Evidence map›Paper›PMID 27358438›Full record

ArticleCirculation2016

The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia.

Mary E Haas, Amy E Levenson, Xiaowei Sun, Wan-Hui Liao, Joseph M Rutkowski, Sarah D de Ferranti, Valerie A Schumacher, Philipp E Scherer, David J Salant, Sudha B Biddinger

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06373913 (The Role of Proprotein-convertase-subtilisin/Kexin-type 9 in Kidney Damage in Nephrotic Syndrom), which is not on this map. Cited by 54 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
54citing papers in PubMed, 2 pooled it
6.9field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT06373913 recruitingnot on this mapstarted 2023, after this paper: background citation

The Role of Proprotein-convertase-subtilisin/Kexin-type 9 in Kidney Damage in Nephrotic Syndrom

TypeobservationalSponsorKolding SygehusRan2023 to 2028Enrolled75ConditionsHyperlipidemias, Nephrotic Syndrome
3 · Its place in the literature

Who cites it

54 citing papers in PubMed, 2 syntheses or guidelines pooled it, 109 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Trial
  4. Trial
  5. Trial
  6. Article
  7. Article
  8. Article
  9. Review
  10. Article
  11. Article
  12. Article
  13. Review
  14. Review
  15. Genetically proxied PCSK9 inhibition is associated with reduced psoriatic arthritis risk.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2024
    Article
  16. Article
  17. Article
  18. Article
  19. Review
  20. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 1 country.

Mary E HaasFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
Amy E LevensonFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
Xiaowei SunFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
Wan-Hui LiaoFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
Joseph M RutkowskiFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
Sarah D de FerrantiFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
Valerie A SchumacherFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
Philipp E SchererFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
David J SalantFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.).
Sudha B BiddingerFrom Division of Endocrinology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (M.E.H., A.E.L., X.S., W.-H.L., S.B.B.); Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas (J.M.R., P.E.S.); Division of Cardiology, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, MA (S.D.d.F.); Division of Nephrology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA (V.A.S.); and Department of Medicine, Section of Nephrology, Boston University Medical Center, MA (D.J.S.). sudha.biddinger@childrens.harvard.edu.
Boston Medical Center · USBoston Children's Hospital · US

Funding

Training Program in Clinical & Translationa Research in Human Glomerular DiseaseU54DK083912 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KRETZLER, MATTHIAS · 2009 to 2023
$20.3M
University of Michigan O'Brien Kidney Translational Core CenterP30DK081943 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KRETZLER, MATTHIAS · 2008 to 2022
$12.9M
Pathogenesis of Dyslipidemia and Atherosclerosis in the Diabetic StateR01HL109650 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI BIDDINGER, SUDHA B · 2011 to 2024
$7.2M
CAREER DEVELOPMENT IN DIABETES RESEARCH FOR PEDIATRIC ENDOCRINOLOGISTSK12DK094721 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI LAFFEL, LORI M, WHITE, MORRIS F. · 2011 to 2021
$6.3M
Role of PLA2R and anti-PLA2R in idiopathic membranous nephropathyR01DK090029 · NIDDK · BOSTON MEDICAL CENTER · PI SALANT, DAVID J · 2011 to 2015
$1.9M
American Heart Association-American Stroke AssociationNHLBI NIH HHS R01 HL109650NIDDK NIH HHS K12 DK094721NIDDK NIH HHS L40 DK065607NIDDK NIH HHS P30 DK081943NIDDK NIH HHS R01 DK090029NIDDK NIH HHS U54 DK083912
6 · The paper itself

Abstract

backgroundIn nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Here, we tested the role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome.

methodsPCSK9 and plasma lipids were studied in nephrotic syndrome patients before and after remission of disease, mice with genetic ablation of the podocyte (Podocyte Apoptosis Through Targeted Activation of Caspase-8, Pod-ATTAC mice) and mice treated with nephrotoxic serum (NTS), which triggers immune-mediated podocyte damage. In addition, mice with hepatic deletion of Pcsk9 were treated with NTS to determine the contribution of PCSK9 to the dyslipidemia of nephrotic syndrome.

resultsPatients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 on remission of their disease (P<0.05, n=47-50). Conversely, Pod-ATTAC mice and NTS-treated mice showed hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9. The induction of plasma PCSK9 appeared to be attributable to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of Pcsk9ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic Pcsk9 showed a 40% to 50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the percentage of low-density lipoprotein-associated cholesterol (from 9% in vehicle-treated Flox mice to 47% after NTS treatment), was lost in mice with hepatic deletion of Pcsk9 (5% in both the presence and absence of NTS).

conclusionsPodocyte damage triggers marked inductions in plasma PCSK9, and knockout of Pcsk9 ameliorates dyslipidemia in a mouse model of nephrotic syndrome. These data suggest that PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome-associated hypercholesterolemia.

Indexed as

AnimalsHumansHypercholesterolemiaLipidsLiverMiceMice, Inbred C57BLMice, KnockoutNephrotic SyndromePodocytesProprotein Convertase 9Recombinant ProteinsLipidsPCSK9 protein, humanPcsk9 protein, mouseProprotein Convertase 9Recombinant Proteinscholesterolhypercholesterolemiakidneynephrotic syndromePCSK9 protein, humanPCSK9 protein, mousepodocytes

Identifiers

PMID27358438
PMCPMC5345853
OpenAlexW2489900224

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.