Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019.

Importance: After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications.

Objective: To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals.

Design, Setting, And Participants: This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals.

Biomarkers of inflammation and repair in kidney disease progression.

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study.

Speed, Evidence, and Safety Characteristics of Vaccine Approvals by the US Food and Drug Administration.

This cross-sectional study evaluates all of the novel vaccines approved by the US Food and Drug Administration over the last decade.

Assessment of Clinical Trials Supporting US Food and Drug Administration Approval of Novel Therapeutic Agents, 1995-2017.

Importance: Since the introduction of the Fast Track designation in 1988, the number of special regulatory programs available for the approval of new drugs and biologics by the US Food and Drug Administration (FDA) has increased, offering the agency flexibility with respect to evidentiary requirements.

Objective: To characterize pivotal efficacy trials supporting the approval of new drugs and biologics during the past 3 decades.

Design, Setting, And Participants: This cross-sectional study included 273 new drugs and biologics approved by the FDA for 339 indications from 1995 to 1997, from 2005 to 2007, and from 2015 to 2017.

Availability of Investigational Medicines Through the US Food and Drug Administration's Expanded Access and Compassionate Use Programs.

Importance: The Right to Try Act of 2017 allows patients with life-threatening conditions to access investigational medicines outside clinical trials without oversight from the US Food and Drug Administration (FDA). A better understanding of existing expanded access programs can inform the consideration and implementation of both the federal Right to Try Act and state right-to-try laws.

Objective: To determine the timing and duration of expanded access programs for investigational medicines initiated prior to FDA approval.

Clinical Trial Evidence Supporting FDA Approval of Drugs Granted Breakthrough Therapy Designation.

This study used the Drugs@FDA database to review FDA-approved “breakthrough” therapies from 2012 to 2017 (characterizing the pivotal clinical trials that serve as the basis of FDA approval), and premarket development and review times to assess the strength of evidence supporting breakthrough approvals.

Relationship of Kidney Injury Biomarkers with Long-Term Cardiovascular Outcomes after Cardiac Surgery.

Clinical AKI, measured by serum creatinine elevation, is associated with long-term risks of adverse cardiovascular (CV) events and mortality in patients after cardiac surgery. To evaluate the relative contributions of urine kidney injury biomarkers and plasma cardiac injury biomarkers in adverse events, we conducted a multicenter prospective cohort study of 968 adults undergoing cardiac surgery. On postoperative days 1-3, we measured five urine biomarkers of kidney injury (IL-18, NGAL, KIM-1, L-FABP, and albumin) and five plasma biomarkers of cardiac injury (NT-proBNP, H-FABP, hs-cTnT, cTnI, and CK-MB).

Biomarkers for the detection of renal fibrosis and prediction of renal outcomes: a systematic review.

Background: Fibrosis is the unifying pathway leading to chronic kidney disease. Identifying biomarkers of fibrosis may help predict disease progression.

Methods: We performed a systematic review to evaluate the reliability of blood and urine biomarkers in identifying fibrosis on biopsy as well as predicting renal outcomes.

Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4.

With-no-lysine kinase 4 (WNK4) regulates electrolyte homeostasis and blood pressure. WNK4 phosphorylates the kinases SPAK (Ste20-related proline alanine-rich kinase) and OSR1 (oxidative stress responsive kinase), which then phosphorylate and activate the renal Na-Cl cotransporter (NCC). WNK4 levels are regulated by binding to Kelch-like 3, targeting WNK4 for ubiquitylation and degradation.

Urine Interleukin 18 and Lipocalin 2 Are Biomarkers of Acute Tubular Necrosis in Patients With Cirrhosis: A Systematic Review and Meta-analysis.

Background & Aims: Acute kidney injury (AKI) is a common complication in patients with cirrhosis that increases mortality. The most common causes of AKI in these patients are prerenal azotemia, acute tubular necrosis (ATN), and hepatorenal syndrome; it is important to determine the etiology of AKI to select the proper treatment and predict patient outcome. Urine biomarkers could be used to differentiate between patients with ATN and functional causes of AKI.

YKL-40 Associates with Renal Recovery in Deceased Donor Kidney Transplantation.

Deceased donor kidneys with AKI are often discarded for fear of poor transplant outcomes. Donor biomarkers that predict post-transplant renal recovery could improve organ selection and reduce discard. We tested whether higher levels of donor urinary YKL-40, a repair phase protein, associate with improved recipient outcomes in a prospective cohort study involving deceased kidney donors from five organ procurement organizations.

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation.

Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K(+) reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K(+) secretion.

Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4.

Pseudohypoaldosteronism type II (PHAII) is a rare Mendelian syndrome featuring hypertension and hyperkalemia resulting from constitutive renal salt reabsorption and impaired K(+) secretion. Recently, mutations in Kelch-like 3 (KLHL3) and Cullin 3 (CUL3), components of an E3 ubiquitin ligase complex, were found to cause PHAII, suggesting that loss of this complex's ability to target specific substrates for ubiquitination leads to PHAII. By MS and coimmunoprecipitation, we show that KLHL3 normally binds to WNK1 and WNK4, members of WNK (with no lysine) kinase family that have previously been found mutated in PHAII.