Amyloidosis-associated kidney disease DEMBER, Laura M
Journal of the American Society of Nephrology,
12/2006, Letnik:
17, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing progressive organ dysfunction. The kidney is one of ...the most frequent sites of amyloid deposition in AL, AA, and several of the hereditary amyloidoses. Amyloid fibril formation begins with the misfolding of an amyloidogenic precursor protein. The misfolded variants self-aggregate in a highly ordered manner, generating protofilaments that interact to form fibrils. The fibrils have a characteristic appearance by electron microscopy and generate birefringence under polarized light when stained with Congo red dye. Advances in elucidating the mechanisms of amyloid fibril formation, tissue deposition, and tissue injury have led to new and more aggressive treatment approaches for these disorders. This article reviews the pathogenesis, diagnosis, clinical manifestations, and treatment of the amyloidoses, focusing heavily on the renal aspects of each of these areas.
Twenty to 60% of newly created hemodialysis arteriovenous fistulas do not mature adequately for use. One barrier to developing interventions to improve fistula outcomes is a lack of standardized ...criteria for maturation.
Using data from the multicenter, prospective Hemodialysis Fistula Maturation (HFM) Study, we determined sensitivities, specificities, and positive and negative predictive values of multiple candidate maturation criteria using the HFM Study maturation criteria as the reference. We also compared, across the maturation criteria, relationships between maturation and fistula survival using Cox proportional hazards models.
We included 535 of the 602 HFM Study participants. The median (interquartile range) age was 57 (47-65) years, 70% were men, and 45% were Black participants. Depending on the criterion and time frame for ascertainment (3, 4, 5, 6, or 9 months), sensitivities ranged from 57% to 100%, specificities ranged from 85% to 100%, positive predictive values ranged from 88% to 100%, and negative predictive values ranged from 65% to 100%. For all criteria, areas under the curve for the 6-month (0.90-0.97 for unassisted maturation and 0.89-0.95 for overall maturation) and 9-month time frames were similar. Attainment of unassisted maturation was associated with lower risks of fistula abandonment, with hazard ratios ranging from 0.10 to 0.40 depending on the criterion and time frame. Eliminating dialysis adequacy indicators, or simplifying the criteria in other ways, had little effect on performance characteristics.
High performance characteristics are maintained with maturation criteria that are simpler and less burdensome to ascertain than the HFM Study outcome measure.
ABSTRACT
Acute kidney injury (AKI) is a growing epidemic and is independently associated with increased risk of death, chronic kidney disease (CKD) and cardiovascular events. Randomized-controlled ...trials (RCTs) in this domain are notoriously challenging and many clinical studies in AKI have yielded inconclusive findings. Underlying this conundrum is the inherent heterogeneity of AKI in its etiology, presentation and course. AKI is best understood as a syndrome and identification of AKI subphenotypes is needed to elucidate the disease's myriad etiologies and to tailor effective prevention and treatment strategies. Conventional RCTs are logistically cumbersome and often feature highly selected patient populations that limit external generalizability and thus alternative trial designs should be considered when appropriate. In this narrative review of recent developments in AKI trials based on the Kidney Disease Clinical Trialists (KDCT) 2020 meeting, we discuss barriers to and strategies for improved design and implementation of clinical trials for AKI patients, including predictive and prognostic enrichment techniques, the use of pragmatic trials and adaptive trials.
Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate ...binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes.
Multicenter, pragmatic, cluster-randomized clinical trial.
HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis.
Phosphate binder prescriptions and dietary recommendations to achieve the “Hi” serum phosphate target (≥6.5 mg/dL) or the “Lo” serum phosphate target (<5.5 mg/dL).
Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome.
The trial is currently enrolling.
HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes.
HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome.
Registered at ClinicalTrials.gov with study number NCT04095039.
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The clinical research enterprise is not producing the evidence decision makers arguably need in a timely and cost effective manner; research currently involves the use of labor-intensive parallel ...systems that are separate from clinical care. The emergence of pragmatic clinical trials (PCTs) poses a possible solution: these large-scale trials are embedded within routine clinical care and often involve cluster randomization of hospitals, clinics, primary care providers, etc. Interventions can be implemented by health system personnel through usual communication channels and quality improvement infrastructure, and data collected as part of routine clinical care. However, experience with these trials is nascent and best practices regarding design operational, analytic, and reporting methodologies are undeveloped.
To strengthen the national capacity to implement cost-effective, large-scale PCTs, the Common Fund of the National Institutes of Health created the Health Care Systems Research Collaboratory (Collaboratory) to support the design, execution, and dissemination of a series of demonstration projects using a pragmatic research design.
In this article, we will describe the Collaboratory, highlight some of the challenges encountered and solutions developed thus far, and discuss remaining barriers and opportunities for large-scale evidence generation using PCTs.
A planning phase is critical, and even with careful planning, new challenges arise during execution; comparisons between arms can be complicated by unanticipated changes. Early and ongoing engagement with both health care system leaders and front-line clinicians is critical for success. There is also marked uncertainty when applying existing ethical and regulatory frameworks to PCTS, and using existing electronic health records for data capture adds complexity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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