ICAM-1 antisense oligodesoxynucleotides prevent reperfusion injury and enhance immediate graft function in renal transplantation

BACKGROUND: Ischemia-reperfusion injury after organ transplantation is a major cause of delayed graft function. We showed earlier that antisense oligodesoxynucleotides (ODN) for intercellular adhesion molecule-1 (ICAM-1) ameliorate reperfusion injury after acute ischemia. This study tested the hypothesis that antisense ODN for ICAM-1 prevents ischemia-reperfusion injury and facilitates immediate graft function in a rat autotransplantation model. METHODS: Both kidneys were removed from male Lewis rats and re-implanted the left kidney after 30 minutes of cold ischemia time. The warm ischemia time was 60 minutes. Sham operated, uninephrectomized animals served as controls for renal function and histology. ICAM-1 antisense ODN (5 mg/kg), reverse ODN, or saline-vehicle were administered to donor animals i.v. six hours before autotransplantation. Glomerular filtration rate (insulin clearance), and serum creatinine concentrations were measured 24 hours post-transplantation. Tubular necrosis severity was assessed by histological grading scale. ICAM-1 expression was determined by immunohistochemistry and Western blot. RESULTS: Antisense ODN decreased ICAM-1 expression and leukocyte infiltration significant. Antisense ODN-treated animals showed significantly less tubular necrosis, than controls. Serum creatinine of antisense ODN-treated animals (N = 6) was 0.55 +/- 0.02 mg/dl compared to 1.92 +/- 0.07 mg/dl in reverse ODN-treated controls (N = 6; P < 0.01), 24 hours after transplantation. Antisense ODN-treated animals had normal GFR (0.93 +/- 0.07 ml/min/kidney wt) compared to sham-operated animals (0.95 +/- 0.09 ml/min/kidney wt), while autotransplanted animals treated with reverse ODN or saline-vehicle were all anuric. The ischemia-reperfusion-induced up-regulation of MHC class II was totally prevented by antisense ODN. CONCLUSIONS: ICAM-1 inhibition ameliorates ischemia-reperfusion injury and prevents delayed graft function. Antisense ODN-treatment of donors or donor organs for ICAM-1 may be useful for the prevention of reperfusion injury in human renal transplantation.     

Growth of rats' kidneys after unilateral uretero-caval anastomosis

1. The relative significance of reduced excretion of urinary constituents and reduced renal mass, as stimuli to growth of one kidney after the other has been removed, has been investigated. 2. To abolish the excretory function of one kidney without removing it, the right ureter was drained into the vena cava through a compound cannula for 6 weeks. Uretero-caval anastomoses were performed in twenty-four male rats at 10 weeks of age: six survived without evidence of ureteric obstruction (and a further five with minimal obstruction). 3. The rats with anastomoses grew less than six other rats from which the right kidney had been removed or six which had been submitted to a sham operation, and their plasma urea and creatinine concentrations were higher. 4. Relative to body weight, the dry weight of each kidney after uretero-caval anastomosis without obstruction was 18% greater than after sham operation; taking both kidneys together, the total increase was almost as much as in the left kidney alone after right nephrectomy (46%). 5. Histologically and in terms of DNA concentration, the growth of both kidneys after uretero-caval anastomosis was of the same kind as in the left kidney after right nephrectomy. 6. The return of urine from one kidney into the blood provided a powerful stimulus to renal growth in spite of the restraining effect of increased renal mass.     

The importance of the kidney in primary hypertension: insights from cross-transplantation

Experimental renal cross-transplantation studies with genetically hypertensive and normotensive rats have shown that hypertension travels with the kidney. The underlying mechanisms are currently not well understood. Genetically normotensive recipients of a kidney from spontaneously hypertensive rats show a decreased capacity to excrete sodium when challenged with a high-salt diet. Furthermore, they retain more sodium than recipients of a kidney from genetically normotensive donors immediately after transplantation and removal of the native kidneys. Sodium retention precedes hypertension and may contribute to its development. Most recently, it has been shown that bilateral nephrectomy and transplantation of a genetically normotensive kidney attenuates the development of hypertension in young transplanted spontaneously hypertensive rats. Thus, long-term blood pressure in renal transplanted rats is critically determined by the genetic background of the renal graft. Together, these data indicate that genetically determined renal mechanisms play a major role in primary hypertension.     

Syphilitic lesions of the cardiovascular system]

The changes in arterial pressure, sodium excretion, diuresis, and content of renal prostaglandins were studied in rats with COD-salt hypertension. The administration of DOC to rats with unilateral nephrectomy resulted in more distinct hypertension than in those with both kidneys preserved. Arterial pressure elevation was accompanied by a gradual reduction of renal prostaglandins concentration, the removal of one kidney causing an earlier and more distinct reduction of their content. Unilateral nephrectomy (without DOC administration) resulted in a reduction of prostaglandins concentration in the remaining kidney, but their total content in the medullar layer of this kidney practically did not change.     

Presence of IgM antibodies to Trypanosoma cruzi urinary antigen in sera from patients with acute Chagas'' disease

We have investigated the ability of an antisense immunoglobulin E (IgE) receptor alpha-subunit oligodeoxynucleotide (Fc epsilon RI alpha ODN) specifically to inhibit IgE-mediated allergic reactions in the mouse. Synthetic antisense Fc epsilon RI alpha ODN dose-dependently inhibited passive cutaneous anaphylaxis and histamine release from the mouse peritoneal mast cells (MPMC) activated by anti-dinitrophenyl (DNP) IgE. Northern blot analysis showed that the mast cells treated with antisense Fc epsilon RI alpha ODN exhibited no detectable levels of L-histidine decarboxylase mRNA after anti-DNP IgE stimulation, whereas the cells treated with sense Fc epsilon RI alpha ODN possessed significant amounts of this mRNA. Examination of the elevation of cAMP levels in MPMC following the activation with anti-DNP IgE demonstrated a significant rise in activated cells, but not in the antisense Fc epsilon RI alpha ODN-treated cells. Moreover, antisense Fc epsilon RI alpha ODN had a significant inhibitory effect on anti-DNP IgE-induced tumour necrosis factor-alpha production. Our results demonstrated that antisense Fc epsilon RI alpha ODN inhibited the IgE-mediated allergic reaction in vivo and in vitro.     

Effects of protease therapy in the remnant kidney model of progressive renal failure

This study investigated whether protease treatment ameliorates the progressive course of chronic failure in the rat model of subtotal nephrectomy. Fourteen male Wistar rats underwent 5/6 nephrectomy, and were randomized into a control group (C, n = 7) given 2 ml of 0.9% NaCl intraperitoneally (i.p.) daily, and a study group (P, n = 7) treated with 12 mg Phlogenzym (combination of trypsin, bromelain, and rutosid) in 2 ml saline i.p. daily. After 6 weeks treatment, the Phlogenzym group showed lower proteinuria (C: 19.6 +/- 9.1 vs. 10.2 +/- 6.2 mg/24 h, p < 0.05). Endogenous creatinine clearance was higher (C: 192.3 +/- 99.4, P: 300.5 +/- 47.9 microliters/min per 100 g, p < 0.05), while plasma creatinine was decreased (C: 106.7 +/- 33.9, P: 76.0 +/- 6.3 mumol/l, p < 0.01). Blood urea nitrogen levels did not change, although urea clearance tended to a higher level in the protease-treated rats. Decreased renal formation of cytokines was reflected by a lower urinary excretion ratio of transforming growth factor (TGF)-beta/ creatinine (C: 0.363 +/- 0.183, P: 0.232 +/- 0.085 ng TGF-beta/mg creatinine, p < 0.05). Renal morphology revealed less infiltration of mononuclear cells and an amelioration of interstitial fibrosis as expressed by the volume index of the cortical region (C: 17.17 +/- 1.43; P: 12.3 +/- 0.5%, p < 0.001). In addition, the activities of lysosomal proteinases (cathepsin B, L + B, and H), which are decreased in the remnant kidney model of chronic renal failure, were significantly higher in the enzyme-treated group both in isolated glomeruli and proximal tubules. The body and kidney weight tended to be lower, probably due to a catabolic action of the enzymes. In summary, we provide evidence that protease treatment may be beneficial in a nonimmune mediated renal disease. Phlogenzym ameliorated the course of chronic renal failure in the rat model of subtotal nephrectomy and retarded the development of tubulointerstitial fibrosis. Decreased cytokine formation in the remnant kidney is supposed to play a key role.     

Strength and pain measures associated with lateral epicondylitis bracing

BACKGROUND: In the experiment described here, we investigated the effects of the immunosuppressants FK506 and leflunomide (Lef) on the survival of hamster hearts and liver xenografts in Lewis rats. METHODS: Lewis rats were used as recipients of hamster heart or liver grafts using different regimens of FK506 and Lef. Donor-matched heart grafts were transplanted into long-term surviving Lewis rat recipients of hamster xenografts to test donor-specific prolongation of xenograft survival. Hyperimmune, late xenograft rejection, and naive sera were transferred into long-term surviving Lewis rat recipients of hamster heart xenografts to determine whether these sera could inhibit the efficacy of donor-specific long-term survival. Anti-donor-specific antibodies were analyzed by flow cytometry. RESULTS: After a short induction with FK506 plus Lef, maintenance treatment with FK506 alone was sufficient to prolong survival of hamster xenografts. All hamster heart and four of six hamster liver xenografts survived for more than 3 months. Second hamster hearts were permanently accepted by Lewis rats bearing long-term surviving hamster heart xenografts when rats were treated with FK506 monotherapy (mean survival time >60 days, n=4). Long-term surviving hamster heart grafts were rejected after transfer of hyperimmune serum but not late xenograft rejection serum or naive serum. Lef and FK506 significantly reduced the production of anti-donor-specific antibodies in Lewis rats transplanted with hamster liver and heart xenografts. CONCLUSION: Long-term survival of hamster liver and heart xenografts in Lewis rats could be induced by a regimen of short-term FK506 in combination with Lef followed by FK506 monotherapy. The acquired sensitivity of late xenoreactivity to FK506 reflects primarily a modification in the host immune response to the hamster graft.     

Ischemia causes rapidly progressive nephropathy in the diabetic rat

We examined the influence of renal ischemia in rats with diabetes mellitus (DM). Male Wistar rats were rendered diabetic by streptozotocin treatment. Two weeks later, 30 minutes of complete ischemia was induced in the left kidney of DM and non-DM animals. Both groups were evaluated functionally and morphologically four or eight weeks post-ischemia. In non-DM animals renal function and morphology showed almost complete recovery. In the DM animals, however, this comparatively short period of ischemia caused a substantial loss of renal function. Four weeks post-ischemia inulin clearance in the DM kidneys rendered ischemic was only 20% of that in the corresponding non-DM kidneys, and after eight weeks the DM kidneys were completely anuric. Extensive inflammation and tubulointerstitial fibrosis were evident in DM kidneys four weeks after ischemia and seemed to increase over time. After eight weeks, tubular atrophy was found in the ischemic DM kidneys, resulting in a substantial loss of kidney mass. We conclude that in diabetic rats renal ischemia causes rapidly progressive kidney damage that in several respects resembles diabetic nephropathy in humans. Since advanced renal lesions similar to those seen in human diabetic nephropathy never develop in the rat solely as a result of DM, the present study may provide an experimental model for further studies on renal failure in diabetes mellitus.     

Angiotensin II receptor blockade limits kidney injury in two-kidney, one-clip Goldblatt hypertensive rats with special reference to phenotypic changes

Recent evidence indicates that tubulointerstitial injury plays an important role in hypertensive kidney injury and that phenotypic changes contribute to this pathology. Moreover, angiotensin II is known to be actively involved in the pathogenesis of progressive kidney injury induced by hypertension. The present study was undertaken to see the effect of a newly developed angiotensin II type I receptor (AT1 receptor) antagonist on hypertension-induced kidney injury and to determine the contribution of phenotypic changes to morphologic alterations. Two-kidney, one-clip (2K1C), Goldblatt hypertensive rats (n = 27) were made by clipping the left renal artery. These animals were orally administered 57G709 (a selective non-peptide AT1 receptor antagonist)(10 mg/kg/day), captopril (20 mg/kg/day), or vehicle alone for 23 days beginning 4 weeks after clipping. In the non-clipped kidney of vehicle-treated 2K1 C rats, marked tubulointerstitial injury as well as glomerular sclerosis and/or hyalinosis was found in association with phenotypic changes, as shown by the neoexpression of vimentin in periglomeruli, perivascular walls, distal tubuli, and injured interstitium. Renin expression was markedly suppressed in the non-clipped kidneys of vehicle-treated 2K1C rats as compared with renin expression in normotensive control kidneys of sham-operated rats. Both 57G709 and captopril markedly ameliorated hypertensive kidney injury as reflected by the glomerular sclerosing index and by the tubulointerstitial index as determined by the point-counting method, and this improvement was accompanied by a significant decrease in blood pressure, urinary protein excretion, kidney/body weight ratio, and heart/body weight ratio. In addition, the vimentin neoexpression mentioned above was also suppressed with an inhibition of angiotensin II. These results suggest that in 2K1C Goldblatt hypertensive kidney injury, the AT1 receptor antagonist 57G709 exerts a potent renal protective effect associated with the inhibition of phenotypic changes.     

Rat renal allograft tolerance is associated with local TGF-beta and absence of IL-2r expression within chimeric immunocytic foci

Tolerance was induced in Lewis (LEW) rat renal allograft recipients of Brown Norway kidneys by multiple pretransplant donor-blood transfusions and prior limited cyclosporine A. Rat renal allograft tolerance was associated with the induction of systemic donor T cells (10%), an early phase of nonspecific suppressor-cell generation, followed by maturation of systemic antigen-specific suppressor cells, and renal cellular infiltrates that develop long-term in situ in the kidney graft model. It was hypothesized that these infiltrates represent chimeric immunocytic foci that are locally regulated via a TGF-beta-dependent mechanism. Both immunohistochemical staining and digital image analysis for cellular and extracellular TGF-beta, IL-2 receptor (CD25), and the BN Class I-MHC marker (OX-27) were performed. Control rejecting (REJ) kidneys did not demonstrate any differences with respect to levels of infiltrating immunocyte area vs long-term surviving (TOL) kidneys (3.9% vs 4.5%, P = .303). Immunostaining with the BN Class I MHC marker (OX-27) demonstrated high levels of chimerism within immunocyte foci of the tolerant grafts (OX-27 BN+immunocytes 49.0% +/- 5.1%). In situ cellular IL-2 receptor (CD25) expression was demonstrated in REJ kidney infiltrates but not within TOL immunocytic infiltrating foci, when measured as percent of total lymphocytes (REJ = 5.0% vs TOL = 0.4%, P = .031). Conversely, TGF-beta expression was significantly higher in immunocytes of TOL kidneys when measured as the number of DAB chromogen-staining pixels per total immunocyte area (TOL = .076 vs REJ = .047, P = .003). In conclusion, these results suggested that stable mixed immune chimerism (SMIC) plays an important role in DST-CyA-induced tolerance in situ. SMIC-induced tolerance may involve a local TGF-beta-dependent mechanism that is associated with in situ TGF-beta (+) and IL-2r (-) immunocytes.     

Fetal hydrocolpos

This work studies the role that nitric oxide (NO) plays in ischemia/reperfusion (I/R) of the rat kidney. Sprague-Dawley rats, weighing 250-300 g, were subjected to 75 min of warm ischemia and contralateral nephrectomy. The animals were divided into six groups (n = 12 per group): ischemic control (IC) with normal saline, L-NG-mono-methyl-arginine (L-NMMA) 50 mg/kg, L-arginine (L-Arg) 300 mg/kg, Na-nitroprusside (Na-NP) 2.5 mg/kg, the combination of L-NMMA+Na-NP at the doses used before, and the sham group. All animals received the drug intravenously 60 min prior to ischemia. Survival was evaluated at seven days. Renal damage was assessed by kidney function tests (serum creatinine and blood urea nitrogen) and light histology. Lipid peroxidation was measured in renal tissue using the thiobarbituric acid assay. Significantly better survival was seen in the Na-NP group, as compared to the rest of the study. Serum creatinine at 24 and 48 hr showed a significant difference between the Na-NP group and the other groups. Histological damage was minimal in the Na-NP group. Clearly, the Na-NP had the most beneficial effect in survival and histological structure. Lipid peroxidation was significantly different, with the lower levels seen in the L-NMMA group and the higher levels in the Na-NP group. In base to these results, we conclude that exogenous NO has a beneficial and protective effect of the ischemically damaged rat kidney. This protection is independent of lipid peroxidation. Endogenous NO production does not play a role in I/R injury in our model.     

Effects of fosfomycin and imipenem/cilastatin on nephrotoxicity and renal excretion of vancomycin in rats

PURPOSE: The effects of fosfomycin and imipenem/cilastatin on the nephrotoxicity of vancomycin were studied in rats, and those on the renal handling of vancomycin were also investigated in perfused kidneys. METHODS: The protective effects of fosfomycin and imipenem/cilastatin on vancomycin nephrotoxicity were evaluated by increases in plasma concentration of creatinine and urea nitrogen in rats. The urinary excretion of vancomycin was measured and analyzed kinetically in the perfused rat kidney. RESULTS: The nephrotoxicity induced by vancomycin (500 mg/kg, i.v.) was inhibited almost completely by co-administration of fosfomycin or imipenem/cilastatin. In the perfused rat kidney, the excretion ratio of vancomycin was less than those of p-aminohippurate and cimetidine, and greater than that of arbekacin, suggesting the secretion and reabsorption of vancomycin in renal tubules. The tissue/perfusate ratios of unbound vancomycin were not significantly changed by co-treatment with fosfomycin or imipenem/cilastatin. Imipenem/cilastatin significantly decreased the excretion ratio of vancomycin. Fosfomycin also decreased vancomycin excretion ratio, although this effect was not significant. CONCLUSIONS: The renal handling of vancomycin was different from those of organic anions and cations and an aminoglycoside antibiotic. The protective effects of fosfomycin and imipenem/cilastatin against the nephrotoxicity of vancomycin might be partly due to the change in renal handling of vancomycin, probably in its tubular secretion/ reabsorption, in rats.     

Metabolic responses to preexercise meals containing various carbohydrates and fat

Renal function was examined after unilateral release, bilateral release or unilateral release and contralateral nephrectomy in three groups of rats following 24 h of bilateral ureteral obstruction (BUO). Excretion of water, sodium and urea was significantly greater in rats with unilateral release of BUO than in a single kidney of rats with bilateral release of BUO, in spite of similar levels of glomerular filtration rate (GFR) and effective renal plasma flow. Rats with unilateral release of obstruction and contralateral nephrectomy had a significantly lower GFR than the other two groups. These rats also responded with greater increases in fractional sodium and water excretion to the administration of exogenous atrial peptide. The results demonstrate a marked compensatory increase in sodium and water excretion in rats with unilateral release of the obstruction which serves to maintain homeostasis of fluid and salt. They also suggest a possible influence of the continuously obstructed kidney on the function of the postreleased kidney. The results also provide experimental support for a greater recovery of renal excretory function after bilateral release of obstruction.     

Regulation of compensatory kidney hypertrophy by its own products

1. The ligation of blood vessels of one kidney of adult rats resulted in the compensatory hypertrophy of the other kidney. In most animals the rate of hypertrophy was indistinguishable from that observed after unilateral nephrectomy, but in a few cases the onset was retarded when the renal artery alone had been ligated and the collateral circulation increased.2. When the blood vessels of one kidney of adult rats were ligated and the cortex was excised, the rate of compensatory renal hypertrophy was similar to that observed after unilateral nephrectomy.3. In animals operated for simultaneous partial hepatectomy and unilateral nephrectomy, there was no sign of compensatory renal hypertrophy while the liver was undergoing regeneration. Renal hypertrophy started after 7 days, when about 98% of the amount of liver removed had been regenerated.4. Neither aseptic autolysis of one kidney following suppression of its blood supply, nor unilateral nephrectomy affected the rate of liver regeneration after simultaneous partial hepatectomy.5. Total splenectomy did not affect the rate of compensatory renal hypertrophy following unilateral nephrectomy.6. The heterotopic graft of renal cortical, but not of medullary, cells inhibited compensatory renal hypertrophy in adult rats. The removal of the graft after 14 days was followed by the resumption of compensatory hypertrophy.7. The inhibiting action of fractions of renal cortical extracts fractionated on Sephadex G100 resin and DEAE-52 cellulose were assayed on the ;growth' of renal explants reared in vitro. The final material, though only partially purified, proved to have an inhibiting activity between 250 and 500 times greater than that of the initial extract.8. When injected into unilaterally nephrectomized rats, the partially purified extract from the renal cortex had an inhibiting effect on compensatory renal hypertrophy.9. Immunofluorescence technique showed that the partially purified cortical extract affected the proximal convoluted tubes specifically, irrespective of animal species.     

In situ preservation of kidneys from non-heart-beating donors--a proposal for a standardized protocol

The growing success in renal transplantation has resulted in an increase in the need for donor organs. Procurement of kidneys from heart-beating (HB) donors is unlikely ever to meet this demand. Non-heart-beating (NHB) donors offer a yet untapped source of renal grafts. Cadaver kidneys from patients who have sustained cardiac standstill are often considered unsuitable for transplantation due to prolonged warm ischemia time. Using an emergency in situ perfusion technique it is possible to limit warm ischemic damage and to salvage these kidneys for transplantation. The procedure requires prompt action and cooperation of emergency service personnel. This report presents a protocol for the emergency in situ preservation procedure that can be practiced in most hospitals. At the University Hospital of Maastricht, The Netherlands, implementation of this procedure resulted in 20% more kidneys available for transplantation. Although NHB donor kidneys showed a higher rate of delayed function compared with a matched HB donor kidney population, there was no significant difference in long-term graft survival between the two groups.     

Vicryl mesh for repair of severely injured kidneys: an experimental study

We evaluated the efficacy of wrapping the kidney with semi-elastic Vicryl mesh for control of hemorrhage and preservation of renal function following grade III kidney lacerations (shattered kidney) in dogs in which nephrectomy was indicated clinically. Wrapping of fragmented kidneys resulted in prompt, sustained hemostasis and reapposition of the renal parenchyma. At an average of 80 days after injury the renal lacerations were well healed. The Vicryl mesh had been fully reabsorbed and there was considerably less scar tissue at the site of parenchymal rupture and neither perirenal or intrarenal abscess nor hematoma was found, grossly or microscopically. Among 12 dogs with grade III kidney lacerations, the mean ratio of the effective renal plasma flow (ERPF) in the affected kidney to the ERPF in the uninjured contralateral kidney was 0.53 +/- 0.22. The mean ratio of creatinine clearance of the injured kidney to that of the uninjured contralateral kidney was 0.41 +/- 0.23. Changes in the serum renin levels were not statistically significant following injury. Our results seem to confirm that simple and rapid surgical treatment of severely shattered kidneys using semi-elastic Vicryl mesh is possible. The method may also be suitable for uncontrollable bleeding during nonextirpative kidney surgery.     

Upregulation of atrial natriuretic peptide gene expression in remnant kidney of rats with reduced renal mass

Atrial natriuretic peptide (ANP) is synthesized in the kidney but its physiologic significance there is unclear. To determine whether renal expression of the ANP gene is regulated, renal ANP mRNA expression was assessed in remnant kidneys after 5/6 nephrectomy in Munich-Wistar rats. In normal sodium intake groups, ANP mRNA expression in the remnant kidney was significantly increased by 5.0 +/- 0.8-fold (n = 7, mean +/- SEM) at 4 d when compared with sham-operated controls (n = 6, all sham-operated groups) (*P < 0.001 by Scheffe's test) and by 28.3 +/- 5.1-fold at 14 d. This latter response was markedly diminished to 7.6 +/- 2.1-fold (n = 7, versus sham) in rats maintained on a low sodium diet. At 4 d, on the other hand, no significant downregulation was observed with dietary sodium restriction. Because natriuretic peptides have previously been shown by us to play a major role in the adaptive responses of remnant nephrons to renal mass ablation, these data suggest that ANP of renal origin may contribute to the overall mechanism for enhancing sodium excretion in the face of declining nephron number.     

Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection

BACKGROUND: In cadaveric renal transplantation, delayed graft function (DGF) correlates with poor long-term graft survival; however, whether its effects are independent of acute rejection is controversial. We wished to study the effect of DGF on graft survival, controlling for acute rejection, discharge creatinine, and human leukocyte antigen match. METHODS: We analyzed 27,096 first cadaveric donor renal transplants reported to the UNOS Scientific Renal Transplant Registry between January 1994 and November 1997. DGF was defined as dialysis need in the first week. Acute rejection was recorded for initial hospitalization and within 6 months. Kaplan Meier survival curves were analyzed with the log rank test. RESULTS: DGF increased the incidence of acute rejection before discharge (8% without DGF; 25% with DGF, P<0.01) and any acute rejections by 6 months (25% without DGF, 42% with DGF, P<0.01). Without early rejection, DGF reduced 1-year graft survival from 91 to 75% (P<0.0001) and graft half-life from 12.9 to 8.0 years. In kidneys with acute rejection within 6 months, DGF decreased 3-year graft survival from 77 to 60% and graft half-life from 9.4 to 6.2 years (P<0.001). With a discharge creatinine of less than 2.5 mg/dl, the difference in graft half-life between no DGF and no rejection (13.4 years) and DGF with rejection (9.8 years) was significant (P<0.001). Increased donor age and cold ischemia time additionally decreased graft survival, whereas a good human leukocyte antigen match could not overcome the deleterious effects of DGF or acute rejection. CONCLUSIONS: DGF is an important independent predictor of poor graft survival. Newer immunosuppressive strategies must minimize nonimmune and immune renal injury if long-term graft survival is to improve.