Skip to main content

Advertisement

SpringerLink
Log in

Drug-induced tubulointerstitial nephritis: hypersensitivity and necroinflammatory pathways

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

More than 250 drugs carry a small but important dose-independent risk of initiating a delayed-type hypersensitivity reaction that leads to acute tubulointerstitial nephritis (TIN). Clinical manifestations are often non-specific, making epidemiological studies challenging. In severe cases, if cessation of the offending drug is not followed by a prompt improvement in renal function, corticosteroid therapy appears to enhance renal recovery rates. Other drugs, classified as potential nephrotoxins, may induce dose-dependent acute tubular necrosis. Studies over the past decade have identified a unique form of tubular cell death called “necroptosis” that is accompanied by a specific and significant interstitial inflammatory response to certain insults, including some nephrotoxins. Insights into the molecular basis of this necroinflammatory pathway have emerged. There is still a paucity of pediatric data on these two distinct types of drug-induced TIN. Early recognition is essential to minimize the risk of chronic kidney damage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Nast CC (2017) Medication-induced interstitial nephritis in the 21st century. Adv Chronic Kidney Dis 24:72–79

    PubMed  Google Scholar 

  2. Perazella MA, Markowitz GS (2010) Drug-induced acute interstitial nephritis. Nat Rev Nephrol 6:461–470

    CAS  PubMed  Google Scholar 

  3. Paueksakon P, Fogo AB (2017) Drug-induced nephropathies. Histopathology 70:94–108

    PubMed  Google Scholar 

  4. Baker RJ, Pusey CD (2004) The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant 19:8–11

    PubMed  Google Scholar 

  5. Valluri A, Hetherington L, McQuarrie E, Fleming S, Kipgen D, Geddes CC, Mackinnon B, Bell S (2015) Acute tubulointerstitial nephritis in Scotland. QJM 108:527–532

    CAS  PubMed  Google Scholar 

  6. Howell M, Sebire NJ, Marks SD, Tullus K (2016) Biopsy-proven paediatric tubulointerstitial nephritis. Pediatr Nephrol 31:1625–1630

    PubMed  Google Scholar 

  7. Joyce E, Glasner P, Ranganathan S, Swiatecka-Urban A (2017) Tubulointerstitial nephritis: diagnosis, treatment, and monitoring. Pediatr Nephrol 32:577–587

    PubMed  Google Scholar 

  8. Praga M, Gonzalez E (2010) Acute interstitial nephritis. Kidney Int 77:956–961

    PubMed  Google Scholar 

  9. Fletcher A (2008) Eosinophiluria and acute interstitial nephritis. N Engl J Med 358:1760–1761

    CAS  PubMed  Google Scholar 

  10. Muriithi AK, Nasr SH, Leung N (2013) Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol 8:1857–1862

    PubMed  PubMed Central  Google Scholar 

  11. Lusica M, Rondon-Berrios H, Feldman L (2017) Urine eosinophils for acute interstitial nephritis. J Hosp Med 12:343–345

    PubMed  Google Scholar 

  12. Jahnukainen T, Ala-Houhala M, Karikoski R, Kataja J, Saarela V, Nuutinen M (2011) Clinical outcome and occurrence of uveitis in children with idiopathic tubulointerstitial nephritis. Pediatr Nephrol 26:291–299

    PubMed  Google Scholar 

  13. Robles NR, Lopez-Gomez J, Garcia-Pino G, Ferreira F, Alvarado R, Sanchez-Casado E, Cubero JJ (2014) Use of alpha1-microglobulin for diagnosing chronic interstitial nephropathy. Clin Exp Med 14:315–320

    CAS  PubMed  Google Scholar 

  14. Verghese PS, Luckritz KE, Eddy AA (2016) Interstitial nephritis in children. In: Geary DF, Schaefer F (eds) Pediatric kidney disease. Springer-Verlag, Heidelberg, pp 1013–1036

    Google Scholar 

  15. Raghavan R, Shawar S (2017) Mechanisms of drug-induced interstitial nephritis. Adv Chronic Kidney Dis 24:64–71

    PubMed  Google Scholar 

  16. Dibek Misirlioglu E, Guvenir H, Bahceci S, Haktanir Abul M, Can D, Usta Guc BE, Erkocoglu M, Toyran M, Nacaroglu HT, Civelek E, Buyuktiryaki B, Ginis T, Orhan F, Kocabas CN (2017) Severe cutaneous adverse drug reactions in pediatric patients: a multicenter study. J Allergy Clin Immunol Pract 5:757–763

    PubMed  Google Scholar 

  17. Geevasinga N, Coleman PL, Webster AC, Roger SD (2006) Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol 4:597–604

    CAS  PubMed  Google Scholar 

  18. Buysen JG, Houthoff HJ, Krediet RT, Arisz L (1990) Acute interstitial nephritis: a clinical and morphological study in 27 patients. Nephrol Dial Transplant 5:94–99

    CAS  PubMed  Google Scholar 

  19. Rossert J (2001) Drug-induced acute interstitial nephritis. Kidney Int 60:804–817

    CAS  PubMed  Google Scholar 

  20. Moledina DG, Perazella MA (2017) Drug-induced acute interstitial nephritis. Clin J Am Soc Nephrol 12:2046–2049

    PubMed  PubMed Central  Google Scholar 

  21. Fernandez-Juarez G, Perez JV, Caravaca-Fontan F, Quintana L, Shabaka A, Rodriguez E, Gadola L, de Lorenzo A, Cobo MA, Oliet A, Sierra M, Cobelo C, Iglesias E, Blasco M, Galeano C, Cordon A, Oliva J, Praga M, Spanish Group for the Study of Glomerular Diseases (GLOSEN) (2018) Duration of treatment with corticosteroids and recovery of kidney function in acute interstitial nephritis. Clin J Am Soc Nephrol 13:1851–1858

    PubMed  PubMed Central  Google Scholar 

  22. Moledina DG, Perazella MA (2018) Treatment of drug-induced acute tubulointerstitial nephritis: the search for better evidence. Clin J Am Soc Nephrol 13:1785–1787

    PubMed  PubMed Central  Google Scholar 

  23. Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A (2018) Origin and consequences of necroinflammation. Physiol Rev 98:727–780

    CAS  PubMed  Google Scholar 

  24. Land W, Schneeberger H, Schleibner S, Illner WD, Abendroth D, Rutili G, Arfors KE, Messmer K (1994) The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation 57:211–217

    CAS  PubMed  Google Scholar 

  25. Linkermann A, Stockwell BR, Krautwald S, Anders HJ (2014) Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol 14:759–767

    CAS  PubMed  Google Scholar 

  26. Mulay SR, Linkermann A, Anders HJ (2016) Necroinflammation in kidney disease. J Am Soc Nephrol 27:27–39

    CAS  PubMed  Google Scholar 

  27. Xu Y, Ma H, Shao J, Wu J, Zhou L, Zhang Z, Wang Y, Huang Z, Ren J, Liu S, Chen X, Han J (2015) A role for tubular necroptosis in cisplatin-induced AKI. J Am Soc Nephrol 26:2647–2658

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Xu Y, Han J (2016) The necrosome in acute kidney injury. Semin Nephrol 36:199–207

    CAS  PubMed  Google Scholar 

  29. Mulay SR, Kumar SV, Lech M, Desai J, Anders HJ (2016) How kidney cell death induces renal necroinflammation. Semin Nephrol 36:162–173

    CAS  PubMed  Google Scholar 

  30. Liu BC, Tang TT, Lv LL, Lan HY (2018) Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int 93:568–579

    CAS  PubMed  Google Scholar 

  31. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119

    CAS  PubMed  Google Scholar 

  32. Kinsey GR, Sharma R, Okusa MD (2013) Regulatory T cells in AKI. J Am Soc Nephrol 24:1720–1726

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bonavia A, Singbartl K (2018) A review of the role of immune cells in acute kidney injury. Pediatr Nephrol 33:1629–1639

    PubMed  Google Scholar 

  34. Kelly KJ, Williams WW Jr, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, Bonventre JV (1996) Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 97:1056–1063

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kelly KJ, Meehan SM, Colvin RB, Williams WW, Bonventre JV (1999) Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int 56:922–931

    CAS  PubMed  Google Scholar 

  36. Li J, Liu CH, Xu DL, Gao B (2015) Clinicopathological significance of CD206-positive macrophages in patients with acute tubulointerstitial disease. Int J Clin Exp Pathol 8:11386–11392

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Greenberg JH, Zappitelli M, Devarajan P, Thiessen-Philbrook HR, Krawczeski C, Li S, Garg AX, Coca S, Parikh CR, TRIBE-AKI Consortium (2016) Kidney outcomes 5 years after pediatric cardiac surgery: the TRIBE-AKI study. JAMA Pediatr 170:1071–1078

    PubMed  PubMed Central  Google Scholar 

  38. Hayes W (2017) Stop adding insult to injury-identifying and managing risk factors for the progression of acute kidney injury in children. Pediatr Nephrol 32:2235–2243

    PubMed  PubMed Central  Google Scholar 

  39. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z (2017) Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int 91:1482–1494

    CAS  PubMed  Google Scholar 

  40. Yu F, Wu LH, Tan Y, Li LH, Wang CL, Wang WK, Qu Z, Chen MH, Gao JJ, Li ZY, Zheng X, Ao J, Zhu SN, Wang SX, Zhao MH, Zou WZ, Liu G (2010) Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system. Kidney Int 77:820–829

    PubMed  Google Scholar 

  41. Garneau AP, Riopel J, Isenring P (2015) Acute methotrexate-induced crystal nephropathy. N Engl J Med 373:2691–2693

    PubMed  Google Scholar 

  42. Mulay SR, Anders HJ (2016) Crystallopathies. N Engl J Med 374:2465–2476

    CAS  PubMed  Google Scholar 

  43. Mulay SR, Anders HJ (2017) Crystal nephropathies: mechanisms of crystal-induced kidney injury. Nat Rev Nephrol 13:226–240

    CAS  PubMed  Google Scholar 

  44. Minhas JS, Wickner PG, Long AA, Banerji A, Blumenthal KG (2016) Immune-mediated reactions to vancomycin: a systematic case review and analysis. Ann Allergy Asthma Immunol 116:544–553

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Luque Y, Louis K, Jouanneau C, Placier S, Esteve E, Bazin D, Rondeau E, Letavernier E, Wolfromm A, Gosset C, Boueilh A, Burbach M, Frere P, Verpont MC, Vandermeersch S, Langui D, Daudon M, Frochot V, Mesnard L (2017) Vancomycin-associated cast nephropathy. J Am Soc Nephrol 28:1723–1728

    PubMed  PubMed Central  Google Scholar 

  46. Sinha Ray A, Haikal A, Hammoud KA, Yu AS (2016) Vancomycin and the risk of AKI: a systematic review and meta-analysis. Clin J Am Soc Nephrol 11:2132–2140

    PubMed  PubMed Central  Google Scholar 

  47. Brodsky SV (2014) Anticoagulants and acute kidney injury: clinical and pathology considerations. Kidney Res Clin Pract 33:174–180

    PubMed  PubMed Central  Google Scholar 

  48. An JN, Ahn SY, Yoon CH, Youn TJ, Han MK, Kim S, Chin HJ, Na KY, Chae DW (2013) The occurrence of warfarin-related nephropathy and effects on renal and patient outcomes in korean patients. PLoS One 8:e57661

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Brodsky SV, Collins M, Park E, Rovin BH, Satoskar AA, Nadasdy G, Wu H, Bhatt U, Nadasdy T, Hebert LA (2010) Warfarin therapy that results in an international normalization ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease. Nephron Clin Pract 115:c142–c146

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kapoor KG, Bekaii-Saab T (2008) Warfarin-induced allergic interstitial nephritis and leucocytoclastic vasculitis. Intern Med J 38:281–283

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author acknowledges a research establishment grant from the British Columbia Children’s Hospital Research Institute and the University of British Columbia and support from the James & Annabel McCreary Chair in Pediatrics and the Hudson Family Hospital Chair in Pediatric Medicine. The artistic work of Dr. Jyaysi Desai, Moleculart (www.moleculart.org), for the production of Fig. 2 is appreciated.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of British Columbia and BC Children’s Hospital Research Institute, Vancouver, Canada

    Allison A. Eddy

  2. Department of Pediatrics, BC Children’s and Women’s Hospitals & Sunny Hill Health Centre, Provincial Health Services Authority, Room 2D15 – 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada

    Allison A. Eddy

Authors
  1. Allison A. Eddy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Allison A. Eddy.

Ethics declarations

Conflict of interest

The author declares that she has no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eddy, A.A. Drug-induced tubulointerstitial nephritis: hypersensitivity and necroinflammatory pathways. Pediatr Nephrol 35, 547–554 (2020). https://doi.org/10.1007/s00467-019-04207-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-019-04207-9

Keywords

Search

Navigation