, Volume 46, Issue 2, pp 187–195 | Cite as

Primary hyperoxaluria in populations of Pakistan origin: results from a literature review and two major registries

  • Jamsheer Jehangir Talati
  • Sally-Anne Hulton
  • Sander F. Garrelfs
  • Wajahat Aziz
  • Shoaib Rao
  • Amanullah Memon
  • Zafar Nazir
  • Raziuddin Biyabani
  • Saqib Qazi
  • Iqbal Azam
  • Aysha Habib Khan
  • Jamil Ahmed
  • Lena Jafri
  • Mohammad Zeeshan


Primary hyperoxalurias (PH) are devastating, autosomal recessive diseases causing renal stones. Undifferentiated hyperoxaluria is seen in up to 43% of Pakistani paediatric stone patients. High rates of consanguinity in Pakistan suggest significant local prevalence. There is no detailed information regarding number of cases, clinical features, and genetics in Pakistan-origin (P-o) patients. We reviewed available information on P-o PH patients recorded in the literature as well as from two major PH registries (the Rare Kidney Stone Consortium PH Registry (RKSCPHR) and the OxalEurope PH Registry (OxER); and the Aga Khan University Hospital in Pakistan. After excluding overlaps, we noted 217 P-o PH subjects (42 in OxER and 4 in RKSCPHR). Presentations were protean. Details of mutations were available for 94 patients of 201 who had genetic analyses. Unique mutations were noted. Mutation [c.508G>A (p. Gly170Arg)] (present in up to 25% in the West) was reported in only one case. In one series, only 30% had mutations on exons 1,4,7 of AGXT. Of 42 P-o patients in OxER, 52.4% were PH1, 45.2% PH2, and 2.4% PH3. Of concern is that diagnosis was made after renal transplant rejection (four cases) and on bone-marrow aspiration (in five). Lack of consideration of PH as a diagnosis, late diagnosis, and loss of transplanted kidneys mandates that PH be searched for diligently. Mutation analysis will need to extend to all exons and include PH 1,2,3. There is a need to spread awareness and identify patients through a scoring or screening system that alerts physicians to consider a diagnosis of PH.


Primary hyperoxaluria Consanguinity Oxalate stones Oxalosis End-stage renal disease Pakistan origin Oxalate crystals Mutation analysis 



We acknowledge the support and valued critique of earlier drafts of this paper by Professor Dawn S Milliner, Director, Rare Kidney Stone Consortium, and principal investigator, Primary Hyperoxaluria group, Mayo Clinic Hyperoxaluria Center, Rochester. We acknowledge with gratitude the contribution of data from the OxalEurope registry (see and the sharing of laboratory data by Farooq Ghani, M.B.B.S., M.S., Ph.D., FACB, Diplomate American Board, Service Chief & Director Clinical Laboratories, Associate Professor, Department of Pathology, Aga Khan University.

Compliance with ethical standards

Conflict of interest

All authors have declared that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


This study has not received any grant funding.


  1. 1.
    The News correspondent (2015) Sukkur has become a ‘red zone’ with regards to Kidney diseases: Dr Adib. Dawn. Accessed 26 Sept 2016
  2. 2.
    Rizvi SA, Sultan S, Zafar MN, Ahmed B, Faiq SM, Hossain KZ, Naqvi SA (2007) Evaluation of children with urolithiasis. Indian J Urol 23(4):420CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cochat P, Nogueira PCK, Mahmoud MA, Jamieson NV, Scheinman JI, Rolland M-O (1999) Primary hyperoxaluria in infants: medical, ethical, and economic issues. J Pediatr 135(6):746–750CrossRefPubMedGoogle Scholar
  4. 4.
    Spasovski G, Beck BB, Blau N, Hoppe B, Tasic V (2010) Late diagnosis of primary hyperoxaluria after failed kidney transplantation. Int Urol Nephrol 42(3):825–829CrossRefPubMedGoogle Scholar
  5. 5.
    Hashmi M (1997) Frequency of consanguinity and its effect on congenital malformation-a hospital based study. J Pakistan Med Assoc 47:75–77Google Scholar
  6. 6.
    Kamoun A, Lakhoua R (1996) End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol 10(4):479–482CrossRefPubMedGoogle Scholar
  7. 7.
    Cochat P (1999) Primary hyperoxaluria type 1. Kidney Int 55(6):2533–2547CrossRefPubMedGoogle Scholar
  8. 8.
    Khaliq S, Abid A, Shahid S, Hashmi S, Sultan S, Aziz T, Rizvi SAH, Mehdi SQ (2013) Comprehensive mutation screening of the AGXT gene in patients with primary hyperoxaluria type-1. Paper presented at the 63rd annual meeting of the American Society of Human Genetics, BostonGoogle Scholar
  9. 9.
    Sajid R, Moiz B, Adil S, Khurshid M (2009) Calcium oxalate crystals in the bone marrow. Br J Haematol 146(1):1CrossRefPubMedGoogle Scholar
  10. 10.
    Johnson SA, Rumsby G, Cregeen D, Hulton S-A (2002) Primary hyperoxaluria type 2 in children. Pediatr Nephrol 17(8):597–601CrossRefPubMedGoogle Scholar
  11. 11.
    Illum N, Lavard L, Danpure C, Horn T, AErenlund JH, Skovby F (1991) Primary hyperoxaluria type 1: clinical manifestations in infancy and prenatal diagnosis. Child Nephrol Urol 12(4):225–227Google Scholar
  12. 12.
    Monico CG, Rossetti S, Belostotsky R, Cogal AG, Herges RM, Seide BM, Olson JB, Bergstrahl EJ, Williams HJ, Haley WE (2011) Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol 6(9):2289–2295CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chanchlani R, Sinha A, Gulati A, Agarwal V, Bagga A (2012) Common mutation underlying primary hyperoxaluria type1 in three Indian children. Indian J Nephrol 22(6):459CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    von Schnakenburg C, Rumsby G (1997) Identification of new mutations in primary hyperoxaluria type 1 (PH1). J Nephrol 11:15–17Google Scholar
  15. 15.
    von Schnakenburg C, Hulton SA, Milford DV, Roper HP, Rumsby G (1998) Variable presentation of primary hyperoxaluria type 1 in 2 patients homozygous for a novel combined deletion and insertion mutation in exon 8 of the AGXT gene. Nephron 78(4):485–488CrossRefGoogle Scholar
  16. 16.
    Chu W (2011) Case report renal and musculoskeletal manifestations of primary hyperoxaluria in a girl 女孩原發性高尿酸血症的腎臟及肌肉骨胳的臨床表現. HK J Paediatr 16(1):41–46Google Scholar
  17. 17.
    Perera MTP, Sharif K, Lloyd C, Foster K, Hulton SA, Mirza DF, McKiernan PJ (2011) Pre-emptive liver transplantation for primary hyperoxaluria (PH-I) arrests long-term renal function deterioration. Nephrol Dial Transpl 26(1):354–359CrossRefGoogle Scholar
  18. 18.
    Takayama T, Takaoka N, Nagata M, Johnin K, Okada Y, Tanaka S, Kawamura M, Inokuchi T, Ohse M, Kuhara T (2014) Ethnic differences in GRHPR mutations in patients with primary hyperoxaluria type 2. Clin Genet 86(4):342–348CrossRefPubMedGoogle Scholar
  19. 19.
    Williams EL, Acquaviva C, Amoroso A, Chevalier F, Coulter-Mackie M, Monico CG, Giachino D, Owen T, Robbiano A, Salido E (2009) Mutation update. Hum Mutat 30:910–917CrossRefPubMedGoogle Scholar
  20. 20.
    Harambat J, Fargue S, Acquaviva C, Gagnadoux M-F, Janssen F, Liutkus A, Mourani C, Macher M-A, Abramowicz D, Legendre C (2010) Genotype–phenotype correlation in primary hyperoxaluria type 1: the p. Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int 77(5):443–449CrossRefPubMedGoogle Scholar
  21. 21.
    Mandrile G, van Woerden CS, Berchialla P, Beck BB, Bourdain CA, Hulton S-A, Rumsby G (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(6):1197–1204CrossRefPubMedGoogle Scholar
  22. 22.
    Coulter-Mackie MB, Rumsby G (2004) Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis. Mol Genet Metab 83(1):38–46CrossRefPubMedGoogle Scholar
  23. 23.
    Danpure CJ (2005) Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transpl 20(8):1525–1529CrossRefGoogle Scholar
  24. 24.
    Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, Lieske JC, Milliner DS, Harris PC, Consortium RKS (2015) Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol 26(10):2559–70. doi: 10.1681/ASN.2014070698
  25. 25.
    Beck BB, Baasner A, Buescher A, Habbig S, Reintjes N, Kemper MJ, Sikora P, Mache C, Pohl M, Stahl M, Toenshoff B, Pape L, Fehrenbach H, Jacob DE, Grohe B, Wolf MT, Nürnberg G, Yigit G, Salido EC, Hoppe B (2013) Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies. Eur J Hum Genet 21(2):162–172. doi: 10.1038/ejhg.2012.139 CrossRefPubMedGoogle Scholar
  26. 26.
    Hutchesson A, Bundey S, Preece M, Hall S, Green A (1998) A comparison of disease and gene frequencies of inborn errors of metabolism among different ethnic groups in the West Midlands, UK. J Med Genet 35(5):366–370CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Darr A, Modell B (1988) The frequency of consanguineous marriage among British Pakistanis. J Med Genet 25(3):186–190CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bittles AH (2001) Consanguinity and its relevance to clinical genetics. Clin Genet 60(2):89–98CrossRefPubMedGoogle Scholar
  29. 29.
    Overall A, Ahmad M, Nichols R (2002) The effect of reproductive compensation on recessive disorders within consanguineous human populations. Heredity 88(6):474–479CrossRefPubMedGoogle Scholar
  30. 30.
    Liebow A, Li X, Racie T, Hettinger J, Bettencourt BR, Najafian N, Haslett P, Fitzgerald K, Holmes RP, Erbe D, Querbes W, Knight 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. doi: 10.1681/ASN.2016030338 CrossRefPubMedGoogle Scholar
  31. 31.
    Gambaro G, Ferraro MP, D’Addessi A (2011) Ayurvedic medicine and NADPH oxidase: a possible approach to the prevention of ESRD in hyperoxaluria. Nephrol Dial Transpl 26(6):1759–1761CrossRefGoogle Scholar
  32. 32.
    Naderi G, Tabassomi F, Latif A, Ganji M (2015) Primary hyperoxaluria type 1 diagnosed after kidney transplantation: the importance of pre-transplantation metabolic screening in recurrent urolithiasis. Saudi J Kidney Dis Transpl 26(4):783CrossRefPubMedGoogle Scholar
  33. 33.
    Clifford-Mobley O, Hewitt L, Rumsby G (2016) Simultaneous analysis of urinary metabolites for preliminary identification of primary hyperoxaluria. Ann Clin Biochem 53(4):485–494CrossRefPubMedGoogle Scholar
  34. 34.
  35. 35.
    Alsuwaida A, Hayat A, Alwakeel JS (2007) Oxalosis presenting as early renal allograft failure. Saudi J Kidney Dis Transpl 18(2):253PubMedGoogle Scholar
  36. 36.
    Hassan K, Qaisrani JH, Qazi H, Naseem L, Zaheer HA, Zafar T (2006) Oxalosis in the bone and bone marrow. Int J Pathol 4(2):129–131Google Scholar
  37. 37.
    Tang X, Bergstralh EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske JC (2015) Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria. Kidney Int 87(3):623–631CrossRefPubMedGoogle Scholar
  38. 38.
    Ehsan A, Lone A, Sabir O, Riaz S, Tareef N, Tanvir I (2015) Refractory anemia with Hyperoxaluria. J Adv Plant Biol 1(1):1–5. Accessed 26 June 2017
  39. 39.
    Raza F, Hussain CA, Khan SA, Saeed H, Ayyub M (2016) Crystalline bone marrow in young lady Pakistan Society of Hematology Newsletter 10(1):7–12. Accessed 26 June 2017

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Jamsheer Jehangir Talati
    • 1
  • Sally-Anne Hulton
    • 2
  • Sander F. Garrelfs
    • 3
  • Wajahat Aziz
    • 1
  • Shoaib Rao
    • 1
  • Amanullah Memon
    • 1
  • Zafar Nazir
    • 1
  • Raziuddin Biyabani
    • 1
  • Saqib Qazi
    • 1
  • Iqbal Azam
    • 4
  • Aysha Habib Khan
    • 5
  • Jamil Ahmed
    • 1
  • Lena Jafri
    • 5
  • Mohammad Zeeshan
    • 6
  1. 1.Department of Surgery (Urology)Aga Khan UniversityKarachiPakistan
  2. 2.Department of NephrologyBirmingham Children’s Hospital NHS Foundation TrustBirminghamUK
  3. 3.Department of Pediatric Nephrology, Emma Children’s HospitalAcademic Medical Center (AMC)AmsterdamThe Netherlands
  4. 4.Department of Community Health SciencesAga Khan UniversityKarachiPakistan
  5. 5.Department of Pathology and Laboratory MedicineAga Khan UniversityKarachiPakistan
  6. 6.Department of MicrobiologyAga Khan UniversityKarachiPakistan

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