TY - JOUR
T1 - Determinants of Kidney Failure in Primary Hyperoxaluria Type 1
T2 - Findings of the European Hyperoxaluria Consortium
AU - Metry, Elisabeth L.
AU - Garrelfs, Sander F.
AU - Deesker, Lisa J.
AU - Acquaviva, Cecile
AU - D'Ambrosio, Viola
AU - Bacchetta, Justine
AU - Beck, Bodo B.
AU - Cochat, Pierre
AU - Collard, Laure
AU - Hogan, Julien
AU - Ferraro, Pietro Manuel
AU - Franssen, Casper F. M.
AU - Harambat, J. rôme
AU - Hulton, Sally-Anne
AU - Lipkin, Graham W.
AU - Mandrile, Giorgia
AU - Martin-Higueras, Cristina
AU - Mohebbi, Nilufar
AU - Moochhala, Shabbir H.
AU - Neuhaus, Thomas J.
AU - Prikhodina, Larisa
AU - Salido, Eduardo
AU - Topaloglu, Rezan
AU - Oosterveld, Michiel J. S.
AU - Groothoff, Jaap W.
AU - Peters-Sengers, Hessel
N1 - Funding Information: JWG, MJSO, SFG, LJD, and ELM have received an unconditional grant from both Alnylam Pharmaceuticals and Dicerna (Novo Nordisk) Pharmaceuticals to fund the OxalEurope Registry. SFG received a PhD scholarship from the Amsterdam University Medical Centers. SAH and SHM have received consultation fees from Alnylam Pharmaceuticals and Dicerna Pharmaceuticals. BBB, CA, GM, JB, JHa, JHo, LC, MJSO, and PMF have received consultation fees from Alnylam Pharmaceuticals. CMH has received consultation fees from Dicerna Pharmaceuticals and funding from Fundación Disa. All the other authors declared no competing interests. Publisher Copyright: © 2023 International Society of Nephrology
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
KW - kidney failure
KW - nephrocalcinosis
KW - primary hyperoxaluria
KW - urinary glycolate
KW - urinary oxalate
KW - urolithiasis
UR - http://www.scopus.com/inward/record.url?scp=85168740353&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ekir.2023.07.025
DO - https://doi.org/10.1016/j.ekir.2023.07.025
M3 - Article
C2 - 37849991
SN - 2468-0249
VL - 8
SP - 2029
EP - 2042
JO - Kidney International Reports
JF - Kidney International Reports
IS - 10
ER -