Child Kidney Dis.  2023 Dec;27(2):70-75. 10.3339/ckd.23.019.

An overview of Dent disease

• Yang EM
• Chang SH

• KMID: 2549736
• DOI: http://doi.org/10.3339/ckd.23.019

Abstract

Dent disease is a rare inherited kidney tubulopathy caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes, and which is often underdiagnosed in practice. A diagnosis is clinically suspected in patients with low-molecular-weight proteinuria, hypercalciuria, and one of the following: hematuria, nephrolithiasis, nephrocalcinosis, hypophosphatemia, or chronic kidney disease. Inheritance is X-linked recessive, meaning, these symptoms are generally only found in males; female carriers may have mild phenotypes. Genetic testing is only a method to confirm the diagnosis, approximately 25% to 35% of patients have neither the CLCN5 nor OCRL1 pathogenic variants (Dent disease 3), making diagnosis more challenging. The genotype-phenotype correlations are not evident with the limited clinical data available. As with many other genetic diseases, the management of patients with Dent disease concentrates on symptom relief rather than any causative process. The current treatments are mainly supportive to reduce hypercalciuria and prevent nephrolithiasis. Chronic kidney disease progresses to end-stage between the ages of the third to fifth decades in 30% to 80% of affected males. In this review, we aimed to summarize the literature on Dent disease and reveal the clinical characteristics and molecular basis of Korean patients with Dent disease.

Keyword

Dent disease; Genetic diseases, X-Linked; Proteinuria

Figure

• 

  Fig. 1. Genes and loci for Dent disease.

• 

  Fig. 2. Genetic heterogeneity in Dent disease. a)Only patients with a molecular diagnosis of Dent disease were included in the analysis.

Reference

References

1. Wrong OM, Norden AG, Feest TG. 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. 1994; 87:473–93.

2. Dent CE, Friedman M. Hypophosphataemic osteomalacia with complete recovery. Br Med J. 1964; 1:1676–9.

3. Frymoyer PA, Scheinman SJ, Dunham PB, Jones DB, Hueber P, Schroeder ET. X-linked recessive nephrolithiasis with renal failure. N Engl J Med. 1991; 325:681–6.

4. Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, et al. A common molecular basis for three inherited kidney stone diseases. Nature. 1996; 379:445–9.

5. Devuyst O, Thakker RV. Dent's disease. Orphanet J Rare Dis. 2010; 5:28.

6. Scheinman SJ. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int. 1998; 53:3–17.

7. Ye Q, Shen Q, Rao J, Zhang A, Zheng B, Liu X, et al. Multicenter study of the clinical features and mutation gene spectrum of Chinese children with Dent disease. Clin Genet. 2020; 97:407–17.

8. Sekine T, Komoda F, Miura K, Takita J, Shimadzu M, Matsuyama T, et al. Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe/USA: genetic and clinical studies of 86 unrelated patients with low-molecular-weight proteinuria. Nephrol Dial Transplant. 2014; 29:376–84.

9. Zaniew M, Mizerska-Wasiak M, Zaluska-Lesniewska I, Adamczyk P, Kilis-Pstrusinska K, Halinski A, et al. Dent disease in Poland: what we have learned so far? Int Urol Nephrol. 2017; 49:2005–17.

10. Blanchard A, Curis E, Guyon-Roger T, Kahila D, Treard C, Baudouin V, et al. Observations of a large Dent disease cohort. Kidney Int. 2016; 90:430–9.

11. Hoopes RR, Raja KM, Koich A, Hueber P, Reid R, Knohl SJ, et al. Evidence for genetic heterogeneity in Dent's disease. Kidney Int. 2004; 65:1615–20.

12. Hoopes RR, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, et al. Dent disease with mutations in OCRL1. Am J Hum Genet. 2005; 76:260–7.

13. Anglani F, D'Angelo A, Bertizzolo LM, Tosetto E, Ceol M, Cremasco D, et al. Nephrolithiasis, kidney failure and bone disorders in Dent disease patients with and without CLCN5 mutations. Springerplus. 2015; 4:492.

14. Poroca DR, Pelis RM, Chappe VM. ClC channels and transporters: structure, physiological functions, and implications in human chloride channelopathies. Front Pharmacol. 2017; 8:151.

15. Wang Y, Cai H, Cebotaru L, Hryciw DH, Weinman EJ, Donowitz M, et al. ClC-5: role in endocytosis in the proximal tubule. Am J Physiol Renal Physiol. 2005; 289:F850–62.

16. Jin YY, Huang LM, Quan XF, Mao JH. Dent disease: classification, heterogeneity and diagnosis. World J Pediatr. 2021; 17:52–7.

17. Gianesello L, Del Prete D, Ceol M, Priante G, Calo LA, Anglani F. From protein uptake to Dent disease: an overview of the CLCN5 gene. Gene. 2020; 747:144662.

18. Mansour-Hendili L, Blanchard A, Le Pottier N, Roncelin I, Lourdel S, Treard C, et al. Mutation update of the CLCN5 gene responsible for Dent disease 1. Hum Mutat. 2015; 36:743–52.

19. Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA, et al. The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature. 1992; 358:239–42.

20. Claverie-Martin F, Ramos-Trujillo E, Garcia-Nieto V. Dent's disease: clinical features and molecular basis. Pediatr Nephrol. 2011; 26:693–704.

21. Raucher D, Stauffer T, Chen W, Shen K, Guo S, York JD, et al. Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion. Cell. 2000; 100:221–8.

22. Oltrabella F, Pietka G, Ramirez IB, Mironov A, Starborg T, Drummond IA, et al. The Lowe syndrome protein OCRL1 is required for endocytosis in the zebrafish pronephric tubule. PLoS Genet. 2015; 11:e1005058.

23. Shrimpton AE, Hoopes RR, Knohl SJ, Hueber P, Reed AA, Christie PT, et al. OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron Physiol. 2009; 112:27–36.

24. Lloyd SE, Gunther W, Pearce SH, Thomson A, Bianchi ML, Bosio M, et al. Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders. Hum Mol Genet. 1997; 6:1233–9.

25. van Berkel Y, Ludwig M, van Wijk JAE, Bokenkamp A. Proteinuria in Dent disease: a review of the literature. Pediatr Nephrol. 2017; 32:1851–9.

26. Gianesello L, Del Prete D, Anglani F, Calo LA. Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon. Hum Genet. 2021; 140:401–21.

27. Devuyst O, Pirson Y. Genetics of hypercalciuric stone forming diseases. Kidney Int. 2007; 72:1065–72.

28. Bokenkamp A, Bockenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, et al. Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr. 2009; 155:94–9.

29. Sayer JA, Carr G, Simmons NL. Calcium phosphate and calcium oxalate crystal handling is dependent upon CLC-5 expression in mouse collecting duct cells. Biochim Biophys Acta. 2004; 1689:83–90.

30. Scheinman SJ. Dent’s disease. In : Lifton RP, Somlo S, Giebisch GH, Seldin DW, editors. Genetic disease of the kidney. 1st ed. Elsevier Inc;2009. p. 213–26.

31. Ehlayel AM, Copelovitch L. Update on Dent disease. Pediatr Clin North Am. 2019; 66:169–78.

32. Raja KA, Schurman S, D'mello RG, Blowey D, Goodyer P, Van Why S, et al. Responsiveness of hypercalciuria to thiazide in Dent's disease. J Am Soc Nephrol. 2002; 13:2938–44.

33. Blanchard A, Vargas-Poussou R, Peyrard S, Mogenet A, Baudouin V, Boudailliez B, et al. Effect of hydrochlorothiazide on urinary calcium excretion in dent disease: an uncontrolled trial. Am J Kidney Dis. 2008; 52:1084–95.

34. Frishberg Y, Dinour D, Belostotsky R, Becker-Cohen R, Rinat C, Feinstein S, et al. Dent's disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg? Pediatr Nephrol. 2009; 24:2369–73.