Determinants of Kidney Failure in Primary Hyperoxaluria Type 1: Findings of the European Hyperoxaluria Consortium

Elisabeth L Metry; Sander F Garrelfs; Lisa J Deesker; Cecile Acquaviva; Viola D'Ambrosio; Justine Bacchetta; Bodo B Beck; Pierre Cochat; Laure Collard; Julien Hogan; Pietro Manuel Ferraro; Casper F M Franssen; Jérôme Harambat; Sally-Anne Hulton; Graham W Lipkin; Giorgia Mandrile; Cristina Martin-Higueras; Nilufar Mohebbi; Shabbir H Moochhala; Thomas J Neuhaus; Larisa Prikhodina; Eduardo Salido; Rezan Topaloglu; Michiel J S Oosterveld; Jaap W Groothoff; Hessel Peters-Sengers

doi:10.1016/j.ekir.2023.07.025

Determinants of Kidney Failure in Primary Hyperoxaluria Type 1: Findings of the European Hyperoxaluria Consortium

Kidney Int Rep. 2023 Aug 4;8(10):2029-2042. doi: 10.1016/j.ekir.2023.07.025. eCollection 2023 Oct.

Authors

Elisabeth L Metry¹, Sander F Garrelfs¹, Lisa J Deesker¹, Cecile Acquaviva², Viola D'Ambrosio³, Justine Bacchetta⁴, Bodo B Beck^{5

6}, Pierre Cochat⁴, Laure Collard⁷, Julien Hogan⁸, Pietro Manuel Ferraro³, Casper F M Franssen⁹, Jérôme Harambat¹⁰, Sally-Anne Hulton¹¹, Graham W Lipkin¹², Giorgia Mandrile¹³, Cristina Martin-Higueras¹⁴, Nilufar Mohebbi¹⁵, Shabbir H Moochhala¹⁶, Thomas J Neuhaus¹⁷, Larisa Prikhodina¹⁸, Eduardo Salido¹⁹, Rezan Topaloglu²⁰, Michiel J S Oosterveld¹, Jaap W Groothoff¹, Hessel Peters-Sengers²¹

Affiliations

¹ Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
² Service de Biochimie et Biologie Moléculaire, UM Pathologies Héréditaires du Métabolisme et du Globule Rouge, Hospices Civils de Lyon, France.
³ Department of Nephrology, Catholic University of the Sacred Heart, Rome, Italy.
⁴ Centre de Référence des Maladies Rares Néphrogones, Hospices Civils de Lyon et Université Claude-Bernard Lyon 1, Lyon, France.
⁵ Institute of Human Genetics, Center for Molecular Medicine Cologne, University Hospital of Cologne, Cologne, Germany.
⁶ Center for Rare and Hereditary Kidney Disease Cologne, University Hospital of Cologne, Cologne, Germany.
⁷ Department of Pediatric Nephrology, Center Hospitalier Universitaire Liège, Liège, Belgium.
⁸ Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris Robert-Debré, University of Paris, Paris, France.
⁹ Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁰ Department of Pediatrics, Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France.
¹¹ Department of Nephrology, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
¹² Department of Nephrology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹³ Genetic Unit and Thalassemia Center, San Luigi University Hospital, Orbassano, Italy.
¹⁴ Institute of Biomedical Technology, CIBERER, University of Laguna, San Cristóbal de La Laguna, Spain.
¹⁵ Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
¹⁶ UCL Department of Renal Medicine, Royal Free Hospital, London, UK.
¹⁷ Department of Pediatrics, Children's Hospital Lucerne, Lucerne, Switzerland.
¹⁸ 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.
¹⁹ Department of Pathology, Center for Biomedical Research on Rare Diseases, Hospital Universitario Canarias, Universidad La Laguna, Tenerife, Spain.
²⁰ Division of Pediatric Nephrology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
²¹ Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

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.

Keywords: kidney failure; nephrocalcinosis; primary hyperoxaluria; urinary glycolate; urinary oxalate; urolithiasis.