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

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.

Graphical abstract

Figure 1

Age at onset of symptoms, age at diagnosis, and age at onset of kidney failure for patients with PH1 in genotype-based groups. Median and interquartile ranges for age at onset of symptoms, age at diagnosis, and age at onset of kidney failure. Dots represent outliers. PH1, primary hyperoxaluria type 1.

Figure 2

Kaplan-Meier survival curve for AGXT genotype-based groups of patients with PH1. The left survival curve displays kidney failure-free survival for the 6 genotype-based groups. The right survival curve displays kidney failure-free survival for patients with homozygous c.508G>A, c.731 T>C or null variants. PH1, primary hyperoxaluria type 1.

Figure 3

Kaplan-Meier survival curve for PH1 patient groups based on clinical features at time of diagnosis. Kidney-failure free survival rates for patients with no stones or NC (nephrocalcinosis), only NC, only stones, or both stones and NC. PH1, primary hyperoxaluria type 1.

Figure 4

Flowchart. This flowchart shows the number of patients included in the OxalEurope registry (N = 932), the number of patients with genetically established PH1 (n = 760) and the number of patients with available data on kidney outcome at last follow-up (primary outcome; n = 740). In a subset of patients (n = 149), urinary oxalate and glycolate measurements were available and could be related to kidney outcome. The number of patients here correspond to the number of patients included in Figure 5 and 6. BSA, body surface area; Uox, urinary oxalate; Ugly, urinary glycolate.

Figure 5

Urinary oxalate and glycolate excretion rates in patients with PH1 with and without kidney failure at last follow-up. All open circles represent measurements in 24-hour urine collections, measurements after onset of kidney failure or after transplantation were excluded. Green and red circles represent measurements in patients with and without kidney failure at last follow-up (ESKD, end-stage kidney failure = 1 and 0, respectively). Circles connected to each other represent repeated measurements in the same patient. Reference values of oxalate/creatinine and glycolate/creatinine ratios are respectively <0.17 and <0.29 mmol/mmol for children younger than 2 years, <0.10 and <0.23 mmol/mmol for children from 1 to 5 years, <0.08 and <0.19 mmol/mmol for children younger than 14 years, and <0.04 and <0.13 mmol/mmol for children older than 16 years. PH1, primary hyperoxaluria type 1.

Figure 6

Mixed model analyses: urinary oxalate and glycolate excretion rates in patients with PH1 with and without kidney failure at last follow-up. Outcome trajectory of urinary oxalate and glycolate excretion between patients with and without kidney failure at last follow-up, excluding measurements after onset of kidney failure. The mixed model was fitted on logarithmically transformed data, taking group (with or without kidney failure at last follow-up), age (only for oxalate/creatinine and glycolate/creatinine ratios), and their interaction as fixed effects, and patient-specific intercept and slope of time as random effects. Outcomes were back transformed to original scale for graphical interpretation. PH1, primary hyperoxaluria type 1.