Abstract
Autosomal recessive disorders are prevalent in Pakistan, a developing South Asian country where consanguineous marriages are common. This study seeks to determine the prevalence of monogenic causes in children presenting with nephrocalcinosis and nephrolithiasis at a dialysis and transplant center in Karachi, Pakistan. A retrospective analysis was conducted in children aged 1–18 years presenting with nephrocalcinosis, between 2010 and 2019. Demographic information, clinical profile, laboratory parameters and stone analysis were collected, on a pre-designed questionnaire. One hundred and twenty-six children were included, with 11 and 3 diagnosed with renal tubular acidosis and Bartter’s syndrome respectively. Next-generation sequencing and Sanger sequencing was performed on 112 children. Eighty-seven patients were diagnosed with primary hyperoxaluria, with mutations in alanine–glyoxylate-aminotransferase gene found in 73, followed by glyoxylate reductase/hydroxy-pyruvate reductase in 13, and 4-hydroxy-2-oxaloglutarate aldolase in 1. Twenty-five patients reported negative for mutations. Sixty-four percent were males, with a statistically significant difference (p < 0.05). History of parental consanguineous marriage was found in 98% of the cohort. Fifty-four and 40 patients presented to the clinic with Chronic Kidney Disease Stage 1 and Stage 5, respectively, with a statistically significant difference p = 0.007. Mutations noted in our cohort are different and more severe than those reported in the developed world. The disease poses a major disease burden in developing world context with the only treatment option of combined liver–kidney transplantation not available in Pakistan.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The data underlying this article cannot be shared publicly to protect confidentiality of individual participants but will be shared on reasonable request to the corresponding author.
References
Braun DA, Hildebrandt F (2016) Prevalence of monogenic causes in pediatric patients with nephrolithiasis and nephrocalcinosis. Clin J Am Soc Nephrol 11:664–672
Giovanna P (2017) Understanding the pathophysiology of Nephrocalcinosis. IntechOpen
Hunter DJ, Lange M (2002) Genetic contribution to renal function and electrolyte balance: a twin study. Clin Sci (London) 103:259–265
Goldfarb DS, Fischer ME, Keich Y, Goldberg J (2005) A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. Kidney Int 67:1053–1061
Milliner DS (2015) Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria. Kidney Int 87:623–631
Belostotsky R, Seboun E, Idelson GH, Milliner DS, Becker-Cohen R, Rinat C, Monico CG, Feinstein S, Ben-Shalom E, Magen D, Weissman I (2010) Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am J Hum Genet 87(3):392–399
Soliman NA, Nabhan MM, Abdelrahman SM (2017) Clinical spectrum of primary hyperoxaluria type1. Experience of a tertiary care center. Nephrol Ther 13(3):176–182
Hoppe B, Latta K, von Schnakenburg C (2005) Primary hyperoxaluria-the german experience. Am J Nephrol 25:276–281
Frishberg Y, Rinat C, Rumsby G (2005) Intra-Familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel. Am J Nephrol 25:269–275
Rizvi SA, Sultan S et al (2016) Pediatric urolithiasis in emerging economies. Int J Surg 36:705–712
Talati JJ, Hulton S-A, Garrelfs S, Aziz W (2018) Primary hyperoxaluria in population of Pakistan origin: result from a literature review and two major registries. Urolithiasis 46:187–195
Amar A, Majmundar AJ, Ullah I, Afzal A, Hildebrandt F (2019) Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis. Human Genet 138(3):211–219
Habbig S, Bernd H et al (2011) Nephrocalcinosis and urolithiasis in children. Kidney Int 80:1278–1291
Halbritter J, Michelle B, Hildebrandt F (2015) Fourteen monogenic genes account for 15% of nephrolithiasis /nephrocalcinosis. J Am Soc Nephrol 26(3):543–551
Shekhani SS, Lanewala AA (2021) Ethical challenges in dialysis and transplantation: perspectives from the developing world. Semin Nephrol 41(3):211–219
Lanewala AA, Shekhani SS (2022) Indirect costs associated with “free” paediatric hemodialysis: experience from Karachi Pakistan. Indian J Med Ethics. https://doi.org/10.20529/IJME.2022.006
Cousin Marriage playing havoc with health in Pakistan. The News, International, November 6, 2021. https://www.thenews.com.pk/print/906418-cousin-marriage-playing-havoc-with-health-in-pakistan
Hunte PA, Sultana F (1992) Health-seeking behavior and the meaning of medications in Balochistan, Pakistan. Soc Sci Med 34:1385–1397. https://doi.org/10.1016/0277-9536(92)90147-I
Hamamy H (2012) Consanguineous marriages. Preconception consultation in primary healthcare settings. J Community Genet 3(3):185–192
Gargah T, Khelil N, Youssef G (2011) Primary hyperoxaluria type1 in Tunisian children. Tunis Med 89:163–167
Harambat J, Fargue S, Acquaviva C, Cochat P (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
Rumsby G, Williams E, Coulter-Mackie M (2004) Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int 66:959–963
Milosevic D, Rinat C, Batinic D, Frishberg Y (2002) Genetic analysis—a diagnostic tool for primary hyperoxaluria type 1. Pediatric Nephrol 17:896–898
Milliner DS, Wilson DM, Smith LH (2001) Phenotypic expression of primary hyperoxaluria: comparative features of type 1 and 2. Kidney Int 59:31–36
Liebow A, Li X, Racie T, Hettinger J (2017) An investigational RNAi therapeutic targeting glycolate oxidase reduces oxalate production in models of primary hyperoxaluria. J Am Soc Nephrol 28(2):494–503
Gambaro G, Ferraro MP (2011) Ayurvedic medicine and NADPH oxidase: a possible approach to the prevention of ESRD in hyperoxaluria. Nephrol Dial Transpl 26(6):1759–1761
Acknowledgements
We are thankful to the patients and their families for their active participation. In addition, we would like to thank Ms. Dhanwanti Dileep and Mr. Iqbal Mujtaba from the Department of Epidemiology and Statistics, SIUT. We are also grateful to Dr. Faiz Rasool for his contribution in analyzing our results.
Author information
Authors and Affiliations
Contributions
SH: conceptualized, designed the study, collected data, and wrote the manuscript. AA: performed genetic testing. SS: helped in data collection. SS: revised and edited the paper. AL: helped in data collection. MN Zafar: supervised the study.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All the authors have seen the manuscript and approved its submission to your journal. This study was approved by our institutional review board and was performed in accordance with the ethical standards laid down in the 1964 declaration of Helsinki and its later amendments.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Hashmi, S., Abid, A., Sultan, S. et al. Primary hyperoxaluria and genetic linkages: an insight into the disease burden from Pakistan. Urolithiasis 50, 439–445 (2022). https://doi.org/10.1007/s00240-022-01338-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00240-022-01338-x