosis leading to epithelial-mesenchymal transition have been identified, so have cytokines that efficiently antagonize renal fibrosis, particularly bone morphogenic protein-7 and hepatocyte growth factor. Summary In combination with traditional angiotensin converting enzyme inhibitors, newly identified cytokines may eventually form the basis for new therapeutic strategies aimed at inhibiting the progression of renal disease.

PURPOSE Academic departments of medicine must compete effectively for extramural research support and access to patients while preserving their teaching mission. There is not much literature describing plausible mechanisms for ensuring success. The authors describe the design, implementation, and testing of a performance-based compensation plan in a department of medicine that is closely linked to the faculty appointment track. METHOD Over a three-year period, the changes this plan effected in research portfolio, clinical enterprise, and faculty satisfaction as well as the teaching perceptions of students and housestaff were measured. RESULTS The compound annual growth rate (CAGR) for clinical work grew 40% faster after plan implementation. Federal funding increased at a CAGR that was 170% greater than before. The department halved its award rankings at the National Institutes of Health and faculty satisfaction improved compared with the former method of compensation. Faculty who better understood the plan were more satisfied with the conversion. High measures of teaching quality were maintained by faculty with no apparent change in satisfaction among students or housestaff. CONCLUSIONS This performance-based compensation plan with its emphasis on the objectives of career orientation and faculty track assignment strengthened the opportunity to grow both clinical productivity and the funded research portfolio.

Background Alport syndrome is a hereditary disorder of basement membranes especially affecting the kidneys, ears, and eyes. Some patients who undergo renal transplantation lose their kidneys as a result of posttransplant anti-glomerular basement membrane (anti-GBM) disease. Methods In the present study, we analyzed serum from 21 unselected Alport patients who underwent renal transplantation. Eleven samples were from patients without posttransplant anti-GBM nephritis, and 10 were from patients with this disease. Results Thirteen serum samples [10 alport posttransplant nephritis serum (APTN) and three Alport posttransplant serum (APT)] revealed linear binding to the GBM by indirect immunofluorescence. By using direct ELISA and immunoblotting with GBM constituents and type IV collagen NC1 domains from bovine, human, and recombinant sources, we detected anti-GBM antibodies in all Alport patients in varying titers. Five samples showed specific reactivity to the alpha3 chain, four to the alpha5 chain, six to both alpha3 and alpha5 chains, one to the alpha3 and alpha4 chains, and two to the alpha3, alpha4, and alpha5 chains of type IV collagen. The varied spectrum of reactivities was present equally in nephritic and non-nephritic sera. Ten control samples from non-Alport transplant patients did not exhibit specific binding to the GBM. Conclusions These results suggest that the absence of alpha3, alpha4, and alpha5 chains of type IV collagen in the Alport kidney leads to alloantibodies in all Alport patients who receive transplants, irrespective of whether they develop nephritis or not. Although all Alport transplant patients develop this humoral response, only a select few develop anti-GBM disease. We suggest that this difference could be attributable to a genotypic effect on the ability of some individuals to launch a cell-mediated immune response.

There is growing miasma in our national correspondence over the increasing heft and metabolic dysfunction of everyday Americans. The origin of this mounting poundage has many parents, not the least of which is our appetite for nutritive (read caloric) sweeteners in processed foods and beverages. The

Whether we like it or not, nephrologists around the world have been called to action. Our mission is to attenuate the growth of chronic kidney disease (CKD). Several conditions will need to gel for us to succeed. Although we now have a better understanding of its alarming incidence and prevalence

This study assessed the effects of exogenous isoproterenol on the proliferation of the proximal tubular cell lines MCT and LLC-PK1. Both cell lines express beta-adrenergic receptors as demonstrated by Scatchard analysis of binding data, receptor-cross linking studies, and mRNA expression for beta 2-adrenergic receptors. Isoproterenol (10(-7) M) for 15 min stimulated the formation of intracellular cAMP in MCT cells (controls, 8.0 +/- 0.7; isoproterenol, 12.6 +/- 0.89 fmol of cAMP/microgram of protein; P < 0.01). This effect was blocked by the beta-receptor antagonist propranolol (10(-6) M). Isoproterenol, in a dose-dependent manner, also induced proliferation in MCT and LLC-PK1 cells, as measured by [3H]thymidine incorporation and direct cell counts. Time-course experiments demonstrated maximal mitogenesis 48 h after a single dose of 10(-7) M isoproterenol. This mitogenic effect was mimicked by a stable cAMP analog or cholera toxin, but not by a cGMP analog, indicating that the isoproterenol-mediated growth effects are likely caused by cAMP. These results provide evidence that isoproterenol is a mitogenic growth factor for cultured proximal tubular cells. These findings may be important in the growth mechanisms involved in the proliferative remodeling of injured tubules after acute renal failure.

In a world where patients are exposed to countless prescription drugs, it is amazing that more humans do not develop autoimmune drug reactions that lead to tissue injury. Of course, the chance of drug-related inflammation rises in proportion to use, but it still seems most of us are comfortably protected from such events by the high activation threshold of our immune systems. Genetic polymorphisms that modulate the initiation of antigen-specific immune responses, particularly in the MHC, are a determining influence, but the whole story is more complicated. Drugs in body fluids or their metabolites often form adducts (hapten protein carrier) that modify their physical structures, occasionally making them immunogenic and prone to drug reactions (1). These adducts can be taken up by macrophages or dendritic cells and presented on the cell surface to attract the surveillance arm of the immune system. Sometimes a drug without a carrier also can interact directly with T cell receptors within the nao ¨ve repertoire or be processed by antigen-presenting cells for potential simulation of new T cells. Some of these drug reactions are influenced by changes in metabolism induced by other drugs taken simultaneously; some are modified by the variability in local cytokine expression or the polymorphisms of enzymes that affect levels of metabolites, particularly cytochrome P-450; and in some cases, the inflammatory state depresses normal drug metabolism (2).

With this issue JASN completes its 20th year of continuous publication. JASN 's origin was no accident. Many members of the American Society of Nephrology had long sought to compete in the scientific and clinical marketplace of ideas and, …

We draw attention to a commentary published in this issue of JASN by Knepper1 regarding studies undertaken in search of new biomarkers using urinary proteomics. Many of us who review or read these studies want important information to grace our journal pages. Proteomic technology today, even as it rapidly evolves, is capable of clever measurement and presentation , but harnessing this technology to better understand clinical or experimental disease is …

With this issue of JASN , we introduce a new feature for original manuscripts, the Brief Communication. These articles are short, about 1500 words, and written in letter format followed by concise methods and no more than four figures; some of the dataset may be submitted supplemental to the

Welcome to the new JASN . This is the launch issue for a new editorial team, and all of us are honored to edit the finest kidney journal in the world. We accepted this exciting opportunity knowing Bill Couser and his associate editors have done a remarkable job in advancing the quality and substance