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• W2010610576 abstract "The influence of chronic renal failure on renal susceptibility to an acute ischemic insult was evaluated. Recipient Lewis rats were randomly assigned to undergo 5/6 nephrectomy (chronic renal failure, CRF) or sham operation (normal renal function, NRF). After 11 weeks, normal kidneys of Lewis donor rats were transplanted in the recipients. The outcome of the isografts was assessed. Filtration capacity of the isografts in the CRF rats was preserved to approximately one-quarter of its normal capacity on the 1st day post-transplantation, whereas it fell to 0 in the NRF rats. This was reflected by a significantly higher increase in serum creatinine in the latter group. The isografts in the CRF rats had a significantly lower degree of acute tubular necrosis and no increase in the number of macrophages and T lymphocytes in the first 24 h in contrast to the NRF rats. Epithelial regeneration and repair started earlier in the CRF group. In conclusion, the present study indicated that CRF blunted ischemia/reperfusion injury of a transplanted kidney, and that its regeneration capacity was certainly not hampered by the presence of chronic uremia. These results will be the basis for studies on modulation of early leukocyte–endothelial interactions resulting from immunological disturbances inherent to the uremic environment. The influence of chronic renal failure on renal susceptibility to an acute ischemic insult was evaluated. Recipient Lewis rats were randomly assigned to undergo 5/6 nephrectomy (chronic renal failure, CRF) or sham operation (normal renal function, NRF). After 11 weeks, normal kidneys of Lewis donor rats were transplanted in the recipients. The outcome of the isografts was assessed. Filtration capacity of the isografts in the CRF rats was preserved to approximately one-quarter of its normal capacity on the 1st day post-transplantation, whereas it fell to 0 in the NRF rats. This was reflected by a significantly higher increase in serum creatinine in the latter group. The isografts in the CRF rats had a significantly lower degree of acute tubular necrosis and no increase in the number of macrophages and T lymphocytes in the first 24 h in contrast to the NRF rats. Epithelial regeneration and repair started earlier in the CRF group. In conclusion, the present study indicated that CRF blunted ischemia/reperfusion injury of a transplanted kidney, and that its regeneration capacity was certainly not hampered by the presence of chronic uremia. These results will be the basis for studies on modulation of early leukocyte–endothelial interactions resulting from immunological disturbances inherent to the uremic environment. Despite the advances in management of critically ill patients and technological advances in renal replacement therapy, the incidence and mortality of acute renal failure (ARF) have remained unchanged over the last decades (1Lameire N Verbeke M Vanholder R. Prevention of clinical acute tubular necrosis with drug therapy.Nephrol Dial Transplant. 1995; 10: 1992-2000PubMed Google Scholar, 2DuBose TD Warnock Jr, DG Mehta RL et al.Acute renal failure in the 21st century: recommendations for management and outcomes assessment.Am J Kidney Dis. 1997; 29: 793-799Abstract Full Text PDF PubMed Scopus (90) Google Scholar). The major reason for this distressing lack of change in incidence and prognosis is thought to result from the increasing age of the patients and, furthermore, a rise in severity of the underlying disease with a growing proportion of subjects acquiring multiple organ system dysfunction (3Druml W Lax F Grimm G Schneeweiss B Lenz K Laggner AN. Acute renal failure in the elderly 1975-1990.Clin Nephrol. 1994; 41: 342-349PubMed Google Scholar). The relationship between pre-existent renal insufficiency or chronic nephropathy and renal susceptibility to an acute insult is a poorly studied subject. Most studies rely on mortality as the main outcome to assess ARF, rather than on addressing issues such as susceptibility to develop ARF, and other outcomes such as the degree of renal recovery, residual renal function, etc. (2DuBose TD Warnock Jr, DG Mehta RL et al.Acute renal failure in the 21st century: recommendations for management and outcomes assessment.Am J Kidney Dis. 1997; 29: 793-799Abstract Full Text PDF PubMed Scopus (90) Google Scholar, 4Chew SL Lins RL Daelemans R De Broe ME. Outcome in acute renal failure.Nephrol Dial Transplant. 1993; 8: 101-107Crossref PubMed Scopus (50) Google Scholar, 5Novis BK Roizen MF Aronson S Thisted RA. Association of preoperative risk factors with postoperative acute renal failure.Anesth Analg. 1994; 78: 143-149Crossref PubMed Scopus (227) Google Scholar). As the size of the aging population is growing, and patients are surviving longer with both acute and chronic diseases, more studies are needed that address age and pre-existing renal failure as contributors to disease risk, outcomes, and successful therapies (6Abrass CK. Renal biopsy in the elderly [editorial].Am J Kidney Dis. 2000; 35: 544-546Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). In this respect, special attention must be given to the field of kidney transplantation, which is performed in a patient with chronic renal failure (CRF) and where a variable period of cold and warm ischemia predisposes to delayed graft function. The incurred ischemia/reperfusion injury (I/R injury) leads to a nonspecific inflammation of the kidney and indirectly to allorecognition and rejection, overall being a burden on long-term graft survival (7Lu CY Penfield JG Kielar ML Vazquez MA Jeyarajah DR. Hypothesis: is renal allograft rejection initiated by the response to injury sustained during the transplant process?.Kidney Int. 1999; 55: 2157-2168Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Experimental data on this syndrome of ‘acute on chronic renal failure’ are scarce. In our previous experimental study, I/R injury was blunted in remnant kidney (RK) rats (8Vercauteren SR Ysebaert DK De Greef KE Eyskens EJ De Broe ME. Chronic reduction in renal mass in the rat attenuates ischemia/reperfusion injury and does not impair tubular regeneration.J Am Soc Nephrol. 1999; 10: 2551-2561Crossref PubMed Google Scholar). Two possible explanations for this unexpected resistance of the RK towards acute I/R injury are the presence of a chronic uremic environment and/or a preconditioning of the RK itself. The present study evaluated the influence of a chronic uremic milieu on renal susceptibility to an acute ischemic insult. To that end, the functional and morphological outcomes after isogeneic transplantation of a normal kidney in normal vs. chronic uremic rats was investigated. This study indicated that I/R injury of a transplanted kidney is mitigated in a rat model of CRF and that the regeneration capacity of the transplanted kidney was certainly not hampered by the presence of chronic uremia. The experimental study was approved by the Ethical Committee of the University of Antwerp and was carried out in accordance with NIH Guide for the Care and Use of Laboratory Animals (1985). Rats were housed in a 24 °C and 65% humidity controlled room on a 12-h light/dark cycle, with ad libitum access to standard rat chow (16.5% protein content) and water during the entire study. Figure 1 describes the sequence of operations, ending with the transplantation of a healthy donor kidney 11 weeks after renal mass reduction or sham operation. Inbred male LEWIS rats (260–340 g) were used in order to avoid rejection as a confounding factor. Anesthesia was achieved in both experimental groups by inhalation of a mixture of isoflurane (Forene®, Abbott Laboratories Ltd, Queenborough, Kent, UK), nitrous oxide and oxygen. No difference in the amount of anesthesia needed was noted between the two groups. Rats (n = 37) were randomly assigned to undergo 5/6 nephrectomy (chronic renal failure rats, CRF group) or sham operation (rats with normal renal function, NRF group). Chronic renal failure was induced by ligation of two to three extrarenal branches of the left renal artery, followed by a right nephrectomy 1 week later (5/6 nephrectomy or remnant kidney model). The left kidney was harvested out of age-matched donor rats (n = 37) and transplanted into the recipient rat. Age-matched control rats consisted out of normal (n = 4) and remnant kidney (n = 4) rats. Heterotopic kidney transplantation was performed according to the microsurgical technique described by Fisher and Lee (9Fisher BLS. Microvascular surgical techniques in research with special reference to renal transplantation in the rat.Surgery. 1965; 58: 904-914Google Scholar), with a slight modification of the ureter-bladder anastomosis (10Provoost AP De Keijzer MH Kort WJ Wolff ED Molenaar JC. The glomerular filtration rate of isogeneically transplanted rat kidneys.Kidney Int. 1982; 21: 459-469Abstract Full Text PDF PubMed Scopus (21) Google Scholar). After intravenous injection of heparin (50 IU) in the donor rat, the donor kidney was removed with elliptical cuffs of aorta and vena cava at the end of the renal vessels; the ureter was freed and transected at 2/3–1/3 distance between the kidney and bladder. The kidney was kept at 37 °C in a 0.9% sodium chloride solution. The abdomen of the receptor rat was opened by a midline incision and the aorta and vena cava were clamped below the renal vessels. Arterial and venous end-to-side anastomoses were made with the infrarenal aorta and caval vein by continuous suturing. During the operation, the transplant was moistened with a 0.9% sodium chloride solution at 37 °C. Surface temperature of the donor kidney and body temperature of the receptor rat were regularly determined. Warm ischemia time of the transplanted kidney was standardized at 60 min. After restoring the blood supply to the transplanted kidney and inspection of reperfusion, the ureter-bladder anastomosis was made. Immediately after heterotopic transplantation of the donor kidney, the recipients' own kidney(s) was/were removed, and served as reference material. Rats were given 2.5 mL of saline (37 °C) to compensate for blood loss and dehydration. The abdominal incision was closed and the rats were placed under a spot during recovery. Before transplantation and sacrifice, rats were housed in metabolic cages for 24 h for urine sampling. Blood samples were taken from the tail at the time of transplantation, at day 1, 2 and 3 after transplantation and at sacrifice. Rats were sacrificed by aortic punction. Creatinine and urea nitrogen were measured in serum on a routine autoanalyzer system (Vitros 750 XRC) by the biochemistry laboratory of Antwerp University Hospital. Urinary creatinine was determined by a colorimetric method (Creatinine Merkotest, Diagnostica Merk, Germany). Creatinine clearance (in µL/min/100 g body weight) was calculated according to the standard formula. Protein concentration in 24-g urine samples was determined colorimetrically using the Bradford's method (11Bradford M. A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding.Annal Biochem. 1976; 72: 248-254Crossref PubMed Scopus (217544) Google Scholar). At the time of sacrifice, special attention was given to the ureter and ureter-bladder anastomosis to detect any leakage or obstruction. The transplanted kidney was checked for color and appearance, removed and weighed. Sagittal slices were made and immediately fixed in methacarn or Bouin's fixative (4 h at room temperature). The slices were processed for light microscopy by embedding in paraffin. Primary antibodies and dilutions used in this study were: PC10 monoclonal antibody (1/300; Dako), directed to proliferating cell nuclear antigen (PCNA); OX-1 (1/200; Serotec), directed to CD45 (all leukocytes); ED-1 (1/15000; Serotec), directed to a cytoplasmic antigen of monocytes/macrophages that is also expressed by dendritic cells; 1F4 (1/1000; PharMingen) directed to CD3 (all T lymphocytes). Sections of 4 µm were mounted on poly-L-lysine-coated microscopic slides and blocked with normal horse serum (1/5 in tris saline buffer), and incubated overnight with the primary antibody. Sections were stained with the avidine-biotine complex method as described previously (8Vercauteren SR Ysebaert DK De Greef KE Eyskens EJ De Broe ME. Chronic reduction in renal mass in the rat attenuates ischemia/reperfusion injury and does not impair tubular regeneration.J Am Soc Nephrol. 1999; 10: 2551-2561Crossref PubMed Google Scholar, 12Ysebaert DK De Greef KE Vercauteren SR et al.Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury.Nephrol Dial Transplant. 2000; 15: 1562-1574Crossref PubMed Scopus (310) Google Scholar). The peroxidase substrate solution was 3,3′-diaminobenzidine or 3-amino-9-ethyl-carbazole and the sections were lightly counterstained with hematoxylin. The immunohistochemical staining for PCNA was combined with the periodic acid Schiff staining (PAS). Hematoxylin-eosin (H&E) staining was performed for neutrophil counting. The remnant kidney of the receptor CRF rats and the kidneys of the NRF rats, which were nephrectomized at the end of the transplantation procedure, and the kidneys of control rats, were evaluated qualitatively for tubulo-interstitial injury on Masson-trichrome-stained sections (Bouin fixed, 4 µm). Tubulo-interstitial injury was defined as tubular atrophy, accumulation of leukocytes and/or interstitial fibrosis (8Vercauteren SR Ysebaert DK De Greef KE Eyskens EJ De Broe ME. Chronic reduction in renal mass in the rat attenuates ischemia/reperfusion injury and does not impair tubular regeneration.J Am Soc Nephrol. 1999; 10: 2551-2561Crossref PubMed Google Scholar). Analysis of the degree of I/R injury was carried out on PAS/PCNA stained 4-µm methacarn-fixed sections (8Vercauteren SR Ysebaert DK De Greef KE Eyskens EJ De Broe ME. Chronic reduction in renal mass in the rat attenuates ischemia/reperfusion injury and does not impair tubular regeneration.J Am Soc Nephrol. 1999; 10: 2551-2561Crossref PubMed Google Scholar). Sixty proximal tubules in the outer stripe of the outer medulla (OSOM) were analyzed, as this is the most vulnerable part of the kidney for ischemic injury (13Brezis M Rosen S Epstein FH. Acute Renal Failure Due To Ischemia (Acute Tubular Necrosis).in: Lazarus JM Brenner BM Acute renal failure. Churchill Livingstone, New York1993: 207-229. 1993; : 207-229Google Scholar). The S3 segments (proximal straight tubules) were assigned to four categories: (1) tubules with a normal appearance; (2) tubules with signs of sublethal injury (loss of apical brush border); (3) tubules with signs of acute tubular necrosis (from a few sloughed epithelial cells to tubules with a complete naked basal membrane); (4) and tubules with signs of regeneration (tubules without brush border, outlined with a flat epithelium containing cells with large PCNA + nuclei and a varying degree of cytoplasmic volume). Proliferation was measured by counting the number of PCNA + cells in 60 circular-shaped proximal tubules in cortex and/or OSOM. The mean number of positive cells per tubule was calculated. The number of total white blood cells (OX1 + cells) and macrophages (ED1 + cells) were counted in 30 randomly chosen gridfields in the outer stripe and inner stripe of the outer medulla (OSOM/ISOM). The number of neutrophils (H&E staining) and T lymphocytes (CD3 + cells) were counted in 20 randomly chosen gridfields in the OSOM/ISOM. Data are expressed as the mean number of cells/mm2 (total analyzed area for white blood cells and macrophages = 1.875 mm2, total analyzed area for neutrophils and T lymphocytes = 0.56 mm2). All values are expressed as mean ± SD. Statistical analysis of the data of the two groups was made using the Mann–Whitney U-test. A value of p < 0.05 was considered statistically significant. A tendency to lose body weight after each step of renal mass reduction was noted, but from the second week onward, rats started to gain weight at the same speed as the sham-operated receptor animals (data not shown). No rat died during or after the transplantation procedure, but eight out of 37 rats were excluded from further analysis for the following reasons: transplantation procedure exceeded the fixed period of ischemia (> 60 min, n = 1); necrosis of the transplant kidney (n = 3); urine leakage (n = 2); and an aberrant course in renal function (no decline in serum creatinine 3 days post-transplantation; n = 2, both in the NRF group). During transplantation, mean surface temperature of the donor kidney was 30 °C (range: 29–31 °C) and mean body temperature of the receptor rat was 35 °C at the start and 32 °C at the end of the procedure. No difference in temperatures was noted between the two groups. As shown in Figure 2A and Table 1 the pretransplantation levels of serum creatinine and serum urea nitrogen were higher in the CRF group: 1.18 ± 0.26 mg/dL and 107.53 ± 27.36 mg/dL in comparison with, respectively, 0.45 ± 0.05 mg/dL and 28.54 ± 4.14 mg/dL in the NRF group (p < 0.01). On the first day after transplantation of a normal, isogeneic kidney, the NRF group presented a severe degree of acute renal failure, whereas the degree of ARF in the CRF group was substantially less pronounced (p < 0.01) (Figure 2A). The mean increase or delta serum creatinine (level at day 1 minus level at day 0) amounted to 3.53 mg/dL in the NRF group and only 0.80 mg/dL in the CRF group. At days 2 and 3, there was still a significant better renal function of the transplanted kidney in the CRF group (p < 0.05). Recovery of normal function was almost complete at 10 days in the two groups. The urinary parameters, diuresis and creatinine clearance confirmed these observations (Figure 2.B,C). In the NRF group, creatinine clearance and urine output fell almost to 0 the 1st day post-transplantation (4 ± 6 µL/min/100 g BW, respectively, 4.2 ± 5.2 mL/24 h), in comparison to a substantial preservation of filtration capacity in the CRF group (165 ± 105 µL/min/100 g BW, respectively, 19.6 ± 7.0 mL/24 h). Recovery of ARF spread out to day 10, marked by the presence of polyuria in both groups (Figure 2C). The recovery was slightly but significantly better in the CRF group (creatinine clearance of 521 ± 78 and 403 ± 39 µL/min/100 g BW, respectively, in the CRF and NRF rats; p < 0.05).Table 1Renal functional and morphological data after isogeneic transplantation of a healthy kidneyTimeSerum urea nitrogen (mg/dl)1,Data are mean ± SD.4Number of rats per group on consecutive days (NRF/CRF n=13/16; n=13/16; n=8/11; n=8/11; n=4/6);Proteinuria (mg/24h)1Data are mean ± SD.,3p<0.05 vs. NRF.Proliferation of tubular epithelium1Data are mean ± SD., 6number of rats per group on consecutive days (NRF/CRF n=0/0; n=5/5; n=0/0; n=4/5; n=4/6);, 7proliferation of tubular epithelial cells in S3 segments in OSOM; expressed as number of PCNA+cells/tubule;Number of leukocytes in OSOM1,Data are mean ± SD. 6number of rats per group on consecutive days (NRF/CRF n=0/0; n=5/5; n=0/0; n=4/5; n=4/6);, 8expressed as the number of cells/mm2.Number of monocytes in OSOM1Data are mean ± SD., 6number of rats per group on consecutive days (NRF/CRF n=0/0; n=5/5; n=0/0; n=4/5; n=4/6);, 8expressed as the number of cells/mm2.Number of T cells in OSOM1Data are mean ± SD., 6number of rats per group on consecutive days (NRF/CRF n=0/0; n=5/5; n=0/0; n=4/5; n=4/6);, 8expressed as the number of cells/mm2.(days)NRFCRFNRFCRFNRFCRFNRFCRFNRFCRFNRFCRF028.5 ± 4.1107.5 ± 27.42p<0.01 vs. NRF;7.9 ± 2.270.3 ± 36.02p<0.01 vs. NRF;––––––––1207.8 ± 30.8196.1 ± 64.313.3 ± 14.647.0 ± 24.11.3 ± 0.82.6 ± 0.43p<0.05 vs. NRF.177 ± 13185 ± 50294 ± 15883 ± 603p<0.05 vs. NRF.67 ± 2023 ± 103p<0.05 vs. NRF.2188.1 ± 63.0148.8 ± 50.4––––––––––3130.6 ± 42.7103.5 ± 21.717.2 ± 8.120.6 ± 10.48.6 ± 3.16.1 ± 4.4100 ± 21154 ± 55257 ± 74113 ± 603p<0.05 vs. NRF.78 ± 2737 ± 271039.8 ± 3.450.6 ± 10.011.7 ± 1.312.2 ± 2.51.2 ± 1.00.7 ± 0.5545 ± 58357 ± 1083p<0.05 vs. NRF.374 ± 55217 ± 542p<0.01 vs. NRF;212 ± 43105 ± 563p<0.05 vs. NRF.5number of rats per group on consecutive days (NRF/CRF n=13/16; n=5/5; n=0/0; n=4/5; n=4/6);1 Data are mean ± SD.2 p<0.01 vs. NRF;3 p<0.05 vs. NRF.4 Number of rats per group on consecutive days (NRF/CRF n=13/16; n=13/16; n=8/11; n=8/11; n=4/6);6 number of rats per group on consecutive days (NRF/CRF n=0/0; n=5/5; n=0/0; n=4/5; n=4/6);7 proliferation of tubular epithelial cells in S3 segments in OSOM; expressed as number of PCNA+cells/tubule;8 expressed as the number of cells/mm2. Open table in a new tab 5number of rats per group on consecutive days (NRF/CRF n=13/16; n=5/5; n=0/0; n=4/5; n=4/6); The remnant kidneys of the CRF rats were nephrectomized at the end of the transplantation procedure and checked qualitatively for tubulo-interstitial lesions (Masson staining). All remnant kidneys had a comparable degree of tubular atrophy, accumulation of leukocytes and interstitial fibrosis (data not shown). A detailed sequential description of functional and morphological changes in the remnant kidney model in the Lewis rat has been reported in a previous study (8Vercauteren SR Ysebaert DK De Greef KE Eyskens EJ De Broe ME. Chronic reduction in renal mass in the rat attenuates ischemia/reperfusion injury and does not impair tubular regeneration.J Am Soc Nephrol. 1999; 10: 2551-2561Crossref PubMed Google Scholar). Kidneys of normal, control rats and the nephrectomized kidneys of NRF rats had a normal histology (data not shown). Proximal tubules in the OSOM were categorized as normal, sublethally injured, necrotic or regenerating on PAS/PCNA-stained sections as described in the Methods section. (Figure 3, Figure 4). After 24 h of reperfusion, only 12.0 ± 9.8% and 29.3 ± 15.6% of the proximal tubules in the OSOM of the transplanted kidneys had a normal appearance in, respectively, the NRF and CRF groups. Necrosis and cast formation in the CRF was less pronounced in comparison with the NRF group (31.0 ± 16.4% and 72.7 ± 13.6%, respectively, p < 0.01). No significant difference in number of sublethally injured S3 segments was found on day 1, but strikingly more tubules had signs of regeneration or repair in the CRF group (31.3 ± 6.3% vs. 5.0 ± 4.7%, respectively; p < 0.01). At day 3 post-transplantation, an equal distribution in the four different categories was found between the two transplant groups. At day 10, restoration of the normal renal morphology was reached in neither group (63.7 ± 12.3% and 79.3 ± 10.7, respectively, for NRF and CRF). The number of PCNA-positive cells (Table 1) was significantly higher at day 1 in the CRF group compared with the NRF group (2.6 ± 0.4 vs. 1.3 ± 0.8 PCNA + cells per tubule in CRF, respectively, NRF; p < 0.05). Maximum proliferation was reached at day 3 in both groups, and did not disappear completely at day 10. The amount of OX-1-positive cells present in the OSOM in a normal kidney was 58 ± 23 cells/mm2 (Table 1). After transplantation, the number of white blood cells increased gradually reaching a maximum at day 10 (545 ± 58 vs. 357 ± 108 OX1 + cells/mm2 in NRF, respectively, CRF; p < 0.05). The number of ED1 + cells (Figure 5, Figure 6) in the ISOM at day 1 post-transplantation was significantly higher in the NRF group (172 ± 38 vs. 79 ± 23 cells/mm2 in NRF, respectively, CRF; p < 0.05; number of ED + cells in a normal kidney: 64 ± 17 cells/mm2). This difference was even more pronounced in the OSOM: 294 ± 158 vs. 83 ± 60 ED1 + cells/mm2 in NRF, respectively, CRF; p < 0.01 (number of ED1 + cells in the OSOM of a normal kidney: 51 ± 10 cells/mm2). The number of ED1 + cells increased towards day 10 in both groups (Table 1). The number of CD3 + cells (Figure 5) in the ISOM at day 1 post-transplantation was significantly higher in the NRF group (31.7 ± 19.9 vs. 4.9 ± 4.0 cells/mm2 in NRF, respectively, CRF; p < 0.05; number of CD3 + cells in a normal kidney: 7.1 ± 0.5 cells/mm2). This difference was slightly more pronounced in the OSOM: 67.0 ± 20.1 vs. 23.2 ± 9.8 ED1 + cells/mm2 in NRF, respectively, CRF; p < 0.01 (number of CD3 + cells in the OSOM of a normal kidney: 20.2 ± 5.5 cells/mm2). The number of CD3 + cells increased gradually towards day 10 in both groups (Table 1). The number of neutrophils (Figure 5) in OSOM and ISOM was not different between the NRF and CRF groups, and was comparable to the number of kidneys in normal rats. Over the last decades, clinical outcome and therapeutic approaches of acute renal failure (ARF) have barely changed, despite a wealth in experimental data. Much of our understanding in the pathophysiological mechanisms of ARF comes from ‘single insult’ animal models. Unfortunately, these experimental models fail to reproduce the complex interplay of different factors involved in human ARF (14Molitoris BA Weinberg JM Venkatachalam MA Zager RA Nath KA Goligorsky MS. Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable.Am J Physiol Renal Physiol. 2000; 278: F1-F12Crossref Google Scholar, 15Sheridan AM Bonventre JV. Cell biology and molecular mechanisms of injury in ischemic acute renal failure.Curr Opin Nephrol Hypertens. 2000; 9: 427-434Crossref PubMed Scopus (251) Google Scholar). The present study with a multifactorial approach was an attempt to emulate the clinical condition of ‘acute on chronic’ renal failure. In a previous study, we have shown that injury after an equal period of ischemia in remnant kidney rats (5/6 nephrectomy) and uninephrectomized rats (3/6 nephrectomy) is less pronounced in the former group (8Vercauteren SR Ysebaert DK De Greef KE Eyskens EJ De Broe ME. Chronic reduction in renal mass in the rat attenuates ischemia/reperfusion injury and does not impair tubular regeneration.J Am Soc Nephrol. 1999; 10: 2551-2561Crossref PubMed Google Scholar). This raises the question whether the observed resistance originates from preconditioning of the remnant kidney or whether the chronic uremic environment is responsible for the protection against I/R injury in the RK group. The present study evaluated the influence of prior CRF on renal susceptibility to an acute ischemic insult. The outcome of an isogeneically transplanted, normal kidney with a standardized period of warm ischemia (60 min) was assessed in rats with a normal renal function or with CRF. The recipients' own native kidney(s) were nephrectomized in order to evaluate the function of the isograft, and to exclude possible interference of residual renal tissue on injury and regeneration of the ischemic kidney (16Finn WF Fernandez-Repollet E Goldfarb D Iaina A Eliahou HE. Attenuation of injury due to unilateral renal ischemia: delayed effects of contralateral nephrectomy.J Lab Clin Med. 1984; 103: 193-203PubMed Google Scholar, 17Fried TA Hishida A Barnes JL Stein JH. Ischemic acute renal failure in the rat: protective effect of uninephrectomy.Am J Physiol. 1984; 247: F568-F574PubMed Google Scholar, 18Coffman TM Sanfilippo FP Brazy PC Yarger WE Klotman PE. Bilateral native nephrectomy improves renal isograft function in rats.Kidney Int. 1986; 30: 20-26Abstract Full Text PDF PubMed Scopus (28) Google Scholar). The functional and morphological data clearly showed that the presence of CRF inhibited to a certain extent the development of ARF after transplantation of a normal kidney. The filtration capacity of the transplanted kidney in the CRF group was preserved to approximately one-quarter of its normal capacity on the 1st day post-transplantation, whereas creatinine clearance and urine output were dramatically reduced and fell nearly to 0 in the NRF group. This was reflected by a more pronounced increase in serum creatinine and urea nitrogen in the latter group. Morphological analysis revealed the same dramatic difference between the two groups: acute tubular necrosis affected 73% of the S3 segments in the NRF group, and only 31% in the CRF group. We examined the early accumulation and/or infiltration of monocytes and T lymphocytes (24 h after reperfusion) in the inner and outer stripe of the medulla of the transplanted kidney as an indicator of early leukocyte–endothelial interactions, which play a pivotal role in I/R injury (19Lieberthal W. Biology of ischemic and toxic renal tubular cell injury: role of nitric oxide and the inflammatory response.Curr Opin Nephrol Hypertens. 1998; 7: 289-295Crossref PubMed Scopus (80) Google Scholar, 20De Greef KE Ysebaert DK Dauwe S et al.Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia.Kidney Int. 2001; 60: 1415-1427Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Endothelial injury together with leukocyte activation leads to enhanced leukocyte–endothelial interactions that physically impede blood flow in the small vessels of the outer medulla. This increases the microcirculatory disturbances with prolonged ischemia and more S3 segment injury as a consequence (15Sheridan AM Bonventre JV. Cell biology and molecular mechanisms of injury in ischemic acute renal failure.Curr Opin Nephrol Hypertens. 2000; 9: 427-434Crossref PubMed Scopus (251) Google Scholar). Leukocytes can directly cause injury through the generation of reactive oxygen species and synthesis of phospholipase metabolites (12Ysebaert DK De Greef KE Vercauteren SR et al.Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury.Nephrol Dial Transplant. 2000; 15: 1562-1574Crossref PubMed Scopus (310) Google Scholar). In contrast to a significant accumulation of monocytes and T cells in the isograft of rats with normal renal function at day 1, no increase in the number of adhering or infiltrating macrophages and T cells was present in the isograft of rats with CRF. These findings suggest that CRF attenuates I/R injury at least in part by" @default.
• W2010610576 created "2016-06-24" @default.
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• W2010610576 date "2003-05-01" @default.
• W2010610576 modified "2023-09-26" @default.
• W2010610576 title "Acute Ischemia/Reperfusion Injury After Isogeneic Kidney Transplantation Is Mitigated in a Rat Model of Chronic Renal Failure" @default.
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