Mechanisms of inherited kidney disorders

Most relevant publications of the last few years

List of full publications of Olivier Devuyst

Selection of original research publications:


Festa BP, Berquez M, Gassama A, Amrein I, Ismail HM, Samardzija M, Staiano L, Luciani A, Grimm C, Nussbaum RL, De Matteis MA, Dorchies OM, Scapozza L, Wolfer DP, Devuyst O. OCRL Deficiency Impairs Endolysosomal Function in a Humanized Mouse Model for Lowe Syndrome and Dent Disease. Hum Mol Genet. 2018; Dec 26. doi: 10.1093/hmg/ddy449.

*** These studies substantiate the first mouse model of Lowe syndrome and give insights into the role of the inositol polyphosphate 5-phosphatase OCRL in cellular trafficking of multiligand receptors in the cells lining the proximal tubule of the kidney. These insights open new avenues for therapeutic interventions in Lowe syndrome and Dent disease.

 

Tokonami N, Olinger E, Debaix H, Houillier P, Devuyst O. The excretion of uromodulin is modulated by the calcium-sensing receptor. Kidney Int. 2018; 94:882-886.

*** Uromodulin is a protein exclusively by the kidney tubule, playing a major role in the urine. Using a multi-level approach, we demonstrated that secretion of uromodulin by thick ascending limb cells is modulated by the calcium-sensing receptor (CaSR), which may be clinically relevant considering the increasing use of CaSR modulators.
 

Tokonami N, Takata T, Beyeler J, Ehrbar I, Yoshifuji A, Christensen EI, Loffing J, Devuyst O*, Olinger EG*. Uromodulin is expressed in the distal convoluted tubule, where it is critical for regulation of the sodium chloride cotransporter NCC. Kidney Int. 2018; 94:701-715. (* Corresponding author) (* Equal last & corresponding authors). Highlighted by a Commentary.

*** These experiments demonstrate a significant expression and a role of uromodulin in the early part of mouse and human DCT. Biosynthesis of uromodulin in the DCT1 is critical for its function, structure and plasticity, suggesting novel links between uromodulin, blood pressure control and risk of kidney stones.
 

Festa BP, Chen Z, Berquez M, Debaix H, Tokonami N, Prange JA, Hoek GV, Alessio C, Raimondi A, Nevo N, Giles RH, Devuyst O*, Luciani A*. Impaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney. Nat Commun. 2018; 9:161. (* Equal last authors and correspondence)

*** Lysosomal storage diseases such as nephropathic cystinosis cause a major dysfunction of epithelial cells lining the kidney tubule, resulting in massive losses of vital solutes in the urine. Here we demonstrate, by combining genetic and pharmacologic approaches, a link between defective lysosome-autophagy degradation pathways and epithelial dysfunction, providing new therapeutic perspectives for lysosomal storage disorders.
 

Corre T, Arjona FJ, Hayward C, Youhanna S, de Baaij JHF, Belge H, Nägele N, Debaix H, Blanchard MG, Traglia M, Harris SE, Ulivi S, Rueedi R, Lamparter D, Macé A, Sala C, Lenarduzzi S, Ponte B, Pruijm M, Ackermann D, Ehret G, Baptista D, Polasek O, Rudan I, Hurd TW, Hastie ND, Vitart V, Waeber G, Kutalik Z, Bergmann S, Vargas-Poussou R, Konrad M, Gasparini P, Deary IJ, Starr JM, Toniolo D, Vollenweider P, Hoenderop JGJ, Bindels RJM, Bochud M, Devuyst O. Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes. J Am Soc Nephrol. 2018; 29:335-348. Highlight of the Month.

*** Magnesium (Mg2+) homeostasis is critical for metabolism. Here, we used a combined observational (meta-GWAS) and experimental (mouse and zebrafish models, in vitro experiments) approach to uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.
 

Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O; REPRISE Trial Investigators. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2017; 377:1930-1942. Highlighted by an Editorial comment.

*** This clinical, phase III study demonstrated that Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. These results consolidated the evidence obtained in the TEMPO3:4 trial and led to the FDA approval of Tolvaptan for the treatment of ADPKD in the USA.
 

Gabriel SS, Belge H, Gassama A, Debaix H, Luciani A, Fehr T, Devuyst O. Bone marrow transplantation improves proximal tubule dysfunction in a mouse model of Dent disease. Kidney Int. 2017; Jan 28. pii: S0085-2538(16)30702-5.

*** This study evidenced, for the first time, that bone marrow transplantation may rescue the epithelial phenotype due to an inherited endosomal defect. Direct contacts between bone marrow-derived cells and diseased tubular cells play a key role in the rescue mechanism. (Paper highlighted in an accompanying Editorial)

 

Ghirotto S, Tassi F, Barbujani G, Pattini L, Hayward C, Vollenweider P, Bochud M, Rampoldi L, Devuyst O. The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution. J Am Soc Nephrol. 2016; 27: 2983-96.

*** We investigated the high prevalence of common risk variants in the UMOD gene, associated with risk of hypertension and CKD. Our results suggest that the UMOD ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a high frequency because of its protective effect against urinary tract infections. (Highlight of the Month, JASN) (Highlight, Nature Rev Nephrol)

 

Terryn S, Tanaka K, Lengelé JP, Olinger E, Dubois-Laforgue D, Garbay S, Kozyraki R, Van Der Smissen P, Christensen EI, Courtoy PJ, Bellanné-Chantelot C, Timsit J, Pontoglio M, Devuyst O. Tubular proteinuria in patients with HNF1α mutations: HNF1α drives endocytosis in the proximal tubule. Kidney Int. 2016; 89: 1075-89.

*** This study, based on mouse, cellular and human data, demonstrated that the transcription factor hepatocyte nuclear factor 1α (HNF1α) drives the constitutive expression of the multiligand receptors megalin and cubilin, hence regulates endocytosis in the proximal tubule of the kidney. These findings provide new insights into genetic interaction networks operating in kidney tubules and a novel phenotype associated with rare inherited forms of diabetes (MODY).

 

Luciani A, Sirac C, Terryn S, Javaugue V, Prange JA, Bender S, Bonaud A, Cogné M, Aucouturier P, Ronco P, Bridoux F, Devuyst O. Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome. J Am Soc Nephrol. 2016; 27: 2049-61.

*** These results revealed the mechanism of light-chain induced renal Fanconi syndrome. The early lysosomal dysfunction, which is similar to that encountered in congenital lysosomal disorders, provides a basis for the selective tubular toxicity of the monoclonal light chains and indicates new therapeutic perspectives for this renal complication of multiple myeloma.

 

Olden M, Corre T, Hayward C, Toniolo D, Ulivi S, Gasparini P, Pistis G, Hwang SJ, Bergmann S, Campbell H, Cocca M, Gandin I, Girotto G, Glaudemans B, Hastie ND, Loffing J, Polasek O, Rampoldi L, Rudan I, Sala C, Traglia M, Vollenweider P, Vuckovic D, Youhanna S, Weber J, Wright AF, Kutalik Z, Bochud M, Fox CS, Devuyst O. Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis. J Am Soc Nephrol. 2014; 25: 1869-82.

*** In this study, we performed the first meta-GWAS in order to identify the genetic factors associated with the excretion of uromodulin, the most abundant protein in normal urine.

 

Glaudemans B, Terryn S, Gölz N, Brunati M, Cattaneo A, Bachi A, Al-Qusairi L, Ziegler U, Staub O, Rampoldi L, Devuyst O. A primary culture system of mouse thick ascending limb cells with preserved function and uromodulin processing. Pflugers Arch. 2014; 466: 343-56.

*** In this technical paper, we characterized a new cell culture system to investigate the functions of the thick ascending limb of the loop od Henle, a tubular segment involved in key transport processes important for blood pressure control, urinary concentration and divalent metals homeostasis.

 

Trudu M, Janas S, Lanzani C, Debaix H, Schaeffer C, Ikehata M, Citterio L, Demaretz S, Trevisani F, Ristagno G, Glaudemans B, Laghmani K, Dell'Antonio G; Swiss Kidney Project on Genes in Hypertension (SKIPOGH) team, Loffing J, Rastaldi MP, Manunta P, Devuyst O*, Rampoldi L*. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med. 2013; 19: 1655-60. (* Equal last authors & correspondence)

*** This investigation provided the mechanistic link between genetic susceptibility to hypertension and CKD and the level of uromodulin expression and its effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function. (Highlighted in Nat Rev Nephrol)

 

Yool AJ, Morelle J, Cnops Y, Verbavatz JM, Campbell EM, Beckett EA, Booker GW, Flynn G, Devuyst O. AqF026 is a pharmacologic agonist of the water channel aquaporin-1. J Am Soc Nephrol. 2013; 24: 1045-52.

*** This study describes the identification (high content screen of furosemide-derived compounds) and validation of the first pharmacologic agonist of the water channel AQP1, with potential utility for peritoneal dialysis and clinical situations associated with defective water handling. (Highlight of the month, JASN)

 

Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012; 367: 2407-18.

*** This phase 3, multicenter, double-blind RCT demonstrated that the vasopressin antagonist tolvaptan slowed the disease progression in autosomal dominant polycystic kidney disease (ADPKD). The study met its primay and secondary endpoints. Tolvaptan is the first drug targeting the disease mechanism and has now been approved for treating ADPKD in Europe, Japan and Canada. (Paper highlighted in an accompanying Editorial)

 

Biver S*, Belge H*, Bourgeois S, Van Vooren P, Nowik M, Scohy S, Houillier P, Szpirer J, Szpirer C, Wagner CA, Devuyst O, Marini AM. A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility. Nature 2008; 456: 339-43. (* Equal first authors)

*** This work resolved a long-standing question in kidney physiology, i.e. the molecular basis of ammonia transport into the urine. The identification of the rhesus-related protein RHCG as the ammonia channel in the collecting duct provided a model for distal urine acidification, opening perspectives in terms of acid-base regulation and reproductive biology (role in epididymal function and sperm maturation). (Highlighted in News &Views article)

 

Belge H, Gailly P, Schwaller B, Loffing J, Debaix H, Riveira-Munoz E, Beauwens R, Devogelaer JP, Hoenderop JG, Bindels RJ, Devuyst O. Renal expression of parvalbumin is critical for NaCl handling and response to diuretics.
Proc Natl Acad Sci U S A. 2007; 104: 14849-54.

 

Jouret F, Bernard A, Hermans C, Dom G, Terryn S, Leal T, Lebecque P, Cassiman JJ, Scholte BJ, de Jonge HR, Courtoy PJ, Devuyst O. Cystic fibrosis is associated with a defect in apical receptormediated endocytosis in mouse and human kidney. J Am Soc Nephrol. 2007; 18: 707-18.

*** This study, based on mouse, cellular and human evidence, demonstrated a role for the chloride channel CFTR in the receptor-mediated endocytosis in the kidney proximal tubule, and identified a novel phenotype in patients with cystic fibrosis.

 

Ni J, Verbavatz JM, Rippe A, Boisdé I, Moulin P, Rippe B, Verkman AS, Devuyst O. Aquaporin-1 plays an essential role in water permeability and ultrafiltration during peritoneal dialysis. Kidney Int. 2006; 69: 1518-25.

*** In this study, we demonstrated the role of the water channel aquaporin-1 (AQP1) as the molecular counterpart of the ultrasmall pore predicted by the three-pore model of fluid transport across the peritoneal membrane. (Highlighted in a Commentary)

 

Persu A, Duyme M, Pirson Y, Lens XM, Messiaen T, Breuning MH, Chauveau D, Levy M, Grünfeld JP, Devuyst O. Comparison between siblings and twins supports a role for modifier genes in ADPKD. Kidney Int. 2004; 66: 2132-6.

*** This study based on twin pairs paved the way for the search for modier genes in polycystic kidney disease (ADPKD).

 

Dahan K*, Devuyst O*, Smaers M, Vertommen D, Loute G, Poux JM, Viron B, Jacquot C, Gagnadoux MF, Chauveau D, Büchler M, Cochat P, Cosyns JP, Mougenot B, Rider MH, Antignac C, Verellen-Dumoulin C, Pirson Y. A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol. 2003; 14: 2883-93. (* Equal contribution)

*** First report of dominant UMOD mutations associated with familial juvenile hyperuricemic nephropathy in Europe, with description of the gain of function mechanism caused by the storage of the mutant protein in tubular cells.

 

Christensen EI*, Devuyst O*, Dom G, Nielsen R, Van der Smissen P, Verroust P, Leruth M, Guggino WB, Courtoy PJ. Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proc Natl Acad Sci U S A. 2003; 100: 8472-7. (* Equal first authors)

*** This study provided novel insights into the proximal tubule defect (renal Fanconi syndrome) associated with Dent disease. The mechanistic link between a rare channelopathy and . We showed that the proximal tubule dysfunction caused by invalidation of the endosomal channel ClC- 5 primarily reflects a generalized trafficking defect in the epithelial cells.

 

Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV. Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. Hum Mol Genet. 1999; 8: 247-57.

 

Selection of reviews:

 

Luciani A, Festa BP, Chen Z, Devuyst O.
Defective autophagy degradation and abnormal tight junction-associated signaling
drive epithelial dysfunction in cystinosis
.
Autophagy. 2018; 14:1157-1159.

 

Olinger E, Houillier P, Devuyst O.
Claudins: a tale of interactions in the thick ascending limb.
Kidney Int. 2018; 93:535-537.

 

Devuyst O, Pattaro C.
The UMOD Locus: Insights into the Pathogenesis and Prognosis of Kidney Disease.
J Am Soc Nephrol. 2018; 29:713-26.
   

Devuyst O, Olinger E, Rampoldi L.
Uromodulin: from physiology to rare and complex kidney disorders.
Nat Rev Nephrol. 2017; 9:525-44.             


De Matteis MA, Staiano L, Emma F, Devuyst O.
The 5-phosphatase OCRL in Lowe syndrome and Dent disease 2.
Nat Rev Nephrol. 2017; 8:455-70.

 

Rossier BC, Bochud M, Devuyst O.
The Hypertension Pandemic: An Evolutionary Perspective.
Physiology (Bethesda). 2017; 32:112-25.
 

Mehrotra R, Devuyst O, Davies SJ, Johnson DW.
The Current State of Peritoneal Dialysis.
J Am Soc Nephrol. 2016; 11: 3238-52.
 

Morelle J, Devuyst O.
Water and solute transport across the peritoneal membrane.
Curr Opin Nephrol Hypertens. 2015; 24: 434-43.
 

Ong AC, Devuyst O, Knebelmann B, Walz G.
Autosomal dominant polycystic kidney disease: the changing face of clinical management.
Lancet 2015; 9981: 1993-2002.
 

Kanaan N, Devuyst O, Pirson Y.
Renal transplantation in autosomal dominant polycystic kidney disease.
Nat Rev Nephrol. 2014; 10: 455-65.
 

Devuyst O, Knoers NV, Remuzzi G, Schaefer F.
Rare inherited kidney diseases: challenges, opportunities, and perspectives.
Lancet 2014; 9931: 1844-1859.
 

Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, Levin A.
Evolving importance of kidney disease: from subspecialty to global health burden.
Lancet 2013; 382: 158-169.
 

Devuyst O, Torres VE.
Osmoregulation, vasopressin, and cAMP signaling in autosomal dominant polycystic kidney disease.
Curr Opin Nephrol Hypertens 2013; 22: 459-470.
 

Terryn S, Ho A, Beauwens R, Devuyst O.
Fluid transport and cystogenesis in autosomal dominant polycystic kidney disease.
Biochim Biophys Acta 2011;1812:1314-1321.
 

Devuyst O, Margetts PJ, Topley N.
The pathophysiology of the peritoneal membrane.
J Am Soc Nephrol. 2010, 21: 1077-1108.
 

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

Jouret F, Devuyst O.
CFTR and defective endocytosis: New insights in the renal phenotype of cystic fibrosis.
Pflugers Arch. 2009, 457: 1227-1236.
 

Devuyst O.
Salt wasting and blood pressure.
Nat Genet. 2008, 40: 495-496.