The Renal Tubulointerstitial Compartment: Site of Nephrotoxin-Induced Injury
By:
Mark A. Perazella Section of Nephrology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut

VA Medical Center, West Haven, Connecticut

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  • 1.

    Kaissling B, Le Hir M: The renal cortical interstitium: Morphological and functional aspects. Histochem Cell Biol 130: 247262, 2008 PubMed

  • 2.

    Zeisberg M, Kalluri R: Physiology of the renal interstitium. Clin J Am Soc Nephrol 10: 18311840, 2015 PubMed

  • 3.

    Schiessl IM: The role of tubule-interstitial crosstalk in renal injury and recovery. Semin Nephrol 40: 216231, 2020 PubMed

  • 4.

    Perazella MA, Rosner MH: Drug-induced acute kidney injury. Clin J Am Soc Nephrol 17: 12201233, 2022 PubMed

  • 5.

    Perazella MA: Pharmacology behind common drug nephrotoxicities. Clin J Am Soc Nephrol 13: 18971908, 2018 PubMed

  • 6.

    Sekine A, Hidaka S, Moriyama T, Shikida Y, Shimazu K, Ishikawa E, et al: Cystic kidney diseases that require a differential diagnosis from autosomal dominant polycystic kidney disease (ADPKD). J Clin Med 11: 6528, 2022 10.3390/jcm11216528 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Lemley KV, Kriz W: Anatomy of the renal interstitium. Kidney Int 39: 370381, 1991 PubMed

  • 8.

    Brooks CR, Bonventre JV: KIM-1/TIM-1 in proximal tubular cell immune response. Oncotarget 6: 4405944060, 2015 PubMed

  • 9.

    Yee J, Kuncio GS, Neilson EG: Tubulointerstitial injury following glomerulonephritis. Semin Nephrol 11: 361366, 1991 PubMed

  • 10.

    Strutz F, Zeisberg M: Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol 17: 29922998, 2006 PubMed

  • 11.

    Schainuck LI, Striker GE, Cutler RE, Benditt EP: Structural-functional correlations in renal disease. II. The correlations. Hum Pathol 1: 631641, 1970 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Ortiz A, Ziyadeh FN, Neilson EG: Expression of apoptosis-regulatory genes in renal proximal tubular epithelial cells exposed to high ambient glucose and in diabetic kidneys. J Investig Med 45: 5056, 1997 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Ricardo SD, van Goor H, Eddy AA: Macrophage diversity in renal injury and repair. J Clin Invest 118: 35223530, 2008 PubMed

  • 14.

    Perazella MA: The role of mast cells in AIN: Friend, foe, bystander, or all of the above? Clin Nephrol 84: 123126, 2015 PubMed

  • 15.

    Soos TJ, Sims TN, Barisoni L, Lin K, Littman DR, Dustin ML, et al: CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int 70: 591596, 2006 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Praga M, González E: Acute interstitial nephritis. Kidney Int 77: 956961, 2010 PubMed

  • 17.

    Krüger T, Benke D, Eitner F, Lang A, Wirtz M, Hamilton-Williams EE, et al: Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis. J Am Soc Nephrol 15: 613621, 2004 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Zeisberg M, Neilson EG: Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 21: 18191834, 2010 PubMed

  • 19.

    Tanaka T, Nangaku M: Pathogenesis of tubular interstitial nephritis. Contrib Nephrol 169: 297310, 2011 PubMed

  • 20.

    Krishnan N, Perazella MA: Drug-induced acute interstitial nephritis: Pathology, pathogenesis, and treatment. Iran J Kidney Dis 9: 313, 2015 PubMed

  • 21.

    Chang C, Gershwin ME: Drugs and autoimmunity—a contemporary review and mechanistic approach. J Autoimmun 34: J266J275, 2010 PubMed

  • 22.

    Neilson EG: Pathogenesis and therapy of interstitial nephritis. Kidney Int 35: 12571270, 1989 PubMed

  • 23.

    Joh K, Aizawa S, Yamaguchi Y, Inomata I, Shibasaki T, Sakai O, et al: Drug-induced hypersensitivity nephritis: Lymphocyte stimulation testing and renal biopsy in 10 cases. Am J Nephrol 10: 222230, 1990 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Kelly CJ, Neilson EG: Contrasuppression in autoimmunity. Abnormal contrasuppression facilitates expression of nephritogenic effector T cells and interstitial nephritis in kdkd mice. J Exp Med 165: 107123, 1987 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Spanou Z, Keller M, Britschgi M, Yawalkar N, Fehr T, Neuweiler J, et al: Involvement of drug-specific T cells in acute drug-induced interstitial nephritis. J Am Soc Nephrol 17: 29192927, 2006 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Adam J, Pichler WJ, Yerly D: Delayed drug hypersensitivity: Models of T-cell stimulation. Br J Clin Pharmacol 71: 701707, 2011 PubMed

  • 27.

    McCluskey RT, Colvin RB: Immunologic aspects of renal tubular and interstitial diseases. Annu Rev Med 29: 191203, 1978 PubMed

  • 28.

    Kurts C: Dendritic cells: Not just another cell type in the kidney, but a complex immune sentinel network. Kidney Int 70: 412414, 2006 PubMed

  • 29.

    Rees A: Cross dendritic cells anger T cells after kidney injury. J Am Soc Nephrol 20: 35, 2009 PubMed

  • 30.

    Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Griffin MD: Antigen presentation by dendritic cells in renal lymph nodes is linked to systemic and local injury to the kidney. Kidney Int 68: 10961108, 2005 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Rogers NM, Ferenbach DA, Isenberg JS, Thomson AW, Hughes J: Dendritic cells and macrophages in the kidney: A spectrum of good and evil. Nat Rev Nephrol 10: 625643, 2014 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Perazella MA, Shirali AC: Immune checkpoint inhibitor nephrotoxicity: What do we know and what should we do? Kidney Int 97: 6274, 2020 PubMed

  • 33.

    Schwartz RH: A cell culture model for T lymphocyte clonal anergy. Science 248: 13491356, 1990 PubMed

  • 34.

    van Kooten C, Gerritsma JS, Paape ME, van Es LA, Banchereau J, Daha MR: Possible role for CD40-CD40L in the regulation of interstitial infiltration in the kidney. Kidney Int 51: 711721, 1997 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    de Haij S, Woltman AM, Trouw LA, Bakker AC, Kamerling SW, van der Kooij SW, et al: Renal tubular epithelial cells modulate T-cell responses via ICOS-L and B7-H1. Kidney Int 68: 20912102, 2005 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Starke A, Lindenmeyer MT, Segerer S, Neusser MA, Rüsi B, Schmid DM, et al: Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses. Kidney Int 78: 3847, 2010 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Waeckerle-Men Y, Starke A, Wüthrich RP: PD-L1 partially protects renal tubular epithelial cells from the attack of CD8+ cytotoxic T cells. Nephrol Dial Transplant 22: 15271536, 2007 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Schnyder B, Pichler WJ: Mechanisms of drug-induced allergy. Mayo Clin Proc 84: 268272, 2009 PubMed

  • 39.

    Gerhardt LMS, McMahon AP: Identifying common molecular mechanisms in experimental and human acute kidney injury. Semin Nephrol 42: 151286, 2022 10.1016/j.semnephrol.2022.10.012 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Hosohata K: Role of oxidative stress in drug-induced kidney injury. Int J Mol Sci 17: 1826, 2016 10.3390/ijms17111826 PubMed

  • 41.

    Ichimura T, Maier JA, Maciag T, Zhang G, Stevens JL: FGF-1 in normal and regenerating kidney: Expression in mononuclear, interstitial, and regenerating epithelial cells. Am J Physiol 269: F653F662, 1995 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 334: 14481460, 1996 PubMed

  • 43.

    Wallin A, Zhang G, Jones TW, Jaken S, Stevens JL: Mechanism of the nephrogenic repair response. Studies on proliferation and vimentin expression after 35S-1,2-dichlorovinyl-L-cysteine nephrotoxicity in vivo and in cultured proximal tubule epithelial cells. Lab Invest 66: 474484, 1992 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Witzgall R, Brown D, Schwarz C, Bonventre JV: Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest 93: 21752188, 1994 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Jang HR, Rabb H: Immune cells in experimental acute kidney injury. Nat Rev Nephrol 11: 88101, 2015 PubMed

  • 46.

    Eddy AA: Proteinuria and interstitial injury. Nephrol Dial Transplant 19: 277281, 2004 PubMed

  • 47.

    Harris RC, Neilson EG: Toward a unified theory of renal progression. Annu Rev Med 57: 365380, 2006 PubMed

  • 48.

    Rosivall L, Mirzahosseini S, Toma I, Sipos A, Peti-Peterdi J: Fluid flow in the juxtaglomerular interstitium visualized in vivo. Am J Physiol Renal Physiol 291: F1241F1247, 2006 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Ruggenenti P, Cravedi P, Remuzzi G: Mechanisms and treatment of CKD. J Am Soc Nephrol 23: 19171928, 2012 PubMed

  • 50.

    Kriz W, Hartmann I, Hosser H, Hähnel B, Kränzlin B, Provoost AP, et al: Tracer studies in the rat demonstrate misdirected filtration and peritubular filtrate spreading in nephrons with segmental glomerulosclerosis. J Am Soc Nephrol 12: 496506, 2001 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Kriz W, Hähnel B, Hosser H, Ostendorf T, Gaertner S, Kränzlin B, et al: Pathways to recovery and loss of nephrons in anti-Thy-1 nephritis. J Am Soc Nephrol 14: 19041926, 2003 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Neumann I, Birck R, Newman M, Schnülle P, Kriz W, Nemoto K, et al: SCG/Kinjoh mice: A model of ANCA-associated crescentic glomerulonephritis with immune deposits. Kidney Int 64: 140148, 2003 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Kriz W, LeHir M: Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 67: 404419, 2005 PubMed

  • 54.

    Abboud H, Henrich WL: Clinical practice. Stage IV chronic kidney disease. N Engl J Med 362: 5665, 2010 PubMed

  • 55.

    Zoja C, Benigni A, Remuzzi G: Cellular responses to protein overload: Key event in renal disease progression. Curr Opin Nephrol Hypertens 13: 3137, 2004 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Abbate M, Zoja C, Remuzzi G: How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17: 29742984, 2006 PubMed

  • 57.

    Tang S, Leung JC, Abe K, Chan KW, Chan LY, Chan TM, et al: Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo. J Clin Invest 111: 515527, 2003 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Wang Y, Chen J, Chen L, Tay YC, Rangan GK, Harris DC: Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J Am Soc Nephrol 8: 15371545, 1997 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Zoja C, Donadelli R, Colleoni S, Figliuzzi M, Bonazzola S, Morigi M, et al: Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kappa B activation. Kidney Int 53: 16081615, 1998 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Sanz AB, Santamaría B, Ruiz-Ortega M, Egido J, Ortiz A: Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol 19: 16341642, 2008 PubMed

  • 61.

    Periyasamy-Thandavan S, Jiang M, Schoenlein P, Dong Z: Autophagy: Molecular machinery, regulation, and implications for renal pathophysiology. Am J Physiol Renal Physiol 297: F244F256, 2009 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Erkan E, De Leon M, Devarajan P: Albumin overload induces apoptosis in LLC-PK(1) cells. Am J Physiol Renal Physiol 280: F1107F1114, 2001 PubMed

  • 63.

    Perazella MA: Clinical approach to diagnosing acute and chronic tubulointerstitial disease. Adv Chronic Kidney Dis 24: 5763, 2017 PubMed

  • 64.

    Basile DP, Bonventre JV, Mehta R, Nangaku M, Unwin R, Rosner MH, et al; ADQI XIII Work Group: Progression after AKI: Understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol 27: 687697, 2016 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Venkatachalam MA, Weinberg JM, Kriz W, Bidani AK: Failed tubule recovery, AKI-CKD transition, and kidney disease progression. J Am Soc Nephrol 26: 17651776, 2015 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66.

    Risdon RA, Sloper JC, De Wardener HE: Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet 2: 363366, 1968 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Schwartz MM, Fennell JS, Lewis EJ: Pathologic changes in the renal tubule in systemic lupus erythematosus. Hum Pathol 13: 534547, 1982 PubMed

  • 68.

    Gibyeli Genek D, Sahin OZ, Çakalağaoğlu F, Özen Yeniay P, Yavas H, Ersoy R, et al: Quantitative evaluation of interstitial fibrosis with Sirius Red in IgA nephritis. Ren Fail 36: 7377, 2014 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69.

    Bohle A, Mackensen-Haen S, von Gise H: Significance of tubulointerstitial changes in the renal cortex for the excretory function and concentration ability of the kidney: A morphometric contribution. Am J Nephrol 7: 421433, 1987 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70.

    Bohle A, Mackensen-Haen S, von Gise H, Grund KE, Wehrmann M, Batz C, et al: The consequences of tubulo-interstitial changes for renal function in glomerulopathies. A morphometric and cytological analysis. Pathol Res Pract 186: 135144, 1990 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71.

    Chevalier RL: The proximal tubule is the primary target of injury and progression of kidney disease: Role of the glomerulotubular junction. Am J Physiol Renal Physiol 311: F145F161, 2016 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72.

    Perazella MA, Herlitz LC: The crystalline nephropathies. Kidney Int Rep 6: 29422957, 2021 PubMed

  • 73.

    Brewster UC, Perazella MA: A review of chronic lead intoxication: An unrecognized cause of chronic kidney disease. Am J Med Sci 327: 341347, 2004 PubMed

  • 74.

    Luciano RL, Perazella MA: Aristolochic acid nephropathy: Epidemiology, clinical presentation, and treatment. Drug Saf 38: 5564, 2015 PubMed

  • 75.

    Floris M, Lepori N, Angioi A, Cabiddu G, Piras D, Loi V, et al: Chronic kidney disease of undetermined etiology around the world. Kidney Blood Press Res 46: 142151, 2021 PubMed

    • PubMed
    • Search Google Scholar
    • Export Citation

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