Primary hyperoxaluria in Italy: the past 30\xa0years and the near future of a (not so) rare disease

Giorgia Mandrile,Renato Romagnoli,Corrado Vitale,Alessandra Pelle,Giovanni Montini,Michele Petrarulo,Elisa Benetti,Maria Michela D’Alessandro,Francesco Emma,Daniela Giachino,Licia Peruzzi,Veronica Sciannameo,Barbara Cellini

doi:10.1007/s40620-022-01258-4

Abstract

BackgroundPrimary hyperoxalurias (PHs) are rare autosomal recessive diseases of the glyoxylate metabolism; PH1 is caused by mutations in the AGXT gene, PH2 in GRHPR and PH3 in HOGA1.MethodsHere we report the first large multi-center cohort of Italian PH patients collected over 30 years (1992–2020 median follow-up time 8.5 years). Complete genotype was available for 94/95 PH1 patients and for all PH2 (n = 3) and PH3 (n = 5) patients. Symptoms at onset were mainly nephrolithiasis (46.3%) and nephrocalcinosis (33.7%). Median age at onset of symptoms and diagnosis were 4.0 years and 9.9 years, respectively.ResultsFifty-four patients (56.8%) were diagnosed after chronic kidney disease. Sixty-three patients (66.3%) developed end stage kidney disease (median age 14.0 years). Twenty-one patients had a kidney-only transplant and, among them, seven had a second kidney transplant combined with liver transplant. A combined kidney–liver transplant was carried out in 29 patients and a sequential kidney–liver transplant was performed in two. In five cases a preemptive liver transplant was performed. Those receiving a liver-only transplant tended to have lower kidney function at last follow-up.ConclusionOur study of PHs in Italy underlines a considerable diagnostic delay, which has only slightly decreased in recent years. Therefore, we suggest a more extensive use of both metabolic screening among patients with recurrent kidney stones and genotyping, including unambiguous assignment of minor/major allele status in order to promptly begin appropriate treatment. This will be fundamental in order to have access to the new therapies, which are mainly focused on substrate reduction for the oxalate-producing enzymes using RNA-interference.Graphical abstract

Highlights

Primary hyperoxalurias (PHs) are rare autosomal recessive diseases of the glyoxylate metabolism; PH type 1 (PH1) is caused by mutations in the AGXT gene, PH type 2 (PH2) in glyoxylate reductase/hydroxypyruvate reductase (GRHPR) and PH type 3 (PH3) in hydroxy-2-oxoglutarate aldolase 1 (HOGA1)
The suspicion of primary hyperoxaluria was based on the patient’s history; diagnosis workup started with biochemical tests, and genetic analysis was required for diagnosis confirmation
We present the first description of the largest cohort of Italian Primary hyperoxaluria patients collected over 30 years, contributing to delineate the genotypic and phenotypic spectrum of PH in different populations

Summary

Introduction

Primary hyperoxalurias (PHs) are rare autosomal recessive diseases of the glyoxylate metabolism; PH1 is caused by mutations in the AGXT gene, PH2 in GRHPR and PH3 in HOGA1. Sixty-three patients (66.3%) developed end stage kidney disease (median age 14.0 years). In five cases a preemptive liver transplant was performed Those receiving a liver-only transplant tended to have lower kidney function at last follow-up. Primary hyperoxalurias (PHs) are a group of rare autosomal recessive diseases driven by alterations in the glyoxylate metabolism and characterized by genetic heterogeneity and variable clinical presentation [1]. It is estimated that Primary hyperoxalurias occur in 7–14% of children with nephrocalcinosis and represent the cause of renal replacement therapy before the age of 15 years in approximately 2% of patients in European and North American countries [1]. Clinical signs range from severe nephrocalcinosis in the first years of life and progression to diffuse multisystem oxalosis, to recurrent urolithiasis in adult patients [1]

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