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Clinical features and outcomes of patients with diacylglycerol kinase epsilon nephropathy: a nationwide experience

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Abstract

Background

Thrombotic microangiopathy (TMA) is usually caused due to dysregulation of the alternative complement pathway. Rarely, thrombotic microangiopathy is caused by non-complement mediated mutations in diacylglycerol kinase epsilon (DGKE); information about therapy and outcome of these patients is limited.

Methods

Medical records of patients, younger than 18 years, diagnosed with TMA and variants in DGKE were reviewed to include 12 patients from seven centers. Genetic studies included targeted exome sequencing and multiplex-ligation dependent probe amplification of CFH-CFHR5.

Results

Patients presented at a median age of 11 (7.5, 12.3) months; all were younger than 2 years. All patients had an infectious prodrome; enteroinvasive, enteropathogenic, and enterotoxigenic Escherichia coli were detected in two patients with diarrhea. Chief features included those of microangiopathic hemolysis (n = 11), microscopic hematuria (n = 10), nephrotic range proteinuria (n = 10), hypoalbuminemia (n = 6), elevated total cholesterol (n = 6), and hypocomplementemia (n = 4). Histopathology showed thrombotic microangiopathy (n = 4), overlapping with membranoproliferative pattern of injury (n = 1). At median 3.3 years of follow-up, significant hypertension and/or proteinuria (40%), relapses (66.7%), and death or progression to CKD (60%) were common. Genetic sequencing showed 13 homozygous and compound heterozygous variants (7 pathogenic, 3 likely pathogenic) located throughout DGKE; 11 variants were novel.

Conclusions

This case series highlights the need to suspect DGKE nephropathy in young patients with TMA, especially those with severe proteinuria. Medium-term outcomes are unsatisfactory with risk of relapses, progressive kidney failure, and death.

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Funding

Funding support by the Indian Council of Medical Research (Advanced Center for Research in Pediatric Kidney Diseases; 5/7/1090/2013-RHN and 5/4/7–18/Nephro/2020-NCDII).

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Authors and Affiliations

  1. Department of Pediatrics, Division of Nephrology, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, 110029, India

    Priyanka Khandelwal, Sharan Thangaraju, Pankaj Hari, Aditi Sinha & Arvind Bagga

  2. Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, India

    Sriram Krishnamurthy

  3. Department of Pediatrics, Bai Jerbai Wadia Hospital and Institute of Child Health, Mumbai, India

    Alpana Ohri

  4. Department of Pediatric Nephrology, St. Johns Medical College and Hospital, Bengaluru, India

    Priya Pais

  5. Department of Pediatrics, Christian Medical College, Vellore, India

    Georgie Mathew

  6. Department of Pediatrics, King Edward Memorial Hospital, Pune, India

    Jyoti Sharma

  7. Department of Pediatrics, Army Hospital Research and Referral, New Delhi, India

    Aditi Sharma

  8. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

    Geetika Singh

Authors
  1. Priyanka Khandelwal
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  2. Sharan Thangaraju
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  8. Aditi Sharma
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  9. Pankaj Hari
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  10. Aditi Sinha
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  11. Geetika Singh
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  12. Arvind Bagga
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Correspondence to Arvind Bagga.

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Khandelwal, P., Thangaraju, S., Krishnamurthy, S. et al. Clinical features and outcomes of patients with diacylglycerol kinase epsilon nephropathy: a nationwide experience. Pediatr Nephrol 38, 3009–3016 (2023). https://doi.org/10.1007/s00467-023-05939-5

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  • DOI: https://doi.org/10.1007/s00467-023-05939-5

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