What is the best way to measure renal fibrosis?: A pathologist’s perspective
2014; Elsevier BV; Volume: 4; Issue: 1 Linguagem: Inglês
10.1038/kisup.2014.3
ISSN2157-1724
AutoresAlton B. Farris, Charles E. Alpers,
Tópico(s)Systemic Sclerosis and Related Diseases
ResumoInterstitial fibrosis is a hallmark structural correlate of progressive and chronic kidney disease. There remain many uncertainties about how to best measure interstitial fibrosis both in research settings and in evaluations of renal biopsies performed for management of individual patients. Areas of uncertainty include determination of the composition of the matrix in a fibrotic parenchyma, the definition of how the interstitium is involved by fibrosing injuries, the choice of histologic stains for evaluation of renal fibrosis, and the reproducibility and robustness of measures currently employed by pathologists, both with and without the assistance of computerized imaging and assessments. In this review, we address some of these issues while citing the key studies that illustrate these difficulties. We point to future approaches that may allow a more accurate and meaningful assessment of renal interstitial fibrosis. Interstitial fibrosis is a hallmark structural correlate of progressive and chronic kidney disease. There remain many uncertainties about how to best measure interstitial fibrosis both in research settings and in evaluations of renal biopsies performed for management of individual patients. Areas of uncertainty include determination of the composition of the matrix in a fibrotic parenchyma, the definition of how the interstitium is involved by fibrosing injuries, the choice of histologic stains for evaluation of renal fibrosis, and the reproducibility and robustness of measures currently employed by pathologists, both with and without the assistance of computerized imaging and assessments. In this review, we address some of these issues while citing the key studies that illustrate these difficulties. We point to future approaches that may allow a more accurate and meaningful assessment of renal interstitial fibrosis. It is commonly accepted that interstitial fibrosis (IF) is a key, and perhaps the key, structural correlate of progressive and chronic kidney disease. It is therefore surprising that there remain many fundamental uncertainties about how to best measure fibrosis and about whether all forms of fibrosis are equally detrimental to the kidney and whether the various approaches available for measurement of fibrosis are robust and reproducible. The review will identify some of the issues underlying these uncertainties, cite some key studies that give us a basis for choosing some approaches over others, and suggest ways in which we may move forward, but regretfully will not resolve the fundamental uncertainties that we will discuss. Chronic kidney injury is manifested by a variety of structural alterations, including the accumulation of extracellular matrix (ECM). Most of what is considered ECM is colloquially termed IF. Tubular atrophy (TA) often accompanies IF and, when occurring together, IF and TA are collectively termed IFTA.1.Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics.Kidney Int. 2006; 69: 213-217Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar, 2.Zeisberg E.M. Potenta S.E. Sugimoto H. et al.Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition.J Am Soc Nephrol. 2008; 19: 2282-2287Crossref PubMed Scopus (689) Google Scholar, 3.Zeisberg M. Kalluri R. Fibroblasts emerge via epithelial-mesenchymal transition in chronic kidney fibrosis.Front Biosci. 2008; 13: 6991-6998Crossref PubMed Scopus (88) Google Scholar, 4.Kaissling B. Le Hir M. The renal cortical interstitium: morphological and functional aspects.Histochem Cell Biol. 2008; 130: 247-262Crossref PubMed Scopus (150) Google Scholar, 5.Christensen E.I. Verroust P.J. Interstitial fibrosis: tubular hypothesis versus glomerular hypothesis.Kidney Int. 2008; 74: 1233-1236Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 6.Wynn T.A. Fibrotic disease and the T(H)1/T(H)2 paradigm.Nat Rev Immunol. 2004; 4: 583-594Crossref PubMed Scopus (1272) Google Scholar, 7.Racusen L.C. Solez K. Colvin R. Fibrosis and atrophy in the renal allograft: interim report and new directions.Am J Transplant. 2002; 2: 203-206Crossref PubMed Scopus (67) Google Scholar, 8.Farris A.B. Colvin R.B. Renal interstitial fibrosis: mechanisms and evaluation.Curr Opin Nephrol Hypertens. 2012; 21: 289-300Crossref PubMed Scopus (249) Google Scholar Taken in isolation, IF is not necessarily a marker of the degree of intactness or function of nephron units. However, studies have shown that IF quantification can help prognosticate renal outcome in renal allografts and in such native kidney diseases as IgA nephropathy, and may be considered the best available histologic marker of chronic kidney injury.9.Grimm P.C. Nickerson P. Gough J. et al.Quantitation of allograft fibrosis and chronic allograft nephropathy.Pediatr Transplant. 1999; 3: 257-270Crossref PubMed Scopus (39) Google Scholar, 10.Risdon R.A. Sloper J.C. De Wardener H.E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis.Lancet. 1968; 2: 363-366Abstract PubMed Google Scholar, 11.Choi B.S. Shin M.J. Shin S.J. et al.Clinical significance of an early protocol biopsy in living-donor renal transplantation: ten-year experience at a single center.Am J Transplant. 2005; 5: 1354-1360Crossref PubMed Scopus (119) Google Scholar, 12.Colvin R.B. Nickeleit V. Renal transplant pathology.in: Jennette J.C. Olson J.L. Schwartz M.M. Silva F.G. 6th edn. Heptinstall's Pathology of the Kidney. vol. 2. Lippincott Williams and Wilkins, Philadelphia, PA, USA2006: 1347-1490Google Scholar, 13.Cosio F.G. Grande J.P. Wadei H. et al.Predicting subsequent decline in kidney allograft function from early surveillance biopsies.Am J Transplant. 2005; 5: 2464-2472Crossref PubMed Scopus (266) Google Scholar, 14.Roberts I.S. Cook H.T. Troyanov S. et al.The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar As many investigators and practitioners ascribe a great deal of importance to the issue of IF, accurate IF measurement is often needed in a variety of applications, including research focused on the therapeutic inhibition of IF, comparison of protocol biopsies in studies of renal allografts,1.Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics.Kidney Int. 2006; 69: 213-217Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar, 15.Vilayur E. Harris D.C. Emerging therapies for chronic kidney disease: what is their role?.Nat Rev Nephrol. 2009; 5: 375-383Crossref PubMed Scopus (66) Google Scholar, 16.Boor P. Sebekova K. Ostendorf T. et al.Treatment targets in renal fibrosis.Nephrol Dial Transplant. 2007; 22: 3391-3407Crossref PubMed Scopus (129) Google Scholar and for clinical prognostication as is the case with IgA nephropathy and lupus nephritis.14.Roberts I.S. Cook H.T. Troyanov S. et al.The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar,17.Austin 3rd., H.A. Muenz L.R. Joyce K.M. et al.Prognostic factors in lupus nephritis. Contribution of renal histologic data.Am J Med. 1983; 75: 382-391Abstract Full Text PDF PubMed Scopus (572) Google Scholar, 18.Alpers C.E. Hudkins K.L. Floege J. et al.Human renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular injury.J Am Soc Nephrol. 1994; 5: 201-209PubMed Google Scholar, 19.Humphreys B.D. Lin S.L. Kobayashi A. et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol. 2010; 176: 85-97Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar, 20.Hunter M.G. Hurwitz S. Bellamy C.O. et al.Quantitative morphometry of lupus nephritis: the significance of collagen, tubular space, and inflammatory infiltrate.Kidney Int. 2005; 67: 94-102Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar However, to do this, one must understand the qualitative and quantitative issues related to the topic of IF. The qualitative issues relate to the actual composition and distribution of the IF (that is, ‘what?’ and ‘where’). The quantitative issues, on the other hand, relate to the amount present (that is, ‘how much?’). In addition, one must understand the systems currently used for IFTA assessment and the implications (that is, ‘who uses this?’ and ‘why’). The cortical interstitial volume normally ranges from 5 to 20% with a mean of 12%,21.Clapp W.L. Croker B.P. Kidney.in: Mills S.E. Histology for Pathologists. 3rd edn. Lippincott Williams & Wilkins, Philadelphia, PA, USA2007Google Scholar, 22.Hestbech J. Hansen H.E. Amdisen A. et al.Chronic renal lesions following long-term treatment with lithium.Kidney Int. 1977; 12: 205-213Abstract Full Text PDF PubMed Scopus (302) Google Scholar, 23.Bohle A. Grund K.E. Mackensen S. et al.Correlations between renal interstitium and level of serum creatinine. Morphometric investigations of biopsies in perimembranous glomerulonephritis.Virchows Arch A Pathol Anat Histol. 1977; 373: 15-22Crossref PubMed Scopus (107) Google Scholar, 24.Kappel B. Olsen S. Cortical interstitial tissue and sclerosed glomeruli in the normal human kidney, related to age and sex. A quantitative study.Virchows Arch A Pathol Anat Histol. 1980; 387: 271-277Crossref PubMed Scopus (144) Google Scholar and this volume reportedly increases with age.24.Kappel B. Olsen S. Cortical interstitial tissue and sclerosed glomeruli in the normal human kidney, related to age and sex. A quantitative study.Virchows Arch A Pathol Anat Histol. 1980; 387: 271-277Crossref PubMed Scopus (144) Google Scholar The normal cortical interstitial volume is estimated at 5% in the rat.25.Bonsib S.M. Renal anatomy and histology.in: Jennette J.C. Olson J.L. Schwartz M.M. Silva F.G. Heptinstall's Pathology of the Kidney. 6th edn. Lippincott Williams & Wilkins, Philadelphia, PA, USA2007Google Scholar The renal interstitium ECM contains sulfated and non-sulfated glycosaminoglycans,21.Clapp W.L. Croker B.P. Kidney.in: Mills S.E. Histology for Pathologists. 3rd edn. Lippincott Williams & Wilkins, Philadelphia, PA, USA2007Google Scholar,26.Wall S.M. Truong A.V. DuBose Jr., T.D. H(+)-K(+)-ATPase mediates net acid secretion in rat terminal inner medullary collecting duct.Am J Physiol. 1996; 271: F1037-F1044PubMed Google Scholar such as biglycan and decorin,27.Stokes M.B. Holler S. Cui Y. et al.Expression of decorin, biglycan, and collagen type I in human renal fibrosing disease.Kidney Int. 2000; 57: 487-498Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Types I and III collagen, and fibronectin.21.Clapp W.L. Croker B.P. Kidney.in: Mills S.E. Histology for Pathologists. 3rd edn. Lippincott Williams & Wilkins, Philadelphia, PA, USA2007Google Scholar,28.Mounier F. Foidart J.M. Gubler M.C. Distribution of extracellular matrix glycoproteins during normal development of human kidney. An immunohistochemical study.Lab Invest. 1986; 54: 394-401PubMed Google Scholar Type VI collagen is also present, particularly in rodents.25.Bonsib S.M. Renal anatomy and histology.in: Jennette J.C. Olson J.L. Schwartz M.M. Silva F.G. Heptinstall's Pathology of the Kidney. 6th edn. Lippincott Williams & Wilkins, Philadelphia, PA, USA2007Google Scholar,29.Karkavelas G. Kefalides N.A. Amenta P.S. et al.Comparative ultrastructural localization of collagen types III, IV, VI and laminin in rat uterus and kidney.J Ultrastruct Mol Struct Res. 1988; 100: 137-155Crossref PubMed Scopus (34) Google Scholar IF is typically considered to be an excess accumulation of fibrillar collagen, and the role of other matrix molecules such as proteoglycans and other non-collagenous proteins has not been comprehensively investigated. Knowing the composition of a fibrotic matrix is important because matrix components may determine the susceptibility of a matrix to undergo degradation by proteases and possibly undergo regression, and may determine the local tethering and/or activation of growth factors and cytokines that mediate IFTA. Fibroblasts constitute a large proportion of renal interstitial cells and are the major cells maintaining constituent ECM, which can be considered the kidney ‘skeleton.’ Fibroblasts lack a good cell type–specific marker, making their study difficult.30.Boor P. Ostendorf T. Floege J. Renal fibrosis: novel insights into mechanisms and therapeutic targets.Nat Rev Nephrol. 2010; 6: 643-656Crossref PubMed Scopus (477) Google Scholar Fibroblasts and other cells may acquire a myofibroblastic phenotype, likely a crucial event in expansion of the ECM.18.Alpers C.E. Hudkins K.L. Floege J. et al.Human renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular injury.J Am Soc Nephrol. 1994; 5: 201-209PubMed Google Scholar,30.Boor P. Ostendorf T. Floege J. Renal fibrosis: novel insights into mechanisms and therapeutic targets.Nat Rev Nephrol. 2010; 6: 643-656Crossref PubMed Scopus (477) Google Scholar, 31.Dussaule J.C. Guerrot D. Huby A.C. et al.The role of cell plasticity in progression and reversal of renal fibrosis.Int J Exp Pathol. 2011; 92: 151-157Crossref PubMed Scopus (29) Google Scholar, 32.Meran S. Steadman R. Fibroblasts and myofibroblasts in renal fibrosis.Int J Exp Pathol. 2011; 92: 158-167Crossref PubMed Scopus (265) Google Scholar, 33.Ru Y. Eyden B. The ultrastructure of human tubulo-interstitial fibrosis.J Submicrosc Cytol Pathol. 2003; 35: 147-160PubMed Google Scholar Lymphocytes appear to have important roles in the development of IFTA.8.Farris A.B. Colvin R.B. Renal interstitial fibrosis: mechanisms and evaluation.Curr Opin Nephrol Hypertens. 2012; 21: 289-300Crossref PubMed Scopus (249) Google Scholar,34.Tapmeier T.T. Fearn A. Brown K. et al.Pivotal role of CD4+ T cells in renal fibrosis following ureteric obstruction.Kidney Int. 2010; 78: 351-362Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 35.Nikolic-Paterson D.J. CD4+ T cells: a potential player in renal fibrosis.Kidney Int. 2010; 78: 333-335Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 36.Snelgrove S.L. Kausman J.Y. Lo C. et al.Renal dendritic cells adopt a pro-inflammatory phenotype in obstructive uropathy to activate T cells, but do not directly contribute to fibrosis.Am J Pathol. 2011; 180: 91-103Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The classes of infiltrating or resident monocyte/macrophages are heterogeneous, displaying a variety of phenotypes.37.Lin S.L. Castano A.P. Nowlin B.T. et al.Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations.J Immunol. 2009; 183: 6733-6743Crossref PubMed Scopus (269) Google Scholar, 38.Anders H.J. Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis.Kidney Int. 2011; 80: 915-925Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar, 39.Machida Y. Kitamoto K. Izumi Y. et al.Renal fibrosis in murine obstructive nephropathy is attenuated by depletion of monocyte lineage, not dendritic cells.J Pharmacol Sci. 2010; 114: 464-473Crossref PubMed Scopus (29) Google Scholar, 40.Pilling D. Fan T. Huang D. et al.Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts.PLoS ONE. 2009; 4: e7475Crossref PubMed Scopus (393) Google Scholar Some macrophages may be preferentially pro-fibrotic,38.Anders H.J. Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis.Kidney Int. 2011; 80: 915-925Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar,41.Vernon M.A. Mylonas K.J. Hughes J. Macrophages and renal fibrosis.Semin Nephrol. 2010; 30: 302-317Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar whereas other classes of monocyte/macrophages may actually attenuate fibrosis.42.Semedo P. Donizetti-Oliveira C. Burgos-Silva M. et al.Bone marrow mononuclear cells attenuate fibrosis development after severe acute kidney injury.Lab Invest. 2010; 90: 685-695Crossref PubMed Scopus (28) Google Scholar Other cells also contribute to IFTA, including pericytes,19.Humphreys B.D. Lin S.L. Kobayashi A. et al.Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.Am J Pathol. 2010; 176: 85-97Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar dendritic cells,8.Farris A.B. Colvin R.B. Renal interstitial fibrosis: mechanisms and evaluation.Curr Opin Nephrol Hypertens. 2012; 21: 289-300Crossref PubMed Scopus (249) Google Scholar,36.Snelgrove S.L. Kausman J.Y. Lo C. et al.Renal dendritic cells adopt a pro-inflammatory phenotype in obstructive uropathy to activate T cells, but do not directly contribute to fibrosis.Am J Pathol. 2011; 180: 91-103Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar,43.Olagne J. Caillard S. Gaub M.P. et al.Post-transplant lymphoproliferative disorders: determination of donor/recipient origin in a large cohort of kidney recipients.Am J Transplant. 2011; 11: 1260-1269Crossref PubMed Scopus (47) Google Scholar, 44.Kurts C. Heymann F. Lukacs-Kornek V. et al.Role of T cells and dendritic cells in glomerular immunopathology.Semin Immunopathol. 2007; 29: 317-335Crossref PubMed Scopus (54) Google Scholar, 45.Macconi D. Chiabrando C. Schiarea S. et al.Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides.J Am Soc Nephrol. 2009; 20: 123-130Crossref PubMed Scopus (83) Google Scholar, 46.Heymann F. Meyer-Schwesinger C. Hamilton-Williams E.E. et al.Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury.J Clin Invest. 2009; 119: 1286-1297Crossref PubMed Scopus (179) Google Scholar mast cells,8.Farris A.B. Colvin R.B. Renal interstitial fibrosis: mechanisms and evaluation.Curr Opin Nephrol Hypertens. 2012; 21: 289-300Crossref PubMed Scopus (249) Google Scholar,47.Roberts I.S. Brenchley P.E. Mast cells: the forgotten cells of renal fibrosis.J Clin Pathol. 2000; 53: 858-862Crossref PubMed Scopus (112) Google Scholar, 48.Kanamaru Y. Scandiuzzi L. Essig M. et al.Mast cell-mediated remodeling and fibrinolytic activity protect against fatal glomerulonephritis.J Immunol. 2006; 176: 5607-5615Crossref PubMed Scopus (53) Google Scholar, 49.Veerappan A. Reid A.C. O'Connor N. et al.Mast cells are required for the development of renal fibrosis in the rodent unilateral ureteral obstruction model.Am J Physiol Renal Physiol. 2012; 302: F192-F204Crossref PubMed Scopus (37) Google Scholar and fibrocytes.6.Wynn T.A. Fibrotic disease and the T(H)1/T(H)2 paradigm.Nat Rev Immunol. 2004; 4: 583-594Crossref PubMed Scopus (1272) Google Scholar,37.Lin S.L. Castano A.P. Nowlin B.T. et al.Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations.J Immunol. 2009; 183: 6733-6743Crossref PubMed Scopus (269) Google Scholar,40.Pilling D. Fan T. Huang D. et al.Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts.PLoS ONE. 2009; 4: e7475Crossref PubMed Scopus (393) Google Scholar,50.Niedermeier M. Reich B. Rodriguez Gomez M. et al.CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes.Proc Natl Acad Sci USA. 2009; 106: 17892-17897Crossref PubMed Scopus (184) Google Scholar, 51.Sakai N. Furuichi K. Shinozaki Y. et al.Fibrocytes are involved in the pathogenesis of human chronic kidney disease.Hum Pathol. 2010; 41: 672-678Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 52.Shao D.D. Suresh R. Vakil V. et al.Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation.J Leukoc Biol. 2008; 83: 1323-1333Crossref PubMed Scopus (238) Google Scholar, 53.Broekema M. Harmsen M.C. van Luyn M.J. et al.Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats.J Am Soc Nephrol. 2007; 18: 165-175Crossref PubMed Scopus (151) Google Scholar, 54.Lin S.L. Kisseleva T. Brenner D.A. et al.Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney.Am J Pathol. 2008; 173: 1617-1627Abstract Full Text Full Text PDF PubMed Scopus (666) Google Scholar Measures of IF rarely take into account the cellularity of the fibrotic areas, and how this may reflect the age of the fibrotic process or its potential for reversibility or other biologic features of the fibrotic process. Patterns of IF vary and likely do not have identical causes or consequences. For example, the patchy, ‘striped’ pattern of IF with corresponding TA has been described with calcineurin inhibitor use. It has been proposed that this is because of the apparent preferential involvement of the medullary rays; however, IF also might be the result of toxic injury to discrete segments of small arteries and arterioles with consequent diminished blood supply to those portions of the cortical parenchyma supplied by the injured vessels. Despite the use of this association as a way to identify calcineurin inhibitor effect, this pattern may also be seen with hypertensive kidney disease. This ‘striped’ fibrosis occurs in addition to the other changes of chronic calcineurin-induced nephrotoxicity, including hyaline arteriopathy, and nonspecific glomerulosclerosis.55.Liptak P. Ivanyi B. Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts.Nat Clin Pract Nephrol. 2006; 2: 398-404Crossref PubMed Scopus (136) Google Scholar Broad scars with the loss of tubules are the sequelae of severe focal injury and destruction of parenchyma, such as in pyelonephritis and infarcts.8.Farris A.B. Colvin R.B. Renal interstitial fibrosis: mechanisms and evaluation.Curr Opin Nephrol Hypertens. 2012; 21: 289-300Crossref PubMed Scopus (249) Google Scholar Chronic obstruction extrinsic to the ureter can lead to IF/TA with relative glomerular sparing, atubular glomeruli, dilated tubules, and intratubular Tamm–Horsfall protein casts with extravasation into the interstitium.56.Klahr S. Morrissey J. Obstructive nephropathy and renal fibrosis: the role of bone morphogenic protein-7 and hepatocyte growth factor.Kidney Int Suppl. 2003: S105-S112Abstract Full Text Full Text PDF Scopus (84) Google Scholar,57.Solez K. Colvin R.B. Racusen L.C. et al.Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN').Am J Transplant. 2007; 7: 518-526Crossref PubMed Scopus (930) Google Scholar The IF resulting from the metabolic injuries of diabetic nephropathy is both diffused and more homogeneous in distribution, although modification of the homogeneous distribution may occur as a result of concurrent vascular disease that may be of irregular severity. As kidneys age, there is often a pattern of subcapsular fibrosis, usually attributed to a marginal blood supply that is not replicated in less superficial portions of the renal cortex. Despite these associations, there is often an essentially nonspecific pattern of fibrosis in renal biopsies of patients with chronic kidney disease, including diffuse or patchy fine IF surrounding tubules, which can be either normal or atrophic. This is associated with either diffuse or focal disease of glomeruli, tubules, or vessels.7.Racusen L.C. Solez K. Colvin R. Fibrosis and atrophy in the renal allograft: interim report and new directions.Am J Transplant. 2002; 2: 203-206Crossref PubMed Scopus (67) Google Scholar,57.Solez K. Colvin R.B. Racusen L.C. et al.Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN').Am J Transplant. 2007; 7: 518-526Crossref PubMed Scopus (930) Google Scholar Although assessment of cortical IF is often stressed, medullary IF likely parallels cortical IF and epithelial loss, as stressed in studies by Farris et al.58.Farris A.B. Lawson D. Cohen C. et al.Medullary injury in the human renal biopsy: fibrosis assessment.Mod Pathol. 2013; 26: 387A-388AGoogle Scholar In allografts, loss of peritubular capillaries (PTCs) occurs following transplantation.59.Steegh F.M. Gelens M.A. Nieman F.H. et al.Early loss of peritubular capillaries after kidney transplantation.J Am Soc Nephrol. 2011; 22: 1024-1029Crossref PubMed Scopus (57) Google Scholar One study has shown that PTCs decrease with time in allografts and are inversely related to renal function; decreased PTC density at 3 months predicts later loss of function at 1 year.59.Steegh F.M. Gelens M.A. Nieman F.H. et al.Early loss of peritubular capillaries after kidney transplantation.J Am Soc Nephrol. 2011; 22: 1024-1029Crossref PubMed Scopus (57) Google Scholar Loss of PTC presumably results in a diminished supply of nutrients to the tubulointerstitium, and these PTC changes are often thought to parallel the presence of IF. However, it remains unclear whether loss of PTCs is causal in the development of IF and, conversely, whether restoration of the PTC density can lead to reversal of IF. Despite the obvious importance of PTC for a healthy tubulointerstitium, PTC density is rarely measured in preclinical studies of fibrosing injuries and is virtually never measured in clinical practice. Trichrome staining (Figure 1) is often used in addition to other conventional histologic stains (hematoxylin and eosin, PAS, Silver Methenamine) to assess collagen content in the interstitium. Trichrome staining is quite practical for both clinical management of individual patients and for research studies, as it is widely available and inexpensive. For quantitation, visual assessment of trichrome-stained slides is the standard practice at many institutions;60.Moreso F. Lopez M. Vallejos A. et al.Serial protocol biopsies to quantify the progression of chronic transplant nephropathy in stable renal allografts.Am J Transplant. 2001; 1: 82-88Crossref PubMed Scopus (73) Google Scholar however, studies have shown that this approach may have poor reproducibility.61.Marcussen N. Olsen T.S. Benediktsson H. et al.Reproducibility of the Banff classification of renal allograft pathology. Inter- and intraobserver variation.Transplantation. 1995; 60: 1083-1089Crossref PubMed Scopus (110) Google Scholar,62.Furness P.N. Taub N. International variation in the interpretation of renal transplant biopsies: report of the CERTPAP Project.Kidney Int. 2001; 60: 1998-2012Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar Part of the reproducibility issue arises from uncertainty as to whether the definition of IF employed is based on total area occupied by the stainable collagen or based on areas containing any amount of stainable collagen (that is, ‘fine fibrosis’) as discussed further below and illustrated in studies by Furness et al.63.Furness P.N. Taub N. Assmann K.J. et al.International variation in histologic grading is large, and persistent feedback does not improve reproducibility.Am J Surg Pathol. 2003; 27: 805-810Crossref PubMed Scopus (166) Google Scholar and Farris et al.64.Farris A.B. Adams C.D. Brousaides N. et al.Morphometric and visual evaluation of fibrosis in renal biopsies.J Am Soc Nephrol. 2011; 22: 176-186Crossref PubMed Scopus (166) Google Scholar Trichrome stains may not be sensitive at milder levels of fibrosis. Trichrome dyes are sensitive to length of formalin fixation, which introduces an important variable in studies of renal biopsies, which are not handled uniformly in multi-institutional studies. Picrosirius Red (also referred to as simply ‘Sirius Red’) is examined under both polarized and unpolarized light. Sirius Red is thought to be specific for collagen types I and III under polarized light.65.Junqueira L.C. Bignolas G. Brentani R.R. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections.Histochem J. 1979; 11: 447-455Crossref PubMed Scopus (1977) Google Scholar, 66.Grimm P.C. Nickerson P. Gough J. et al.Computerized image analysis of Sirius Red-stained renal allograft biopsies as a surrogate marker to predict long-term allograft function.J Am Soc Nephrol. 2003; 14: 1662-1668Crossref PubMed Scopus (168) Google Scholar, 67.Sund S. Grimm P. Reisaeter A.V. et al.Computerized image analysis vs semiquantitative scoring in evaluation of kidney allograft fibrosis and prognosis.Nephrol Dial Transplant. 2004; 19: 2838-2845Crossref PubMed Scopus (46) Google Scholar Because of the high specificity for binding to collagen fibers, this stain has a high signal-to-noise ratio and lends itself to computerized image analysis. However, Sirius Red is not widely used and is subject to discrepancies between polarized and unpolarized measurements. Technical considerations have a large effect on performance, and it will likely be difficult to standardize Sirius Red among different laboratories. Furthermore, studies to test the reproducibility of this methodology across institutions are currently lacking. An important consideration hindering the use of Sirius Red as a standard in measuring IF is that it is more time-consuming and expensive to perform and analyze than a trichrome stain. Collagen III immunohistochemistry is probably the least widely used fibrosis stain and thus has little clinical valida
Referência(s)