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Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1

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Abstract

Background

Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1.

Methods

For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6).

Results

Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups.

Conclusions

Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease.

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References

  1. Sas DJ, Harris PC, Milliner DS (2019) Recent advances in the identification and management of inherited hyperoxalurias. Urolithiasis 47:79–89

    Article  PubMed  Google Scholar 

  2. Hopp K, Cogal AG, Bergstralh EJ et al (2015) Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol 26:2559–2570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Harambat J, Fargue S, Acquaviva C et al (2010) Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int 77:443–449

    Article  CAS  PubMed  Google Scholar 

  4. Stenson PD, Ball EV, Mort M et al (2003) Human gene mutation database (HGMD): 2003 update. Hum Mutat 21:577–581

    Article  CAS  PubMed  Google Scholar 

  5. Danpure CJ (2006) Primary hyperoxaluria type 1: AGT mistargeting highlights the fundamental differences between the peroxisomal and mitochondrial protein import pathways. Biochim Biophys Acta 1763:1776–1784

    Article  CAS  PubMed  Google Scholar 

  6. Monico CG, Rossetti S, Olson JB, Milliner DS (2005) Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 67:1704–1709

    Article  CAS  PubMed  Google Scholar 

  7. Harambat J, van Stralen KJ, Espinosa L et al (2012) Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy. Clin J Am Soc Nephrol 7:458–465

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lieske JC, Monico CG, Holmes WS et al (2005) International registry for primary hyperoxaluria. Am J Nephrol 25:290–296

    Article  PubMed  Google Scholar 

  9. Schwartz GJ, Munoz A, Schneider MF et al (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ladwig PM, Liedtke RR, Larson TS, Lieske JC (2005) Sensitive spectrophotometric assay for plasma oxalate. Clin Chem 51:2377–2380

    Article  CAS  PubMed  Google Scholar 

  11. Wilson DM, Liedtke RR (1991) Modified enzyme-based colorimetric assay of urinary and plasma oxalate with improved sensitivity and no ascorbate interference: reference values and sample handling procedures. Clin Chem 37:1229–1235

    Article  CAS  PubMed  Google Scholar 

  12. Clifford-Mobley O, Tims C, Rumsby G (2015) The comparability of oxalate excretion and oxalate:creatinine ratio in the investigation of primary hyperoxaluria: review of data from a referral centre. Ann Clin Biochem 52:113–121

    Article  CAS  PubMed  Google Scholar 

  13. Gibbs DA, Watts RW (1969) The variation of urinary oxalate excretion with age. J Lab Clin Med 73:901–908

    CAS  PubMed  Google Scholar 

  14. Matos V, Van Melle G, Werner D, Bardy D, Guignard JP (1999) Urinary oxalate and urate to creatinine ratios in a healthy pediatric population. Am J Kidney Dis 34:e1

    Article  CAS  PubMed  Google Scholar 

  15. Garrelfs S, van Harskamp D, Peters-Sengers H et al (2021) Endogenous oxalate production in primary hyperoxaluria type 1 patients. J Am Soc Nephrol 32:3175–3186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shah RJ, Vaughan LE, Enders FT, Milliner DS, Lieske JC (2020) Plasma oxalate as a predictor of kidney function decline in a primary hyperoxaluria cohort. Int J Mol Sci 21:3608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhao F, Bergstralh EJ, Mehta RA et al (2016) Predictors of incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure. Clin J Am Soc Nephrol 11:119–126

    Article  CAS  PubMed  Google Scholar 

  18. Mandrile G, van Woerden CS, Berchialla P et al (2014) Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int 86:1197–1204

    Article  CAS  PubMed  Google Scholar 

  19. Lorenz EC, Lieske JC, Seide BM, Olson JB, Mehta R, Milliner DS (2021) Recovery from dialysis in patients with primary hyperoxaluria type 1 treated with pyridoxine: a report of 3 cases. Am J Kidney Dis 77:816–819

    Article  CAS  PubMed  Google Scholar 

  20. Cellini B, Lorenzetto A, Montioli R, Oppici E, Voltattorni CB (2010) Human liver peroxisomal alanine:glyoxylate aminotransferase: different stability under chemical stress of the major allele, the minor allele, and its pathogenic G170R variant. Biochimie 92:1801–1811

    Article  CAS  PubMed  Google Scholar 

  21. Fargue S, Rumsby G, Danpure CJ (2013) Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type 1. Biochim Biophys Acta 1832:1776–1783

    Article  CAS  PubMed  Google Scholar 

  22. Singh P, Chebib FT, Cogal AG, Gavrilov DK, Harris PC, Lieske JC (2020) Pyridoxine responsiveness in a type 1 primary hyperoxaluria patient with a rare (atypical) AGXT gene mutation. Kidney Int Rep 5:955–958

    Article  PubMed  PubMed Central  Google Scholar 

  23. Dindo M, Conter C, Oppici E, Ceccarelli V, Marinucci L, Cellini B (2019) Molecular basis of primary hyperoxaluria: clues to innovative treatments. Urolithiasis 47:67–78

    Article  CAS  PubMed  Google Scholar 

  24. Oppici E, Fargue S, Reid ES et al (2015) Pyridoxamine and pyridoxal are more effective than pyridoxine in rescuing folding-defective variants of human alanine:glyoxylate aminotransferase causing primary hyperoxaluria type I. Hum Mol Genet 24:5500–5511

    Article  CAS  PubMed  Google Scholar 

  25. Reusz GS, Dobos M, Byrd D, Sallay P, Miltenyi M, Tulassay T (1995) Urinary calcium and oxalate excretion in children. Pediatr Nephrol 9:39–44

    Article  CAS  PubMed  Google Scholar 

  26. Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A (2005) Changes in liver volume from birth to adulthood: a meta-analysis. Liver Transpl 11:1481–1493

    Article  PubMed  Google Scholar 

  27. Paccaud Y, Rios-Leyvraz M, Bochud M et al (2020) Spot urine samples to estimate 24-hour urinary calcium excretion in school-age children. Eur J Pediatr 179:1673–1681

    Article  PubMed  Google Scholar 

  28. Garrelfs SF, Frishberg Y, Hulton SA et al (2021) Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med 384:1216–1226

    Article  CAS  PubMed  Google Scholar 

  29. Milliner DS, McGregor TL, Thompson A et al (2020) End points for clinical trials in primary hyperoxaluria. Clin J Am Soc Nephrol 15:1056–1065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Porowski T, Zoch-Zwierz W, Konstantynowicz J, Korzeniecka-Kozerska A, Michaluk-Skutnik J, Porowska H (2008) Reference values of plasma oxalate in children and adolescents. Pediatr Nephrol 23:1787–1794

    Article  PubMed  Google Scholar 

  31. Milliner DS, Cochat P, Hulton SA et al (2021) Plasma oxalate and eGFR are correlated in primary hyperoxaluria patients with maintained kidney function-data from three placebo-controlled studies. Pediatr Nephrol 36:1785–1793

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was funded by the Rare Kidney Stone Consortium (U54DK83908), which is part of Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS). This consortium was funded through collaboration between NCATS, and the National Institute of Diabetes and Digestive and Kidney Diseases. This work was also supported by an industry grant from Alnylam, as well as funding from the Oxalosis and Hyperoxaluria Foundation (EIN: 91–1457505).

Author information

Authors and Affiliations

  1. Division of Pediatric Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    David J. Sas & Dawn S. Milliner

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    David J. Sas & John C. Lieske

  3. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA

    David J. Sas, Barbara M. Seide, Carly J. Banks, John C. Lieske & Dawn S. Milliner

  4. Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA

    Kristin Mara & Ramila A. Mehta

  5. Alnylam Pharmaceuticals, Cambridge, MA, USA

    David S. Danese & Tracy L. McGregor

Authors
  1. David J. Sas
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Contributions

D.J.S., J.C.L., D.S.M., and K.M. contributed to the research idea, study design, data analysis/interpretation, and manuscript preparation; K.M. and R.A.M. contributed to data analysis/interpretation and performed statistical analysis. B.M.S. and C.J.B. contributed to data acquisition and subject recruitment. D.S.D. and T.L.M. contributed to study idea, data analysis/interpretation, and content feedback. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to David J. Sas.

Ethics declarations

Ethics approval and consent to participate

The relevant institutional review boards and ethics committees approved the study, and all participants gave informed consent.

Conflict of interest

Alnylam provided partial funding for this study. The investigators had full responsibility for the study design, data collection, data interpretation, and preparation of the manuscript. TLM is former employee of Alnylam Pharmaceuticals and holds shares in Alnylam Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Sas, D.J., Mara, K., Mehta, R.A. et al. Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1. Pediatr Nephrol 39, 141–148 (2024). https://doi.org/10.1007/s00467-023-06074-x

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  • DOI: https://doi.org/10.1007/s00467-023-06074-x

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