Difficulties in understanding human “acute tubular necrosis”: Limited data and flawed animal models
2001; Elsevier BV; Volume: 60; Issue: 4 Linguagem: Inglês
10.1046/j.1523-1755.2001.00930.x
ISSN1523-1755
AutoresSeymour Rosen, Samuel Navarro,
Tópico(s)Renal function and acid-base balance
ResumoDifficulties in understanding human "acute tubular necrosis": Limited data and flawed animal models. This review summarizes the current understanding of the renal biopsy in "acute tubular necrosis" and the attempts to mimic this phenomenon in animal models. Paradoxically, only very limited necrosis is present in the biopsy of patients with this condition and differences in biopsies of patients with sustained and recovering renal failure cannot be clearly defined. The small amount of material examined, the variation in timing of the biopsy, the ability of the nephron to recover from sublethal injury, and the complexity of the clinical situation compound the difficulties in understanding this condition. Morphological findings in the animal studies are not equivalent to those in the human biopsy of "acute tubular necrosis," because they either have too much proximal tubular necrosis (ischemia-reflow model) or show severe injury to distal nephron segments (distal nephron model), the degree of which has not been clearly documented, as yet, in human material. The direct relevance of animal models in part may be tested by new noninvasive methods that define and quantify excreted proteins that reflect nephron injury or measure the status of renal oxygenation by radiological imaging techniques. Finally, it may be time to re-examine the morphology of "acute tubular necrosis," utilizing new techniques that illustrate induction of heat shock proteins, sublethal and apoptotic cellular injury, and alteration of gene expression. Difficulties in understanding human "acute tubular necrosis": Limited data and flawed animal models. This review summarizes the current understanding of the renal biopsy in "acute tubular necrosis" and the attempts to mimic this phenomenon in animal models. Paradoxically, only very limited necrosis is present in the biopsy of patients with this condition and differences in biopsies of patients with sustained and recovering renal failure cannot be clearly defined. The small amount of material examined, the variation in timing of the biopsy, the ability of the nephron to recover from sublethal injury, and the complexity of the clinical situation compound the difficulties in understanding this condition. Morphological findings in the animal studies are not equivalent to those in the human biopsy of "acute tubular necrosis," because they either have too much proximal tubular necrosis (ischemia-reflow model) or show severe injury to distal nephron segments (distal nephron model), the degree of which has not been clearly documented, as yet, in human material. The direct relevance of animal models in part may be tested by new noninvasive methods that define and quantify excreted proteins that reflect nephron injury or measure the status of renal oxygenation by radiological imaging techniques. Finally, it may be time to re-examine the morphology of "acute tubular necrosis," utilizing new techniques that illustrate induction of heat shock proteins, sublethal and apoptotic cellular injury, and alteration of gene expression. Currently it is generally understood that the term "acute tubular necrosis"(ATN) does not accurately reflect the morphological changes in this condition1.Olsen S. Solez K. Acute tubular necrosis and toxic renal injury,.in: Tisher C.C. Brenner B.M. Renal Pathology: With Clinical and Functional Correlations. (2nd ed). J.B. Lippincott, Philadelphia1994: 769-809Google Scholar. In essence, ATN is the situation in which there is adequate renal perfusion such that there is sufficient blood flow to largely maintain tubular integrity, but not to sustain glomerular filtration. Indeed, in 1957 when the first renal biopsies were done by Brun and Munk in patients with ATN2.Brun C. Munk O. Lesions of the kidney in acute renal failure following shock.Lancet. 1957; 1: 603-609Abstract Scopus (34) Google Scholar, they were struck by the fact that there was limited parenchymal compromise in spite of severe organ failure. These observations and their study were the beginning of a new approach to ATN. Their findings were supported by a concurrent autopsy study that found no distinctive lesion of ATN3.Finckh E.S. Jeremy D. Whyte H.M. Structural renal damage and its relation to clinical features in acute oliguric renal failure.Q J Med. 1962; 31: 429-446PubMed Google Scholar. Years later, Solez and Finckh re-examined these data and did find limited, but significant tubular alterations that characterized patients with ATN4.Solez K. Finckh E.S. Is there a correlation between morphologic and functional changes in acute renal failure? The data of Finckh, Jeremy and Whyte re-examined twenty years later,.in: Solez K. Whelton A. Acute Renal Failure: Correlations Between Morphology and Function. Marcel Dekker, New York1984: 3-12Google Scholar. These changes largely focused on distal tubular necrosis and regeneration with, interestingly, an inverse correlation between distal tubular necrosis and urine volume. Although inflammation per se is not considered part of ATN histology, in autopsy studies, the occurrence of vasa recta nucleated cells (possibly hematopoiesis) has been regarded by some investigators as a characteristic feature5.Bacchi C.E. Rocha N. Carvalho M. et al.Immunohistochemical characterisation of probable intravascular haematopoiesis in the vasa rectae of the renal medulla in acute tubular necrosis.Pathol Res Pract. 1994; 190: 1066-1070Crossref PubMed Scopus (6) Google Scholar. One light microscopic study disclosed two lesions significantly less severe in recovering ATN versus sustained ATN: necrosis of individual tubular cells and loss of PAS(+) brush border6.Solez K. Morel-Maroger L. Sraer J.-D. The morphology of "acute tubular necrosis" in man: Analysis of 57 renal biopsies and a comparison with the glycerol model.Medicine (Baltimore). 1979; 58: 362-376Crossref PubMed Scopus (361) Google Scholar. Renal biopsy studies published after those initial observations largely reinforced these renal biopsy and autopsy studies1.Olsen S. Solez K. Acute tubular necrosis and toxic renal injury,.in: Tisher C.C. Brenner B.M. Renal Pathology: With Clinical and Functional Correlations. (2nd ed). J.B. Lippincott, Philadelphia1994: 769-809Google Scholar. Further morphological advances involved ultrastructural analysis and were largely based on 25 biopsies1.Olsen S. Solez K. Acute tubular necrosis and toxic renal injury,.in: Tisher C.C. Brenner B.M. Renal Pathology: With Clinical and Functional Correlations. (2nd ed). J.B. Lippincott, Philadelphia1994: 769-809Google Scholar, 7.Olsen T.S. Olsen H.S. Hansen H.E. Tubular ultrastructure in acute renal failure in man: Epithelial necrosis and regeneration.Virchows Arch. 1985; 406: 75-89Crossref Scopus (46) Google Scholar, 8.Olsen T.S. Hansen H.E. Olsen H.S. Tubular ultrastructure in acute renal failure: Alterations of cellular surfaces (brush-border and basal lateral infoldings).Virchows Arch. 1985; 406: 91-104Crossref Scopus (21) Google Scholar, 9.Olsen T.S. Hansen H.E. Ultrastructure of medullary tubules in ischemic acute tubular necrosis and acute interstitial nephritis in man.APMIS. 1990; 98: 1139-1148Crossref PubMed Scopus (33) Google Scholar. Eleven biopsies were from patients with established acute renal failure (ARF), ages varying from 24 to 71 years and obtained 2 to 25 days after onset of ARF; 14 biopsies were from patients in the recovery phase, ages varying from 17 to 64 years and obtained 2 to 30 days after onset of ARF. The etiologies of the ARF in these patients were shock following surgical operations, trauma, or postpartum hemorrhage as well as sepsis. In half of the patients, poisoning or nephrotoxicity was considered to have contributed to the ARF. The material examined by ultrastructure was limited, averaging 14 tubular profiles per patient (including both cortical and medullary tubules). Amazingly, despite this heterogeneity and sampling limitations, some conclusions could be drawn. In the cortex (principally convoluted tubules), single cell necrosis/desquamation with defects was found in both proximal tubules (0.8 ± 0.4%) and distal tubules (5.2 ± 2.9%). In the medulla, such changes were seen in S3 (3.7 ± 1.5%), medullary thick ascending limbs (10.7 ± 3.2%), and collecting ducts (9.3 ± 5%). This distal tubular "necrosis" was significantly greater in sustained versus recovering renal failure7.Olsen T.S. Olsen H.S. Hansen H.E. Tubular ultrastructure in acute renal failure in man: Epithelial necrosis and regeneration.Virchows Arch. 1985; 406: 75-89Crossref Scopus (46) Google Scholar. There was cellular "simplification" of both proximal and distal tubules (loss of brush border and basolateral membranes). Thus, the major changes—at least in terms of cell necrosis/desquamation—appeared to be in the distal nephron, and the ratio of distal/proximal cell loss in the cortex was 6.5/1 and in the medulla 3/1. Immunohistochemical studies of human biopsies of ATN also point to distal nephron injury (diminished number of tubules staining for Tamm-Horsfall protein) as compared with normal human kidneys10.Nadasdy T. Laszik Z. Blick K.E. et al.Human acute tubular necrosis: A lectin and immunohistochemical study.Hum Pathol. 1995; 26: 230-239Abstract Full Text PDF PubMed Scopus (44) Google Scholar. Thus, both proximal and distal nephron elements are abnormal in ATN, but the most severe injury appears in the distal nephron. The appearance of ATN in the renal transplant is very similar to that of nontransplant ATN, that is, limited parenchymal injury and manifest renal failure11.Solez K. Racusen L.C. Marcussen N. et al.Morphology of ischemic acute renal failure, normal function, and cyclosporine toxicity in cyclosporine-treated renal allograft recipients.Kidney Int. 1993; 43: 1058-1067Abstract Full Text PDF PubMed Scopus (97) Google Scholar. The advantages of studying ATN in this setting are obvious. The kidney is relatively accessible to biopsy. Abundant patient material is available, and the clinical situation is relatively homogeneous. The finding in biopsies of transplant ATN11.Solez K. Racusen L.C. Marcussen N. et al.Morphology of ischemic acute renal failure, normal function, and cyclosporine toxicity in cyclosporine-treated renal allograft recipients.Kidney Int. 1993; 43: 1058-1067Abstract Full Text PDF PubMed Scopus (97) Google Scholar, by light microscopy, is limited necrosis (more than nontransplant ATN), but the necrotic changes are significantly higher in ATN versus groups with stable renal function. On the other hand, fine structural studies show no clear distinction between transplant ATN and groups with stable function11.Solez K. Racusen L.C. Marcussen N. et al.Morphology of ischemic acute renal failure, normal function, and cyclosporine toxicity in cyclosporine-treated renal allograft recipients.Kidney Int. 1993; 43: 1058-1067Abstract Full Text PDF PubMed Scopus (97) Google Scholar,12.Kwon O. Corrigan G. Myers B.D. et al.Sodium reabsorption and distribution of Na+/K+-ATPase during postischemic injury to the renal allograft.Kidney Int. 1999; 55: 963-975Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar. In support of these observations, immunohistochemical studies using Na+, K+-ATPase could not distinguish between sustained and recovering human ATN12.Kwon O. Corrigan G. Myers B.D. et al.Sodium reabsorption and distribution of Na+/K+-ATPase during postischemic injury to the renal allograft.Kidney Int. 1999; 55: 963-975Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar. A systematic morphological examination of the renal medulla in human transplant ATN has not been undertaken. Taken together, these results from biopsy studies of transplant ATN emphasize the disparity between the clinical findings of renal failure and the limited morphological changes. Furthermore, in this more homogeneous population, biopsies from sustained and recovering renal failure do not show clear differences. In an attempt to understand the changes in human ATN, multiple animal models have been devised, and three such models particularly deserve mention. In the warm ischemia-reflow model, the renal artery is completely obstructed. The injury of ischemia-reflow depends on the time of obstruction, with more of the nephron recruited as this time increases13.Shanley P.F. Rosen M.D. Brezis M. et al.Topography of focal proximal tubular necrosis after ischemia with reflow in the rat kidney.Am J Pathol. 1986; 122: 462-468PubMed Google Scholar. 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An analysis of the intrarenal hemodynamics in these kidneys (using Microfil and microsphere injection) showed a profound reduction of blood flow in the deep cortex and juxtamedullary glomeruli35.Norlén B.J. Engberg A. Källskog Ö Wolgast M. Intrarenal hemodynamics in the transplanted rat kidney.Kidney Int. 1978; 14: 1-9Abstract Full Text PDF PubMed Scopus (34) Google Scholar. This kind of diminished medullary blood flow with continued glomerular filtration replicates the circumstances of a distal nephron model, as described next. A third model was developed on the basis of studies with the isolated perfused kidney36.Brezis M. Rosen S. Silva P. Epstein F.H. Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney.J Clin Invest. 1984; 73: 182-190Crossref PubMed Scopus (174) Google Scholar, 37.Brezis M. Rosen S. Silva P. Epstein F.H. 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How do these studies help us understand human ARF? Any conclusions from these experiments must be tempered by the morphological differences between the human kidney and the kidney of the rat, the animal utilized in almost all experimental studies. The latter has a well-developed medullary outer stripe, which in the human has a relatively limited representation. Furthermore, the vascular bundle of the inner stripe in the rat is complex (with inclusion of the thin descending limbs of the short loops of Henle). In humans, this structure is simple (without inclusion)44Kriz W. Barrett J.M. Peter S. The renal vasculature: anatomical-functional aspects,.in: Thurau K. (2nd ed). University Park Press, Baltimore1994: 769-809International Review of Physiology: Kidney and Urinary Tract Physiology II. 1976; vol 11: 1-21Google Scholar. On the other hand, despite these differences, a habitually low medullary pO2 is a constant finding in all mammalian species including humans45.Lübbers D.W. 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Greenfeld Z. et al.Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat.J Clin Invest. 1994; 94: 1069-1075Crossref PubMed Scopus (294) Google Scholar, but the blatant morphological changes that characterize this model are present to a much more limited degree in human material. The paucity of such findings in the human patients who have been studied may relate to reversibility of distal nephron injury, the limited material available, and, perhaps, as well, the inattention to medullary injury by most pathologists. Interestingly, renal failure in the distal nephron model is not improved by insulin-like growth factor-1 (IGF-1), as is the renal failure induced by warm ischemia-reflow47.Hirschberg R. Kopple J. 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For instance, apoptotic cell death is a feature of both the ischemia-reflow52.Lieberthal W. Koh J.S. Levine J.S. Necrosis and apoptosis in acute renal failure.Semin Nephrol. 1998; 18: 505-518PubMed Google Scholar and distal nephron model53.Beeri R. Symon Z. Brezis M. et al.Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys.Kidney Int. 1995; 47: 1806-1810Abstract Full Text PDF PubMed Scopus (125) Google Scholar, and is a documented event in the transplant biopsy as well54.Porter C.J. Ronan J.E. Cassidy M.J. fas-fas-ligand antigen expression and its relationship to increased apoptosis in acute renal transplant rejection.Transplantation. 2000; 69: 1091-1094Crossref PubMed Scopus (18) Google Scholar. However, the involved nephron segment in the latter is usually not clearly delineated54.Porter C.J. Ronan J.E. Cassidy M.J. fas-fas-ligand antigen expression and its relationship to increased apoptosis in acute renal transplant rejection.Transplantation. 2000; 69: 1091-1094Crossref PubMed Scopus (18) Google Scholar. Experiments in the ischemia-reflow model have defined the nature of sublethal proximal tubular injury documenting disruption of the actin cytoskeleton55.Molitoris B.A. Ischemia-induced loss of epithelial polarity: Potential role of the actin cytoskeleton.Am J Physiol. 1991; 260: F769-F778PubMed Google Scholar and loss of the normal polarity of Na+, K+-ATPase56.Fish E. Molitoris B. Alterations in epithelial polarity and the pathogenesis of disease states.N Engl J Med. 1994; 330: 1580-1588Crossref PubMed Scopus (186) Google Scholar. The diminishment of tight junction integrity57.Kroshian V.M. Sheridan A. Lieberthal W. 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Willgoss D.A. et al.Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat.J Am Soc Nephrol. 2000; 11: 454-467PubMed Google Scholar. The consequent growth factors and cytokines released by mTAL cells may aid in the recovery process. Of course, this contrasts sharply with the distal nephron model in which the focus of injury is the mTAL rather than the proximal tubule. Changes in gene expression and induction of heat proteins in this model are not defined yet. The direct relevance of animal models to human disease in part may be tested by new noninvasive methods that define and quantify excreted proteins that reflect nephron injury [kidney injury molecule-1 (KIM-1) is a new biomarker for human renal proximal tubule injury; abstract; Han et al, J Am Soc Nephrol 11:129A, 2000]64.McKee J.A. Kumar S. 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Mechanisms of renal repair and survival following acute injury.Semin Nephrol. 1998; 18: 519-522PubMed Google Scholar, it may be time to re-examine the morphology of ATN. We would like to thank Drs. Frank Epstein and Kim Solez for their criticisms, advice, and encouragement.
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