Cellular and molecular predictors of chronic renal dysfunction after initial ischemia/reperfusion injury of a single kidney.
BACKGROUND
Initial ischemia/reperfusion injury occurring secondary to organ retrieval, storage, and transplantation has been associated with late renal allograft deterioration and failure. In addition, there is an apparent synergy, reported in several clinical series, between the initial injuries of ischemia/reperfusion and acute rejection; the long-term results of graft survival are significantly deceased after both events in combination as compared with either alone or if no such episodes occur.


METHODS
In the present study, we examined patterns of proteinuria, cellular infiltration, cytokine expression, and glomerulosclerosis over time in Lewis and Fischer 344 rats after 45 min of warm ischemia of a single kidney and with or without contralateral nephrectomy. Both early (4 hr to 7 days) and late (2-52 weeks) events were studied serially in the affected kidneys morphologically, by immunohistology and by reverse transcriptase polymerase chain reaction.


RESULTS
Intercellular adhesion molecule 1, endothelin, and major histocompatibility complex class II expression were up-regulated within 2 to 5 days after injury; T cells and macrophages increased transiently. Proteinuria developed after approximately 8 weeks only in animals bearing a single injured kidney, and not in those with a retained native organ. Progressive morphological changes occurred after 16 weeks, including glomerulosclerosis, arterial obliteration, and interstitial fibrosis. After a period of relative quiescence, expression of intercellular adhesion molecule 1 again increased in relation to progressive macrophage infiltration and their associated products, particularly, interleukin 1, tumor necrosis factor-alpha, transforming growth factor-beta, and inducible nitric oxide synthase. Monocyte chemotactic protein 1 was intensely up-regulated by 24 weeks, coincident with a dramatic rise in this infiltrating population. These changes remained virtually at baseline in animals with a retained native kidney.


CONCLUSIONS
These data imply that chronic injury after significant initial ischemia and reperfusion occurs when there is already a 50% renal mass reduction, but not when two kidneys remain in place. Permanent nephron loss resulting from such an insult could account for this phenomenon. Early ischemia and reperfusion, if severe enough in a single kidney, may be an important antigen-independent risk factor for later renal deterioration and failure. In the context of a renal allograft, it may contribute to chronic rejection.
Azuma
H
H
Harvard Medical School, and the Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Nadeau
K
K
Takada
M
M
Mackenzie
H S
HS
Tilney
N L
NL
D000818:Animals; D001835:Body Weight; D002908:Chronic Disease; D016232:Endothelins / Q000235:genetics; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007668:Kidney / Q000033:anatomy & histology / Q000098:blood supply* / Q000737:chemistry / Q000473:pathology; D007674:Kidney Diseases / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D009929:Organ Size; D011507:Proteinuria / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016232:Endothelins; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma