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Nutcracker syndrome: a potentially underdiagnosed cause of proteinuria in children with familial Mediterranean fever

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Abstract

Introduction

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease with an increased risk for secondary amyloidosis. Since lifelong colchicine has been the treatment of choice that prevents renal amyloidosis, non-amyloid kidney diseases are more frequently considered in the differential diagnosis of proteinuria. Nutcracker syndrome (NCS) can be one of the confounding causes. This long-term retrospective study aimed to evaluate the causes of proteinuria in a pediatric cohort of patients with FMF and discuss changing trends in recent years .

Methods

Demographic, clinic, and laboratory data were extracted from electronic medical records of patients with FMF. All urine tests of the study population were reviewed. Patients were evaluated for persistent proteinuria and grouped according to the etiology of proteinuria.

Results

A total of 576 patients with FMF were identified with a mean follow-up of 6.3 years in the last 10 years; 8% had persistent proteinuria. The etiology was NCS in 67.5% of the patients with proteinuria, and renal amyloidosis was less commonly encountered (15%) without any new diagnosis for the last 8 years. Non-amyloid kidney diseases were also diagnosed in 17.5% of the patients. Patients with NCS had significantly lower BMI than other patients in the cohort and less subclinical inflammation, higher hemoglobin concentration, and milder levels of proteinuria with normal serum albumin and eGFR than other patients with proteinuria.

Conclusion

Nutcracker syndrome is the leading cause of proteinuria in children with FMF nowadays, and it should be kept in mind during the evaluation of proteinuria in these patients.

Graphical Abstract

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Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

References

  1. Ben-Chetrit E, Levy M (1998) Familial Mediterranean fever. Lancet 351:659–664. https://doi.org/10.1016/S0140-6736(97)09408-7

    Article  CAS  PubMed  Google Scholar 

  2. Schnappauf O, Chae JJ, Kastner DL, Aksentijevich I (2019) The Pyrin Inflammasome in Health and Disease. Front Immunol 10:1745. https://doi.org/10.3389/fimmu.2019.01745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chae JJ, Cho YH, Lee GS, Cheng J et al (2011) Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1β Activation and severe autoinflammation in mice. Immunity 34:755–768. https://doi.org/10.1016/j.immuni.2011.02.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Goldfinger SE (1972) Colchicine for Familial Mediterranean Fever. N Engl J Med 287:1302. https://doi.org/10.1056/NEJM197212212872514

    Article  CAS  PubMed  Google Scholar 

  5. Özkaya N, Yalçinkaya F (2003) Colchicine treatment in children with familial Mediterranean fever. Clin Rheumatol 22:314–317. https://doi.org/10.1007/s10067-003-0739-9

    Article  PubMed  Google Scholar 

  6. Peleg H, Ben-Chetrit E (2013) The kidney in Familial Mediterranean fever. J Rheumatol 40:1948–1950. https://doi.org/10.3899/jrheum.131135

    Article  CAS  PubMed  Google Scholar 

  7. Kukuy O, Livneh A, Ben-David A, Kopolovic J et al (2013) Familial Mediterranean fever (FMF) with proteinuria: clinical features, histology, predictors, and prognosis in a cohort of 25 patients. J Rheumatol 40:2083–2087. https://doi.org/10.3899/jrheum.130520

    Article  CAS  PubMed  Google Scholar 

  8. Tekin M, Yalçinkaya F, Tümer N, Cakar N et al (1999) Familial Mediterranean fever - renal involvement by diseases other than amyloid. Nephrol Dial Transplant 14:475–479. https://doi.org/10.1093/ndt/14.2.475

    Article  CAS  PubMed  Google Scholar 

  9. Park SJ, Lim JW, Cho B-S, Yoon TJ, Oh JH (2002) Nutcracker syndrome in children with orthostatic proteinuria: diagnosis on the basis of Doppler sonography. J Ultrasound Med 21:39–45

    Article  Google Scholar 

  10. Fitoz S, Ekim M, Ozcakar ZB, Elhan AH, Yalcinkaya F (2007) Nutcracker syndrome in children: the role of upright position examination and superior mesenteric artery angle measurement in the diagnosis. J Ultrasound Med 26:573–580. https://doi.org/10.7863/jum.2007.26.5.573

    Article  PubMed  Google Scholar 

  11. Mazzoni MBM, Kottanatu L, Simonetti GD, Ragazzi M et al (2011) Renal vein obstruction and orthostatic proteinuria: a review. Nephrol Dial Transplant 26:562–565. https://doi.org/10.1093/ndt/gfq444

    Article  PubMed  Google Scholar 

  12. Ozcakar ZB, Kadioglu G, Siklar Z, Kavaz A et al (2010) The effect of colchicine on physical growth in children with familial mediterranean fever. Eur J Pediatr 169:825–828. https://doi.org/10.1007/s00431-009-1120-z

    Article  CAS  PubMed  Google Scholar 

  13. Deger SM, Karakaya F, Derici U, Arinsoy T, Sindel S (2010) Proteinuria-associated nutcracker syndrome: an amyloid-negative familial Mediterranean fever patient. NDT Plus 3:599–600. https://doi.org/10.1093/ndtplus/sfq169

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ozcan A, Gonul II, Sakallioglu O, Oztas E (2009) Nutcracker syndrome in a child with familial Mediterranean fever (FMF) disease: renal ultrastructural features. Int Urol Nephrol 41:1047–1053. https://doi.org/10.1007/s11255-008-9500-2

    Article  PubMed  Google Scholar 

  15. Yalcinkaya F, Ozen S, Ozcakar ZB, Aktay N et al (2009) A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology 48:395–398. https://doi.org/10.1093/rheumatology/ken509

    Article  PubMed  Google Scholar 

  16. CDC Growth Charts. http://www.cdc.gov/growthcharts/

  17. Tunca M, Kirkali G, Soyturk M, Akar S, Pepys MB, Hawkins PN (1999) Acute phase response and evolution of familial Mediterranean fever. Lancet 353:1415

    Article  CAS  Google Scholar 

  18. Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A, Ingelfinger J (2000) Evaluation and management of proteinuria and nephrotic syndrome in children : recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). Pediatrics 105:1242–1249

    Article  CAS  Google Scholar 

  19. Flynn JT, Falkner BE (2017) New clinical practice guideline for the management of high blood pressure in children and adolescents. Hypertension 70:683–686. https://doi.org/10.1161/HYPERTENSIONAHA.117.10050

    Article  CAS  PubMed  Google Scholar 

  20. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New Equations to Estimate GFR in Children with CKD. J Am Soc Nephrol 20:629–637. https://doi.org/10.1681/ASN.2008030287

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gattorno M, Hofer M, Federici S, Vanoni F et al (2019) Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 78:1025–1032. https://doi.org/10.1136/annrheumdis-2019-215048

    Article  CAS  PubMed  Google Scholar 

  22. Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M et al (2007) Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum 56:1706–1712. https://doi.org/10.1002/art.22507

    Article  PubMed  Google Scholar 

  23. Said R, Hamzeh Y, Said S, Tarawneh M, Al-Khateeb M (1992) Spectrum of renal involvement in familial Mediterranean fever. Kidney Int 41:414–419. https://doi.org/10.1038/ki.1992.57

    Article  CAS  PubMed  Google Scholar 

  24. Akpolat T, Akpolat I, Karagoz F, Yilmaz E, Kandemir B, Ozen S (2004) Familial Mediterranean fever and glomerulonephritis and review of the literature. Rheumatol Int 24:43–45. https://doi.org/10.1007/s00296-003-0329-9

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Rheumatology, Faculty of Medicine, Ankara University, Ankara, Turkey

    Pinar Ozge Avar-Aydin, Zeynep Birsin Ozcakar, Nilgun Cakar, Hatice Dilara Karakas & Fatos Yalcinkaya

  2. Department of Pediatric Radiology, Faculty of Medicine, Ankara University, Ankara, Turkey

    Suat Fitoz

Authors
  1. Pinar Ozge Avar-Aydin
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  2. Zeynep Birsin Ozcakar
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  3. Nilgun Cakar
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  4. Suat Fitoz
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  5. Hatice Dilara Karakas
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  6. Fatos Yalcinkaya
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Correspondence to Fatos Yalcinkaya.

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The study was approved by the Human Research Ethics Committee of Ankara University Faculty of Medicine (i8-540–20).

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Avar-Aydin, P.O., Ozcakar, Z.B., Cakar, N. et al. Nutcracker syndrome: a potentially underdiagnosed cause of proteinuria in children with familial Mediterranean fever. Pediatr Nephrol 37, 1615–1621 (2022). https://doi.org/10.1007/s00467-021-05337-9

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  • DOI: https://doi.org/10.1007/s00467-021-05337-9

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