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Journal of the American Society of Nephrology
Williams and Wilkins
Journal of the American Society of Nephrology

Williams and Wilkins

1046-6673

Journal of the American Society of Nephrology/Journal Journal of the American Society of NephrologyISTPSCIAHCI
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    Decorating Histones in Polycystic Kidney Disease

    Harini RamalingamVishal Patel
    9页
    查看更多>>摘要：Autosomal dominant polycystic kidney disease (ADPKD) is perhaps the most common monogenetic condition known to humankind. The pathologic hallmark is the presence of innumerable fluid-filled tissue sacs called cysts that inundate the renal parenchyma. The cysts are derived from renal tubules, primarily the collecting duct, and are lined by a single layer of epithelial cells that exhibit high proliferation and excessive fluid secretion. Over years and decades, the relentless growth in cyst volume eventually produces massive bilateral kidneys and results in kidney failure in nearly 50% of individuals with ADPKD. The inciting molecular event in virtually all clinically relevant cases is a monoallelic loss-of-function mutation of the PKD1 gene or the PKD2 gene. The precise sequence of events that unfold next is not entirely clear, but we know that multiple signaling cascades get activated. The cAMP pathway is the best studied, and its deregulation is the basis for using tolvaptan, the only Food and Drug Administration-approved treatment for ADPKD. However, the list of deregulated pathways is long and ever expanding. It includes many notable oncogenic and proprolifer-ative pathways, such as c-Myc, STAT, mammalian target of rapamycin, YAP/TAZ, microRNAs, and many other signaling pathways. Not surprisingly, this widespread dysregulation is facilitated by and leads to genome-wide transcriptomic rewiring. How does polycystic kidney disease (PKD) gene loss unleash this broad aberrant signaling? Is there a method behind this madness? There cannot be a single simple answer, but emerging evidence suggests that one clue may be to look at the epigenome.
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    Complement is Complimentary in Membranous Nephropathy

    Ralph KettritzAdrian Schreiber
    3页
    查看更多>>摘要：The complement system provides an ancient, highly conserved, cascade of interacting proteins orchestrating innate and adaptive immune responses. In addition to protecting the host from infections, the complement contributes to the pathogenesis of various disorders, including kidney diseases.1 The exploration of complement-directed treatment strategies in these diseases, including several glomerulonephritides, makes eminent sense. ANCA vasculitis provides the latest example in which preclinical models implicated the complement as an important disease mediator and where the clinical application was not “lost in translation.” Experimental studies in cell and murine vasculitis models identified the interaction of the anaphylatoxin C5a with the activating C5a receptor-1 (C5aRl or CD88) as a central disease process. The human C5aR1 was then introduced into mice, allowing the development of a small molecule that blocked the human C5aRl.3 This complement-directed strategy was recently explored in a randomized controlled trial. The oral C5aR blocker, avacopan, was superior to prednisone taper with respect to sustained remission at 52 weeks. Avacopan is now on its way into routine clinical practice, and it will be our task to position this new tool within existing ANCA vasculitis treatments.
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    Searching for the Risk-Benefit Profile of Higher Potassium Intake in CKD: Primum Non Nocere

    Murilo GuedesRoberto Pecoits-Filho
    3页
    查看更多>>摘要：Observational studies indicate that higher dietary potassium intake is associated with improved BP control, lower risk of cardiovascular disease, and slower CKD progression. Similarly, randomized controlled trials (RCTs) of potassium supplementation and potassium-based salt substitutes demonstrate consistent reductions in BP and in hypertension-associated adverse outcomes in populations with a low risk of hyperkalemia. However, the effect of potassium supplementation on clinical outcomes in patients with moderate to advanced CKD is unknown because these patients are typically excluded from such trials due to concerns of hyperkalemia. In fact, the belief that higher potassium intake increases the risk of hyperkalemia in CKD remains poorly investigated. Alternatively, the risk of adverse outcomes resulting from mild or moderate chronic hyperkalemia in advanced CKD is still a matter of debate, notwithstanding the consistent associations between hyperkalemia and poor outcomes in nondialysis CKD.3 Unmet gaps thus ensue—many guidelines recommen-dlow-potassium diets (e.g, 2-4 g/d by the Kidney Disease Outcomes Quality Initiative [KDOQI]) without clear evidence from RCTs; concerns of hyperkalemia blunt plausible interventions, such as salt substitutes or potassium supplementation, in CKD.
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    Assessing the Carbon Footprint of Hemodialysis: A First Step Toward Environmentally Sustainable Kidney Care

    Katherine A. BarracloughScott McAlister
    3页
    查看更多>>摘要：Climate change has been declared the single biggest health threat facing humanity. Its negative effects on health are broad, extending to all human organ systems, including the kidneys. Increased ambient temperatures and heat extremes translate into more AKI, kidney stones, and urinary tract infections, which may evolve into CKD and kidney failure. Higher temperatures, along with more flooding events, increase diarrheal, rodent- and mosquito-borne disease spread, all major causes of AKI in low-income and tropical regions. Strenuous work and prolonged exposure to high temperatures have been identified as probable contributors to epidemics of CKD in diverse world regions, a health crisis that has disproportionately affected underprivileged populations. The science is clear—no degree of further temperature rise is safe to health. We must urgently curb emissions to avert catastrophic health effects and prevent millions of avoidable deaths. Although every sector needs to play its part in limiting climate change, the responsibility is particularly great for the health care sector, which exists to protect and improve health. Health care is also a major part of the problem, contributing an estimated 4%-6% of global greenhouse gas emissions. Indeed, if global health care were a country, it would be the world’s fifth largest emitter.
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    The Highs and Lows of Potassium Intake in CKD—Does One Size Fit All?

    Andrew S. TerkerTurgay SaritasAlicia A. McDonough
    3页
    查看更多>>摘要：Electrolyte management is integral to the nephrological care of patients with CKD. Clinicians routinely face potassium derangements in settings of kidney dysfunction; hyperkalemia is of high concern given the potential for life-threatening cardiac arrhythmias. This concern drives recommendations of dietary potassium restriction, with diuretics and potassium-binding resins, to lower plasma potassium in these patients. Although effects of elevated plasma potassium on cardiac arrhythmias are well documented, multiple population studies have suggested a protective effect of potassium-rich diets on kidney function that might delay progression of CKD. In addition to these renoprotective effects, a host of studies have detailed beneficial effects of potassium-rich diets on cardiovascular health, including lower BP, incidence of stroke, and mortality (Figure 1). Together, these reports suggest that potassium supplementation, up to a point, may blunt CKD progression, but prospective studies addressing this hypothesis have been lacking. Recently, Hoorn and colleagues5 initiated a clinical trial (NCT03253172) to test the hypothesis that potassium supplementation slows rates of CKD progression on the basis of eGFR. In this issue of JASN, Gritter et al. report findings from the run-in phase of this clinical trial, “Effects of Short-Term Potassium Chloride Supplementation in Patients with Chronic Kidney Disease.”
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    Emerging Insights into Glomerular Vascular Pole and Microcirculation

    Michael S. Goligorsky
    8页
    查看更多>>摘要：The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear function. It has been studied in definitive detail for >30 years, and functionally interrogated in the context of signal transduction from the macula densa to the mesangial cells and afferent arteriolar smooth muscle cells from 10 to 20 years ago. Two recent discoveries shed additional light on the vascular pole, with possibly far-reaching implications. One, which uses novel serial section electron microscopy, reveals a shorter capillary pathway between the basins of the afferent and efferent arterioles. Such a pathway, when patent, may short-circuit the multitude of capillaries in the glomerular tuft. Notably, this shorter capillary route is enclosed within the glomerular mesangium. The second study used anti-Thy1,1-induced mesangiolysis and intravital microscopy to unequivocally establish in vivo the long-suspected contractile function of mesangial cells, which have the ability to change the geometry and curvature of glomerular capillaries. These studies led me to hypothesize the existence of a glomerular perfusion rheostat, in which the shorter path periodically fluctuates between being more and less patent. This action reduces or increases blood flow through the entire glomerular capillary tuft. A corollary is that the GFR is a net product of balance between the states of capillary perfusion, and that deviations from the balanced state would increase or decrease GFR. Taken together, these studies may pave the way to a more profound understanding of glomerular microcirculation under basal conditions and in progression of glomerulopathies.
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    The Potential for Pragmatic Trials to Reduce Racial and Ethnic Disparities in Kidney Disease

    Laura M. Dember
    3页
    查看更多>>摘要：The well-documented and unacceptable racial and ethnic disparities in the prevalence and outcomes of kidney disease are receiving increased attention within and beyond the nephrology community, with numerous calls for intentional, active approaches to ensure that care is equitable and that disparities are eliminated. In 2003, the Institute of Medicine (now the National Academy of Medicine) concluded that elimination of racial disparities in health outcomes requires a multilevel approach directed at health systems, patients, care providers, and payors. While some strategies should be adopted because they are clearly the right thing to do, others require rigorous evaluation before broad uptake to understand the benefits, unanticipated harms, relative value, and challenges to implementation. Pragmatic or “real-world” clinical trials have received substantial interest during the past decade because they yield results that are highly generalizable to the nontrial setting, evaluate interventions that can be readily transferred to clinical practice, and save money by leveraging clinical care systems rather than relying on separate research infrastructure. Pragmatic trials are most often used for comparative effectiveness research to identify advantages and disadvantages of treatment approaches already in widespread clinical use, or to evaluate strategies for implementing or increasing uptake of interventions known to have efficacy.
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    Health Care Equity and Justice Scorecard To Increase Diversity in Clinical Trial Recruitment and Retention

    Susanne B. NicholasLilia Cervanteson behalf of the Clinical CareInnovation Workgroup of the American Society of Nephrology Health Care Justice Committee*...
    4页
    查看更多>>摘要：Black or African American and Hispanic or Latinx groups make up 13.4% and 18.4%, respectively, of the United States (US) population,1 yet they have the highest prevalence of CKD, up to 16% and 14%, respectively, compared with 13% for non-Latinx White people.2 Black or African American people also have a two- to four-fold greater incidence of kidney failure and a 3-fold greater risk of progressing to kidney failure, typically occurring at an earlier age and up to 5 years sooner than their White counterparts and accounting for 35% of adults with kidney failure. A key aspect to advancing health equity and ensuring access to high quality health care for all is by achieving increased diversity in clinical trials. The US Food and Drug Administration (FDA) 2020 Drug Trial Snapshot reports that only 11% Latinx and <10% Black or Asian, compared with 75% non-Latinx White participants were among the 32,000 participants enrolled in clinical trials. To ensure adequate diversity in clinical trial enrollment, trial sponsors should aim to mirror the demographic distribution of patients with the condition, and not simply reflect the US population. For example, clinical trials that target individuals with kidney failure should ensure that Black or African American individuals account for >35% of enrollment, and not 13%-14%, which approximates the US Black or African American population. Indeed, the FDA acknowledged the need to increase diversity in clinical trials so that individuals most likely to use the potential therapeutics are fully represented, and endorses strategies to overcome barriers to clinical trial enrollment for underrepresented populations.
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    Systematic Review and Meta-Analysis of Plasma and Urine Biomarkers for CKD Outcomes

    Gohar MosoyanKinsuk ChauhanGeorge Vasquez-RiosCeline Soudant...
    16页
    查看更多>>摘要：Background Sensitive and specific biomarkers are needed to provide better biologic insight into the risk of incident and progressive CKD. However, studies have been limited by sample size and design heterogeneity. Methods In this assessment of the prognostic value of preclinical plasma and urine biomarkers for CKD outcomes, we searched Embase (Ovid), MEDLINE ALL (Ovid), and Scopus up to November 30, 2020, for studies exploring the association between baseline kidney biomarkers and CKD outcomes (incident CKD, CKD progression, or incident ESKD). We used random-effects meta-analysis. Results After screening 26,456 abstracts and 352 full-text articles, we included 129 studies in the meta-analysis for the most frequently studied plasma biomarkers (TNFR1, FGF23, TNFR2, KIM-1, suPAR, and others) and urine biomarkers (KIM-1, NGAL, and others). For the most frequently studied plasma biomarkers, pooled RRs for CKD outcomes were 2.17 (95% confidence interval [95% Cl], 1.91 to 2.47) for TNFR1 (31 studies); 1.21 (95% Cl, 1.15 to 1.28) for FGF-23 (30 studies); 2.07 (95% Cl, 1.82 to 2.34) for TNFR2 (23 studies); 1.51 (95% Cl, 1.38 to 1.66) for KIM-1 (18 studies); and 1.42 (95% Cl, 1.30 to 1.55) for suPAR (12 studies). For the most frequently studied urine biomarkers, pooled RRs were 1.10 (95% Cl, 1.05 to 1.16) for KIM-1 (19 studies) and 1.12 (95% Cl, 1.06 to 1.19) for NGAL (19 studies). Conclusions Studies of preclinical biomarkers for CKD outcomes have considerable heterogeneity across study cohorts and designs, limiting comparisons of prognostic performance across studies. Plasma TNFR1, FGF23, TNFR2, KIM-1, and suPAR were among the most frequently investigated in the setting of CKD outcomes.
      原文链接:
    • NSTL
    • Amer Soc Nephrology

    Cation Channel Activity of Apolipoprotein L1 is Modulated by Haplotype Background

    Rebecca L. WinklerJonathan BrunoPaula BuchananJohn C. Edwards...
    3页
    查看更多>>摘要：Two variants in apolipoprotein L1 (ApoL1) are known to be responsible for the increased risk of progressive proteinuric kidney disease in people of recent African ancestry. Wild-type ApoL1 protein (designated GO) is an amphipathic protein that can insert into lipid membranes at low pH, where it increases anion permeability; on titration back to neutral, the permeability transitions to cation selectivity. The two kidney disease-associated variants (designated G1 and G2) show increased cation selective channel activity. In addition to G1 and G2, there are other ApoLl protein isoforms, not known to be involved in kidney disease, which are inherited as distinct haplotypes. Three of these haplotypes, designated KIK, EIK, and EMR, account for the majority of protein isoforms in the human population (Supplemental Table 1 and Supplemental Appendix 1). KIK is the most prevalent worldwide. EIK is the most common haplotype in people of African ancestry and is absent from other populations; G1 and G2 variants are only naturally found in the EIK background. EMR (the GenBank refseq, thought to be of Neanderthal origin) is most frequently encountered in European populations.
      原文链接:
    • NSTL
    • Amer Soc Nephrology