Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts

On behalf of the investigators of the Rare Kidney Stone Consortium

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. Methods: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α 1 -microglobulin (α 1 M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α 1 M/Cr, α 1 M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. Results: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α 1 M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α 1 M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. Conclusions: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α 1 M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

Original languageEnglish (US)
JournalPediatric Nephrology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Proteinuria
Creatinine
Molecular Weight
Mutation
Focal Segmental Glomerulosclerosis
Proteins
Dent Disease
Dent disease 1
Sensitivity and Specificity
Staphylococcal Protein A
Immunosuppressive Agents
Chronic Renal Insufficiency
Albumins
Clinical Trials
Therapeutics
Population

Keywords

  • CLCN5
  • Dent disease
  • FSGS
  • Low molecular weight proteinuria
  • Proteinuria
  • α -Microglobulin

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Nephrology

Cite this

Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts. / On behalf of the investigators of the Rare Kidney Stone Consortium.

In: Pediatric Nephrology, 01.01.2019.

Research output: Contribution to journalArticle

On behalf of the investigators of the Rare Kidney Stone Consortium. / Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts. In: Pediatric Nephrology. 2019.
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title = "Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts",
abstract = "Background: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. Methods: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α 1 -microglobulin (α 1 M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α 1 M/Cr, α 1 M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. Results: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α 1 M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α 1 M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. Conclusions: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α 1 M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.",
keywords = "CLCN5, Dent disease, FSGS, Low molecular weight proteinuria, Proteinuria, α -Microglobulin",
author = "{On behalf of the investigators of the Rare Kidney Stone Consortium} and Lada Beara-Lasic and Andrea Cogal and Kristin Mara and Enders, {Felicity T} and Mehta, {Ramila A.} and Zejfa Haskic and Furth, {Susan L.} and Howard Trachtman and Scheinman, {Steven J.} and Milliner, {Dawn S.} and Goldfarb, {David S.} and Harris, {Peter C} and Lieske, {John C}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s00467-019-04210-0",
language = "English (US)",
journal = "Pediatric nephrology (Berlin, Germany)",
issn = "0931-041X",
publisher = "Springer Verlag",

}

TY - JOUR

T1 - Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts

AU - On behalf of the investigators of the Rare Kidney Stone Consortium

AU - Beara-Lasic, Lada

AU - Cogal, Andrea

AU - Mara, Kristin

AU - Enders, Felicity T

AU - Mehta, Ramila A.

AU - Haskic, Zejfa

AU - Furth, Susan L.

AU - Trachtman, Howard

AU - Scheinman, Steven J.

AU - Milliner, Dawn S.

AU - Goldfarb, David S.

AU - Harris, Peter C

AU - Lieske, John C

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. Methods: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α 1 -microglobulin (α 1 M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α 1 M/Cr, α 1 M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. Results: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α 1 M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α 1 M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. Conclusions: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α 1 M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

AB - Background: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. Methods: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α 1 -microglobulin (α 1 M), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, α 1 M/Cr, α 1 M/TP, and A/TP from the CKiD cohort were compared with DD1 and DC. Results: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). α 1 M/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and α 1 M/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. Conclusions: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α 1 M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

KW - CLCN5

KW - Dent disease

KW - FSGS

KW - Low molecular weight proteinuria

KW - Proteinuria

KW - α -Microglobulin

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U2 - 10.1007/s00467-019-04210-0

DO - 10.1007/s00467-019-04210-0

M3 - Article

AN - SCOPUS:85062686610

JO - Pediatric nephrology (Berlin, Germany)

JF - Pediatric nephrology (Berlin, Germany)

SN - 0931-041X

ER -