Advertisement

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

  • Lada Beara-LasicEmail author
  • Andrea Cogal
  • Kristin Mara
  • Felicity Enders
  • Ramila A. Mehta
  • Zejfa Haskic
  • Susan L. Furth
  • Howard Trachtman
  • Steven J. Scheinman
  • Dawn S. Milliner
  • David S. Goldfarb
  • Peter C. Harris
  • John C. Lieske
  • On behalf of the investigators of the Rare Kidney Stone Consortium
Original Article

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 α1-microglobulin (α1M), 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, α1M/Cr, α1M/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). α1M/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 α1M/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. α1M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

Keywords

Dent disease FSGS CLCN5 Proteinuria Low molecular weight proteinuria α1-Microglobulin 

Notes

Acknowledgments

We thank Alicia Meek for her assistance in data collection.

Funding information

This study was supported by Rare Kidney Stone Consortium grant U54KD083908, a part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, the National Center for Advancing Translational Sciences (NCATS).

This consortium is funded through a collaboration between the NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases.

The study sponsor had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.

The Chronic Kidney Disease in Children Cohort Study (CKiD) was conducted by the CKiD Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), with additional funding from the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute (U01-DK-66143, U01-DK-66174, U01DK-082194, U01-DK-66116). The data and samples from the CKiD study reported here were supplied by the NIDDK Central Repositories. This manuscript does not necessarily reflect the opinions or views of the CKiD study, the NIDDK Central Repositories, or the NIDDK.

The Multicenter FSGS-Clinical Trial (FSGS-CT) and Novel Therapies for Resistant FSGS Trial (FONT) was conducted by the FSGS-CT and FONT investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The data and samples from the FSGS-CT and FONT reported here were supplied by the NIDDK Central Repositories. This manuscript does not necessarily reflect the opinions or views of the FSGS-CT and FONT study, the NIDDK Central Repositories, or the NIDDK.

Compliance with ethical standards

This study was approved by the Mayo Clinic Institutional Review Board. Ancillary studies were approved and biospecimens were obtained from CKiD, FSGS-CT, and FONT studies.

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Dent CE, Friedman M (1964) Hypercalciuric rickets associated with renal tubular damage. Arch Dis Child 39:240–249CrossRefGoogle Scholar
  2. 2.
    Scheinman SJ (1998) X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 53:3–17CrossRefGoogle Scholar
  3. 3.
    Lieske JC, Milliner DS, Beara-Lasic L, Harris P, Cogal A, Abrash E (2012, updated 2017) Dent disease. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews®[Internet]. University of Washington: SeattleGoogle Scholar
  4. 4.
    Ludwig M, Utsch B, Monnens LA (2006) Recent advances in understanding the clinical and genetic heterogeneity of Dent’s disease. Nephrol Dial Transplant 21:2708–2717CrossRefGoogle Scholar
  5. 5.
    Frymoyer PA, Scheinman SJ, Dunham PB, Jones DB, Hueber P, Schroeder ET (1991) X-linked recessive nephrolithiasis with renal failure. N Engl J Med 325:681–686CrossRefGoogle Scholar
  6. 6.
    Devuyst O, Thakker RV (2010) Dent’s disease. Orphanet J Rare Dis 5:28CrossRefGoogle Scholar
  7. 7.
    van Berkel Y, Ludwig M, van Wijk JAE, Bokenkamp A (2017) Proteinuria in Dent disease: a review of the literature. Pediatr Nephrol 32:1851–1859CrossRefGoogle Scholar
  8. 8.
    Gambaro G, Vezzoli G, Casari G, Rampoldi L, D’Angelo A, Borghi L (2004) Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis 44:963–986CrossRefGoogle Scholar
  9. 9.
    Copelovitch L, Nash MA, Kaplan BS (2007) Hypothesis: Dent disease is an underrecognized cause of focal glomerulosclerosis. Clin J Am Soc Nephrol 2:914–918CrossRefGoogle Scholar
  10. 10.
    Frishberg Y, Dinour D, Belostotsky R, Becker-Cohen R, Rinat C, Feinstein S, Navon-Elkan P, Ben-Shalom E (2009) Dent’s disease manifesting as focal glomerulosclerosis: is it the tip of the iceberg? Pediatr Nephrol 24:2369–2373CrossRefGoogle Scholar
  11. 11.
    Fervenza FC (2013) A patient with nephrotic-range proteinuria and focal global glomerulosclerosis. Clin J Am Soc Nephrol 8:1979–1987CrossRefGoogle Scholar
  12. 12.
    Wrong OM, Norden AG, Feest TG (1994) Dent’s disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. QJM 87:473–493Google Scholar
  13. 13.
    Wang X, Anglani F, Beara-Lasic L, Mehta AJ, Vaughan LE, Herrera Hernandez L, Cogal A, Scheinman SJ, Ariceta G, Isom R, Copelovitch L, Enders FT, Del Prete D, Vezzoli G, Paglialonga F, Harris PC, Lieske JC, Investigators of the Rare Kidney Stone Consortium (2016) Glomerular pathology in Dent disease and its association with kidney function. Clin J Am Soc Nephrol 11:2168–2176CrossRefGoogle Scholar
  14. 14.
    Wong CJ, Moxey-Mims M, Jerry-Fluker J, Warady BA, Furth SL (2012) CKiD (CKD in children) prospective cohort study: a review of current findings. Am J Kidney Dis 60:1002–1011CrossRefGoogle Scholar
  15. 15.
    Joy MS, Gipson DS, Dike M, Powell L, Thompson A, Vento S, Eddy A, Fogo AB, Kopp JB, Cattran D, Trachtman H (2009) Phase I trial of rosiglitazone in FSGS: I. Report of the FONT Study Group. Clin J Am Soc Nephrol 4:39–47CrossRefGoogle Scholar
  16. 16.
    Ferris M, Norwood V, Radeva M, Gassman JJ, Al-Uzri A, Askenazi D, Matoo T, Pinsk M, Sharma A, Smoyer W, Stults J, Vyas S, Weiss R, Gipson D, Kaskel F, Friedman A, Moxey-Mims M, Trachtman H (2013) Patient recruitment into a multicenter randomized clinical trial for kidney disease: report of the focal segmental glomerulosclerosis clinical trial (FSGS CT). Clin Transl Sci 6:13–20CrossRefGoogle Scholar
  17. 17.
    Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637CrossRefGoogle Scholar
  18. 18.
    Bernard AM, Moreau D, Lauwerys R (1982) Comparison of retinol-binding protein and beta 2-microglobulin determination in urine for the early detection of tubular proteinuria. Clin Chim Acta 126:1–7CrossRefGoogle Scholar
  19. 19.
    Blumsohn A, Morris BW, Griffiths H, Ramsey CF (1991) Stability of beta 2-microglobulin and retinol binding protein at different values of pH and temperature in normal and pathological urine. Clin Chim Acta 195:133–137CrossRefGoogle Scholar
  20. 20.
    Guder WG, Hofmann W (2008) Clinical role of urinary low molecular weight proteins: their diagnostic and prognostic implications. Scand J Clin Lab Investig Suppl 241:95–98CrossRefGoogle Scholar
  21. 21.
    Norden AG, Scheinman SJ, Deschodt-Lanckman MM, Lapsley M, Nortier JL, Thakker RV, Unwin RJ, Wrong O (2000) Tubular proteinuria defined by a study of Dent’s (CLCN5 mutation) and other tubular diseases. Kidney Int 57:240–249CrossRefGoogle Scholar
  22. 22.
    Bokenkamp A, Bockenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, Ludwig M (2009) Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr 155:94–99CrossRefGoogle Scholar
  23. 23.
    Lloyd SE, Pearce SHS, Guenther W, Kawaguchi H, Igarashi T, Jentsch TJ, Thakker RV (1997) Idiopathic low molecular weight proteinuria associated with hypercalciuric nephroclacinosis in Japanese children is due to mutations of teh renal chloride channel (CLCN5). J Clin Invest 99:967–974CrossRefGoogle Scholar
  24. 24.
    Tada M, Jimi S, Hisano S, Sasatomi Y, Oshima K, Matsuoka H, Takebayashi S (2001) Histopathological evidence of poor prognosis in patients with vesicoureteral reflux. Pediatr Nephrol 16:482–487CrossRefGoogle Scholar
  25. 25.
    van Berkel Y, Ludwig M, van Wijk JA, Bokenkamp A (2016) Proteinuria in Dent disease: a review of the literature. Pediatr Nephrol 32:1851–1859CrossRefGoogle Scholar
  26. 26.
    Ceol M, Tiralongo E, Baelde HJ, Vianello D, Betto G, Marangelli A, Bonfante L, Valente M, Della Barbera M, D’Angelo A, Anglani F, Del Prete D (2012) Involvement of the tubular ClC-type exchanger ClC-5 in glomeruli of human proteinuric nephropathies. PLoS One 7:e45605CrossRefGoogle Scholar
  27. 27.
    Erb BC, Velazquez H, Gisser M, Shugrue CA, Reilly RF (1997) cDNA cloning and localization of OCRL-1 in rabbit kidney. Am J Phys 273:F790–F795CrossRefGoogle Scholar
  28. 28.
    Prabakaran T, Christensen EI, Nielsen R, Verroust PJ (2012) Cubilin is expressed in rat and human glomerular podocytes. Nephrol Dial Transplant 27:3156–3159CrossRefGoogle Scholar
  29. 29.
    Prabakaran T, Nielsen R, Larsen JV, Sorensen SS, Feldt-Rasmussen U, Saleem MA, Petersen CM, Verroust PJ, Christensen EI (2011) Receptor-mediated endocytosis of alpha-galactosidase A in human podocytes in Fabry disease. PLoS One 6:e25065CrossRefGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  • Lada Beara-Lasic
    • 1
    • 2
    Email author
  • Andrea Cogal
    • 2
    • 3
  • Kristin Mara
    • 2
    • 4
  • Felicity Enders
    • 2
    • 4
  • Ramila A. Mehta
    • 2
    • 4
  • Zejfa Haskic
    • 5
  • Susan L. Furth
    • 6
  • Howard Trachtman
    • 1
  • Steven J. Scheinman
    • 7
  • Dawn S. Milliner
    • 2
    • 3
  • David S. Goldfarb
    • 1
    • 2
  • Peter C. Harris
    • 2
    • 3
  • John C. Lieske
    • 2
    • 3
  • On behalf of the investigators of the Rare Kidney Stone Consortium
  1. 1.Nephrology Division, Department of Medicine and PediatricsNew York University Langone Health and New York University School of MedicineNew YorkUSA
  2. 2.Rare Kidney Stone ConsortiumRochesterUSA
  3. 3.Division of Nephrology, Department of Medicine and PediatricsMayo ClinicRochesterUSA
  4. 4.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA
  5. 5.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  6. 6.Department of Pediatrics, Children’s Hospital of PhiladelphiaUniversity of Pennsylvania Perelman, School of MedicinePhiladelphiaUSA
  7. 7.Geisinger Commonwealth School of MedicineScrantonUSA

Personalised recommendations