[en] INTRODUCTION: Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G>A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies. METHODS: In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses. RESULTS: The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G>A and c.454T>A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T>C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes (P = 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P < 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure (P = 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals. CONCLUSION: In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1.
Disciplines :
Urology & nephrology
Author, co-author :
Metry, Elisabeth L; Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Garrelfs, Sander F; Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Deesker, Lisa J; Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Acquaviva, Cecile; Service de Biochimie et Biologie Moléculaire, UM Pathologies Héréditaires du Métabolisme et du Globule Rouge, Hospices Civils de Lyon, France.
D'Ambrosio, Viola; Department of Nephrology, Catholic University of the Sacred Heart, Rome, Italy.
Bacchetta, Justine; Centre de Référence des Maladies Rares Néphrogones, Hospices Civils de Lyon et Université Claude-Bernard Lyon 1, Lyon, France.
Beck, Bodo B; Institute of Human Genetics, Center for Molecular Medicine Cologne, University Hospital of Cologne, Cologne, Germany. ; Center for Rare and Hereditary Kidney Disease Cologne, University Hospital of Cologne, Cologne, Germany.
Cochat, Pierre; Centre de Référence des Maladies Rares Néphrogones, Hospices Civils de Lyon et Université Claude-Bernard Lyon 1, Lyon, France.
Collard, Laure ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie
Hogan, Julien; Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris Robert-Debré, University of Paris, Paris, France.
Ferraro, Pietro Manuel; Department of Nephrology, Catholic University of the Sacred Heart, Rome, Italy.
Franssen, Casper F M; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Harambat, Jérôme; Department of Pediatrics, Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France.
Hulton, Sally-Anne; Department of Nephrology, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
Lipkin, Graham W; Department of Nephrology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
Mandrile, Giorgia; Genetic Unit and Thalassemia Center, San Luigi University Hospital, Orbassano, Italy.
Martin-Higueras, Cristina; Institute of Biomedical Technology, CIBERER, University of Laguna, San Cristóbal de La Laguna, Spain.
Mohebbi, Nilufar; Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
Moochhala, Shabbir H; UCL Department of Renal Medicine, Royal Free Hospital, London, UK.
Neuhaus, Thomas J; Department of Pediatrics, Children's Hospital Lucerne, Lucerne, Switzerland.
Prikhodina, Larisa; Department of Inherited and Acquired Kidney Diseases, Veltishev Research and Clinical Institute for Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University, Moscow, Russia.
Salido, Eduardo; Department of Pathology, Center for Biomedical Research on Rare Diseases, Hospital Universitario Canarias, Universidad La Laguna, Tenerife, Spain.
Topaloglu, Rezan; Division of Pediatric Nephrology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Oosterveld, Michiel J S; Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Groothoff, Jaap W; Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Peters-Sengers, Hessel; Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
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