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PubMed1995

Erythropoietin and erythropoiesis in renal transplantation.

This report reviews the features of erythropoietin (Epo) production after renal transplantation. Successful kidney transplantation leads to the correction of renal anaemia over an 8-10 week period. An early ineffective peak of serum Epo may occur when there is delayed graft function. A late peak follows the decrease in serum creatinine and this is associated with a rise in haemoglobin. Serum Epo returns to normal when the haematocrit reaches 32%. Acute early rejection causes a striking reduction in serum Epo and reticulocytosis. In some patients the haematocrit continues to increase after complete correction of anaemia, resulting in post-transplant erythrocytosis (PTE). PTE generally appears to be an idiopathic erythrocytosis independent of Epo secretion. A greater Epo sensitivity of erythroid progenitors has been suggested. Theophylline and angiotensin converting enzyme inhibitors, which attenuate Epo production, can be used to treat PTE. The second part of this report describes the possible impact of human recombinant Epo (rHuEpo) on renal transplantation. The avoidance of blood transfusion with rHuEpo should eliminate the initiation of anti-HLA sensitization in uraemic patients without previous pregnancy and prior allograft. In some but not all presensitized patients transfusion withdrawal may reduce the sensitization level. There is currently no evidence that the reversing of anaemia by rHuEpo in kidney recipients impairs early graft function. Our results suggest that treatment with rHuEpo prior to transplantation may prevent the appearance of PTE. rHuEPO will reverse anaemia in patients with a failing graft and severe anaemia with little risk of accelerating graft failure and adverse events.

Anemia↗
PubMed1998

Pre-emptive kidney transplantation: the attractive alternative.

BACKGROUND: Dialysis can be life-saving for patients with end-stage renal failure. However, not only is it associated with significant morbidity and a greater mortality than transplantation, but it is also expensive. Therefore renal transplantation is generally regarded as the treatment of choice for patients in whom this form of renal replacement therapy is appropriate. Transplantation usually takes place after a variable period of dialytic therapy, but pre-emptive kidney transplantation (PKT) has established itself as an attractive alternative. MATERIALS AND METHODS: 1463 consecutive first kidney transplants performed between January 1980 and December 1995 in a single centre were analysed. The 161 patients (11%) transplanted without prior dialysis were compared with the 1302 patients who had been dialysed prior to being transplanted. The pre-emptive group did not differ from the dialysis group in respect of donor age, donor and recipient gender, HLA mismatch, or cold ischaemic time, although there were more live donor transplants within the pre-emptive group. RESULTS: Delayed graft function occurred more frequently in the dialysis group (25% vs 16%) but more patients experienced an acute rejection episode in the pre-emptive group (67 vs 55%). The actuarial graft survival in the pre-emptive group at 1, 5, and 10 years (84, 76 and 67%) was significantly higher than the respective values in the dialysis group (83, 69, and 56%). Within the live donor recipient cohort the survival advantage for the pre-emptive group was even more striking. CONCLUSION: Pre-emptive kidney transplantation not only avoids the risks, cost, and inconvenience of dialysis, but is also associated with better graft survival than transplantation after a period of dialysis, particularly within the live donor cohort.

Adult↗
PubMed2004

Spousal renal donor transplantation in Chinese subjects: a 10 year experience from a single centre.

BACKGROUND: The shortage of cadaveric kidneys for renal transplantation is a particularly problematic situation in the locality of Hong Kong. Kidneys from spousal donors are therefore increasingly being used for transplantation. This study was undertaken to evaluate the outcome of spousal donor transplant recipients in comparison with that of genetically related living donor (LRD) allograft recipients. METHODS: From 1988, we have transplanted 22 spousal kidney recipients (group 1). All donors must demonstrate a genuine spousal relationship. Their outcome was compared with that of 24 LRD allograft recipients (group 2) transplanted in the same period with similar demographics, pre-transplant dialysis duration, immunosuppressive protocol and length of post-transplant follow-up. RESULTS: The mean (+/-SD) age was 36.5 +/- 8 and 32.5 +/- 6 years for groups 1 and 2, who were followed for 56.6 +/- 35 and 59.1 +/- 38 months, respectively. There was no difference in the incidence of delayed graft function, acute rejection and serum creatinine level at 5 years. Graft survival rates were 86.4 and 79.2% (P = 0.56), while patient survival rates were 100 and 91.7% (P = 0.171) at 5 years for groups 1 and 2, respectively. CONCLUSIONS: Spousal kidney transplantation shares comparable results with LRD transplantation and should be encouraged in places where cadaveric organs remain scarce. Stringent measures must be implemented to prevent the possible emergence of kidney bartering and to protect the interests of living donors. The ethical and social issues regarding the spousal donor in Hong Kong and other countries are discussed.

Adult↗
PubMed2004

The impact of donor age on the results of renal transplantation.

BACKGROUND: The use of elderly donors is becoming more frequent. An increase in the donor's age is associated with a greater incidence of delayed graft function (DGF), chronic allograft nephropathy (CAN) and worse graft survival. Poor renal graft function is a risk factor for cardiovascular (CV) complications and, finally, for mortality of the patients. METHODS: A total of 3365 adult patients transplanted in 1990 (n = 824), 1994 (n = 1075) and 1998 (n = 1466) with a functioning graft after the first year were included. The impact of donor age on renal function, DGF, acute rejection and other clinical factors was evaluated according to two donor and recipient age categories: young (< 60 years old) and elderly (> or =60 years old). Additionally, donor age was categorized by decades for the analysis of patient and graft survival, acute rejection and CV mortality. RESULTS: Donor mean age significantly increased during the three transplantation periods. A total of 478 out of 3365 donors were older than 60 years. Elderly donors showed an increased risk of DGF (38.9 vs 28.8%) and CAN (56.8 vs 46.2%). Mean serum creatinine at 3 and 12 months and proteinuria were significantly higher in the old donor group. Incidence and severity of acute rejection were similar in both groups. Graft and patient survival were significantly lower in the old donor group. Also, risk of mortality due to CV events was also significantly higher. A linear increase in risk of graft loss, patient death or CV mortality was observed when donor age was divided into 10 year increase subsets. CONCLUSIONS: Donor age is a strong predictor of CAN and graft loss. Patient survival is also affected by donor age, particularly by a higher risk of CV mortality.

Adult↗
PubMed2004

Recipient age as a determinant factor of patient and graft survival.

BACKGROUND: Age of renal transplants has been related to death, alloimmune response and graft outcome. We reviewed the influence of patient age on transplant outcome in three cohorts of patients transplanted in Spain during the 1990 s. METHODS: Patient age was categorized into four groups (I, 18-40; II, 41-50; III, 51-60; and IV, > 60 years). Risks factors for acute rejection were evaluated by logistic regression adjusting for transplant centre and transplantation year, while a Cox proportional hazard model was employed for analysing patient and graft survival. RESULTS: Older patients had a higher death rate (I, 3.5%; II, 7.7%; III, 13.2%; and IV, 16.9%; P<0.001), but a lower standardized mortality index (I, 7.6; II, 7.0; III, 5.8; and IV, 4.1; P = 0.0019). Older patients had the lowest risk of acute rejection [odds ratio (OR) 0.79 and 95% confidence interval (CI) 0.66-0.97 for group II; OR 0.75 and 95% CI 0.62-0.91 for group III; OR 0.43 and 95% CI 0.33-0.56 for group IV). Death-censored graft survival was poorer in patients older than 60 years (relative risk 1.40; 95% CI 1.09-1.80), but this result was not explained by any combination of patient age with donor age, delayed graft function or immunosuppression. CONCLUSIONS: Patient age is a main determinant of transplant outcome. Although death rate is higher for older patients, standardized mortality was not. Thus, the efforts to reduce mortality should be also implemented in younger patients. Old patients have a low risk of acute rejection but a poorer death-censored graft survival. This last result was not explained by any controlled variable in our study.

Adolescent↗
PubMed2004

Evidence for protective roles of polyethylene glycol plus high sodium solution and trimetazidine against consequences of renal medulla ischaemia during cold preservation and reperfusion in a pig kidney model.

BACKGROUND: The renal medulla is particularly sensitive to oxidant stress and to ischaemia-reperfusion injury (IRI). In organ transplantation, delayed graft function is an important problem and cold ischaemia is thought to be the most important factor in short- and long-term complications. Our aim was to study cold-induced damage in proximal tubular segments and renal medulla osmolite excretion during use of various preservation solutions, and to clarify the role of trimetazidine (TMZ) in limiting renal dysfunction. METHODS: Using an autotransplanted pig kidney model, we assessed renal tubule function, medullary osmolite excretion and renal damage between day 1 and week 2 after 24 or 48 h cold storage in University of Wisconsin solution (UW), Celsior and ECPEG (two new high Na(+) preservation solutions) or the Hopital Edouard Herriot solution (HEH; a high Na(+) version of UW). In additional groups, TMZ was added to these preservation solutions for 24 and 48 h cold storage. RESULTS: Renal function was reduced under these preservation conditions. Tubular injury was associated with aminoaciduria and with a limited Na(+) reabsorbtion. Medullary damage led to the early appearance of trimethylamine-N-oxide and dimethylamine in urine. However, renal damage was modulated by preservation conditions. In addition, TMZ added to each of the solutions efficiently protected against IRI even after prolonged preservation. CONCLUSION: TMZ efficiently protected kidneys against damage when added to the HEH and particularly ECPEG solutions, even after 24 h cold storage. These findings point to a role for drugs that target mitochondria, and demonstrate that TMZ may provide a valuable therapeutic tool against IRI and could be included in therapeutic protocols.

Animals↗
PubMed2006

Comprehensive immunohistological analysis of the endothelin system in human kidney grafts.

BACKGROUND: In experimental models of renal transplantation, upregulation of the endothelin (ET) system and amelioration of renal injury by ET-receptor blockers have been documented. In contrast, little information is available on the expression of the ET system in human kidney allografts. It was the purpose of the present study to analyse by immunohistology the expression of ET-1 as well as of the two ET receptors (ET-RA and ET-RB) in the different cells and compartments of kidney grafts and control kidneys. METHODS: Fifty-five graft biopsies were taken from 55 kidney allograft recipients (mean age: 32+/-2.8 years) who were all on a calcineurin inhibitor. The indication for biopsies was delayed graft function or suspected rejection. The underlying diagnoses were acute allograft rejection (n = 14), chronic allograft nephropathy (n = 14), cyclosporin A (CSA) toxicity (n = 10), post-operative acute tubular necrosis (ATN) (n = 11) and recurrent primary disease (n = 6). As control, tissues of non-grafted kidneys with ATN (mean age: 35+/-24 years), of primary glomerulonephritis (mean age: 69+/-10 years) and of non-tumour-bearing parts of eight tumour nephrectomy specimens (mean age: 67+/-5 years) were assessed. The biopsies were scored using the 1997 Banff criteria. Expression of ET-1, ET-RA and ET-RB as well as of vascular endothelial growth factor was evaluated by immunohistochemistry and a semi-quantitative scoring system. Interstitial infiltrating cells were characterized using antibodies against T cells, B cells and macrophages (CD3, CD20 and CD68). RESULTS: Control cases showed only faint expression of ET-1 in glomeruli (in podocytes and endothelial cells), whereas marked expression was seen in distal, but less in proximal tubular cells. The interstitium was completely negative. ET-1 expression was seen in vascular endothelial cells (VEC) and vascular smooth muscle cells (VSMC). Only faint expression of ET-RA and ET-RB was found in glomeruli and tubuli (distal more than proximal). Marked ET-RA and ET-RB expression was seen in VEC and VSMC. In all transplanted kidneys, irrespective of the underlying diagnosis, expression of ET-1, ET-RA and ET-RB was markedly higher compared with control kidneys. ET-1 was strikingly upregulated in glomeruli and tubuli, but surprisingly not in the vasculature of grafts with CSA toxicity. Expression of ET-RB was markedly increased in CSA toxicity in glomeruli, tubuli and vessels. In grafts with ATN and acute rejection, pronounced expression of ET-RA was noted. There was a strong correlation between proteinuria and expression of ET-1 in glomeruli and proximal tubuli and of ET-RB in proximal tubuli. CONCLUSIONS: The above data in human kidney allograft biopsies are consistent with an important role of the ET system in different types of renal allograft damage. This finding extends and clarifies the somewhat contradictory results in animal models.

Acute Disease↗
PubMed2006

Retrospective analysis of surgical complications following cadaveric kidney transplantation in the modern transplant era.

BACKGROUND: Risk factors for surgical complications (SCs) following kidney transplantation in the modern transplant era need to be identified to perform appropriate prophylactic interventions. METHODS: Records from 870 consecutive adult cadaveric kidney transplants done at a single centre were reviewed. SCs were classified into four groups: (i) vascular (12%, thrombosis or stenosis); (ii) haemorrhagic (12%); (iii) ureteral (7.5%, leaks and stenosis) and (iv) wound (16%, lymphocoeles or dehiscences). RESULTS: One or more SCs occurred in 299 (34%) patients, with multiple SCs in 65 (7.4%). By logistic regression analysis, recipient vessel atherosclerosis and delayed graft function (DGF) were significantly associated with both thrombotic complications [odds ratio (OR) 4, 95% confidence interval (CI), 1.4-11, P = 0.010 and OR 3.8, 1.3-12, P < 0.00001, respectively] and graft artery stenosis (OR 2.9, 1.2-6.8, P = 0.015 and OR 5.6, 2.3-13.4, P < 0.0001, respectively). Acute rejection increased the risk of graft artery or ureteral stenosis by 2.5 (CI 1.02-6.4, P = 0.045) and 3.3 (CI 1.1-10, P = 0.034), respectively. Older recipients were related to urinary leak (OR 1.04, CI 1.01-1.07, P = 0.011). Difficult bench surgery, DGF and the use of antiplatelet drugs increased the risk of bleeding by 3.6 (CI 1.9-6.4, P < 0.0001), 2.7 (CI 1.5-4.7, P < 0.0001) and 1.8 (CI 1.03-3.29, P = 0.038), respectively. Each month on dialysis increased the risk by 1.02 (CI 1.01-1.03, P = 0.002). Sirolimus increased the risk for wound SCs by 4.1 (CI 2.1-8.3, P < 0.0001) and obesity, retransplant and acute rejection were additional risk factors. CONCLUSIONS: Adult renal transplant recipients at risk for SCs can be identified by age, DGF, graft vessel and recipient atheromatosis, difficult bench surgery, obesity, rejection and the use of antiplatelet drugs and rapamycin.

Adolescent↗
PubMed1999

The role of intraoperative heparin in cyclosporine treated cadaveric renal transplant recipients.

PURPOSE: We analyze the effect of intraoperative heparin in cadaveric renal transplantation. MATERIALS AND METHODS: We examined the records of 100 consecutive cadaveric transplant recipients who received 5,000 units of heparin at the time of vascular clamping (group 1), and compared the incidence of graft thrombosis and postoperative hemorrhagic complications to 100 consecutive cadaveric transplant recipients who did not receive heparin (group 2). The groups were similar in terms of donor age, sex, number of transplant recipients, sensitization, multiple vessels, delayed graft function and human leukocyte antigen mismatch. All patients received cyclosporine based triple therapy immunosuppression. All explanted grafts were examined histologically to rule out hyperacute rejection. RESULTS: There was no statistical difference between the 2 groups. The overall incidence of graft thrombosis was 5% (6% in group 1 and 4% in group 2). There was a greater need for blood transfusion in group 1, with 25 patients requiring transfusion postoperatively versus 14 in group 2. CONCLUSIONS: Intraoperative heparin did not reduce the incidence of graft thrombosis in this retrospective study. It did increase the postoperative blood transfusion requirements. As a result of this analysis, we have abandoned its use.

Adult↗
PubMed1986

Multivariate analysis of risk factors in cadaver donor kidney transplantation.

Data collected prospectively on 3811 kidney transplants performed between June 1977 and July 1982 with follow-up to July 1984 by the 42 member institutions of the South-Eastern Organ Procurement foundation were analyzed to identify factors associated with graft and patient outcome in patients not receiving cyclosporine. Multivariate Cox regression analysis was used to examine the association and relative risk of 24 variables with three actuarial outcomes: overall graft failure, irreversible rejection, and patient death. Factors having no suggested association with any outcome included: recipient sex, history of pregnancy, blood group, and time on dialysis; organ preservation method, time and source; donor race; crossmatch test sensitivity; and annual center transplant rate. In decreasing order of relative risk, the factors most significantly associated with irreversible rejection were: loss of two or more prior grafts, low HLA-A,B match, lack of pretransplant blood transfusion, high (greater than 60%) pretransplant sensitization to leukocyte (HLA) antigens, and delayed graft function. Splenectomy, insulin-dependent diabetes, and antilymphocyte serum therapy provided the greatest risk of patient death. Factors such as recipient age, race, and native nephrectomy had suggested associations with outcome. By adding each center as a separate covariate in the analysis, other center-dependent factors were quantitated and found in some cases to have a highly significant association with graft and patient outcome. These results provide a basis for evaluating the potential risk of graft loss or patient death for those prospective cadaver kidney transplant recipients not being considered for cyclosporine therapy.

Cadaver↗
PubMed1990

Beneficial effect of cyclosporine on renal transplantation. A multicenter long-term study.

Data were collected prospectively on 8581 cadaveric renal transplants performed by institutions of the South-Eastern Organ Procurement Foundation (SEOPF) during the period November 1, 1983 through December 31, 1987. Cyclosporine was the initial then always used immunosuppressant for 5742 of these patients while 1050 never received cyclosporine. The drug was started late in the course of 481 transplants and stopped early in 378 cases. This allowed for 7651 transplants to be analyzed regarding these four categories of cyclosporine use or non-use. Actuarial graft survival for the cyclosporine "ALWAYS" group was 75% at one year, 68% at two years, 62% at three years, and 59% at four years compared with 55%, 49%, 45%, and 43%, respectively for the cyclosporine "NEVER" group (P less than 0.0001). Inclusion of the 930 cases that could not be categorized regarding cyclosporine use or for which actuarial data was not complete allowed all 8581 transplants to be analyzed by multivariate methods. This analysis disclosed significant effects on graft survival due to delayed graft function, prior transplant, recipient race, HLA match, level of PRA, and cyclosporine use. Organ sharing had no effect on graft outcome. While cyclosporine improves outcome in renal transplantation, the importance of other biologic factors affecting graft survival is not diminished by its use.

Cadaver↗
PubMed1990

A randomized trial comparing double-drug and triple-drug therapy in primary cadaveric renal transplants.

A controlled trial was carried out in 209 primary cadaveric renal transplants to compare the effects of cyclosporine and steroids (double therapy) with those of cyclosporine in lower initial dose, azathioprine, and steroids (triple therapy). Patients have been followed 1-36 months since transplantation. Actuarial two-year graft survival (double 74%, triple 76%) and two-year patient survival (double 90%, triple 93%) were similar for both groups. Further analysis of particular risk factors including age, diabetes, HLA matching, acute renal failure, and use of sequential Minnesota antilymphocyte globulin in patients with delayed graft function also showed similar outcomes with both immunosuppressive regimens. Initial hospitalization time, rate of rejection, incidence of serious infection, and rate of rehospitalization were not different. Mean CsA doses and mean trough whole-blood levels were higher in double-therapy patients at hospital discharge but not by three months posttransplant. There were no differences between the two groups in iothalamate clearance at any time. Hypertension was more frequent six months posttransplant in the triple-therapy group (p less than 0.05). Thus, similar results were obtained with both regimens, and except for hypertension no regimen appeared to have increased side effects up to three years posttransplant.

Adrenal Cortex Hormones↗
PubMed1992

The ability of pretransplant test-dose pharmacokinetic profiles to reduce early adverse events after renal transplantation.

Pretransplant test-dose pharmacokinetic profiles were used to determine individual cyclosporine drug bioavailability and clearance rates in renal transplant patients. Assuming a linear relation between dose and area under the concentration curve (AUC), starting i.v. and p.o. CsA doses were computed from the test-dose results. Target values were 400 ng/ml steady-state concentration (Css) during continuous intravenous infusion, and 500 ng/ml average drug concentration (Cavss = AUC/dosing interval) after oral administration, based upon measurements with the specific monoclonal antibody 3H-tracer radioimmunoassay. The outcomes after dose individualization with a 1-(n = 32), 2-(n = 38), or 3-(n = 41) hr i.v. infusion test dose and a p.o. test dose (n = 111) were compared with 228 historical control patients who received a uniform protocol of CsA i.v. at 2.5 mg/kg/day and p.o. at 14 mg/kg/day. The observed Css after i.v. CsA was within 10% of the target concentration in 73% of recipients tested with the 3-hr protocol, a significantly greater fraction than achieved with either the uniform dose (14%), or the 1-(34%) and 2-(25%) hr protocols. Patients in the 3-hr protocol group showed reduced incidences of delayed graft function, early graft loss, and rejection episodes, and a lower mean serum creatinine value, particularly at 7 but also at 30 days posttransplantation. Administration of the predicted oral dose produced a peak concentration of greater than or equal to 700 ng/ml drug absorption in 60% of recipients at 3 days, 90% at 5 days, and 98% at 7 days. The test-dose method less effectively predicted the appropriate oral CsA dose to produce target Cssav and failed to reduce the 90-day rejection incidence. Despite its limitations with the more-complicated p.o. route, the test-dose method successfully predicts i.v. CsA doses, thereby reducing the incidence of early adverse events.

Administration, Oral↗
PubMed1996

Tacrolimus in pediatric renal transplantation.

Tacrolimus was used as the primary immunosuppressive agent in 69 pediatric renal transplantations between December 17, 1989, and June 30, 1995. Children undergoing concomitant or prior liver and/or intestinal transplantation were excluded from analysis. The mean recipient age was 10.3+/-5.0 years (range, 0.7-17.5 years). Seventeen (24.6%) children were undergoing retransplantation, and six (8.7%) had a panel reactive antibody level of 40% or higher. Thirty-nine (57%) cases were with cadaveric kidneys, and 30 (43%) were with living donors. The mean donor age was 28.0+/-14.7 years (range, 1.0-50.0 years), and the mean cold ischemia time for the cadaveric kidneys was 27.0+/-9.4 hr. The antigen match was 2.7+/-1.2, and the mismatch was 3.1+/-1.2. All patients received tacrolimus and steroids, without antibody induction, and 26% received azathioprine as well. The mean follow-up was 32+/-20 months. One- and 4-year actuarial patient survival rates were 100% and 95%. One- and 4-year actuarial graft survival rates were 99% and 85%. The mean serum creatinine level was 1.2+/-0.8 mg/dl, and the calculated creatinine clearance was 82+/-26 ml/min/1.73 m2. The mean tacrolimus dose was 0.22+/-0.14 mg/ kg/day, and the level was 9.5+/-4.8 ng/ml. The mean prednisone dose was 2.1+/-4.9 mg/day (0.07+/-0.17 mg/kg/day), and 73% of successfully transplanted children were off prednisone. Seventy-nine percent were not taking any antihypertensive medications. The mean serum cholesterol level was 158+/-54 mg/dl. The incidence of delayed graft function was 4.3%. The incidence of rejection was 49%, and the incidence of steroid-resistant rejection was 6%. The incidence of rejection decreased to 27% in the most recent 26 cases (January 1994 through June 1995). The incidence of new-onset diabetes was 10.1%; six of the seven affected children were able to be weaned off insulin. The incidence of cytomegalovirus disease was 13%, and that of posttransplant lymphoproliferative disorder was 10%; the incidence of posttransplant lymphoproliferative disorder in the last 40 transplants was 5% (two cases). All of the children who developed posttransplant lymphoproliferative disorder are alive and have functioning allografts. Based on this data, we believe that tacrolimus is a superior immunosuppressive agent in pediatric renal transplant patients, with excellent short- and medium-term patient and graft survival, an ability to withdraw steroids in the majority of patients, and, with more experience, a decreasing rate of rejection and viral complications.

Adolescent↗
PubMed1997

Nitric oxide synthase activity in renal ischemia-reperfusion injury in the rat: implications for renal transplantation.

Cadaveric kidney transplants with delayed graft function have poorer graft survival by an unknown mechanism. Nitric oxide, produced by nitric oxide synthase (NOS), has a proven role in both recovery of ischemia and promotion of rejection. We therefore wished to study the patterns of NOS activity in a model of renal ischemia. The left renal pedicle of Fisher rats was occluded for 1 hr. Both kidneys were removed at various times and frozen. Renal NOS activity was measured by conversion of [3H]arginine to [3H]citrulline and the content of endothelial NOS isoenzyme (eNOS) was compared by Western blot. NOS activity increased significantly in the left ischemic kidney over the first 24 hr, from a control of 33.8 pmol/min/mg to 79.8 at 2 hr and 56.8 at 24 hr. NOS activity then dropped below baseline, returning to near normal levels at day 21. eNOS content was stimulated over the entire time course, consistent with the presence of an eNOS inhibitor. Oral treatment with the NOS substrate L-arginine at 5 g/L significantly hastened the return of serum creatinine to baseline, if simultaneous contralateral nephrectomy was performed. The lazaroid U74389G given perioperatively also improved renal function and hastened recovery of NOS activity. Because nitric oxide plays an important role in maintaining blood flow during recovery from renal ischemia, the observed decrease in NOS activity may be prevented by perioperative treatment with oral L-arginine and corticosteroids. In addition, U74389G may provide a clinically useful method of minimizing and/or shortening DGF, thereby improving graft function and survival.

Animals↗
PubMed1997

Trimetazidine prevents renal injury in the isolated perfused pig kidney exposed to prolonged cold ischemia.

BACKGROUND: Ischemia caused by cold storage (CS) and reperfusion of the kidney is often responsible for delayed graft function after transplantation. Significant attention has been focused on the cascade of events involved in ischemia-reperfusion injury, with the objective of identifying drugs to ameliorate the functional damage that occurs. METHODS: The purpose of this study was to evaluate the renal function of isolated perfused pig kidneys after 48 hr of CS with Euro-Collins (EC) solution plus trimetazidine (EC+TMZ), standard EC solution, or University of Wisconsin (UW) solution. Normothermic isolated perfused pig kidneys were randomized into five experimental groups: (A) control group (cold flush with cold heparinized saline and immediately reperfused; n=6); (B) cold flush with cold heparinized saline with TMZ (10(-6) M), n=6; (C) 48 hr of CS with EC and reperfusion (n=8); (D) 48 hr of CS with EC+TMZ alone and reperfusion (n=8); (E) 48 hr of CS with UW and reperfusion (n=8). Proton nuclear magnetic resonance spectroscopy and biochemical studies were performed for the functional evaluation during reperfusion. Lipid peroxidation was also determined. Histological examination (optical and electron microscopy) was performed after CS and reperfusion. RESULTS: Using TMZ, the renal perfusate flow rate as well as the glomerular filtration rate and proximal tubular function were significantly improved. This improvement of renal function during reperfusion was correlated with a less significant cellular and interstitial edema. In addition, tubular injury markers were significantly lower in the group preserved with EC+TMZ, and TMZ reduced lipid peroxidation dramatically during reperfusion. CONCLUSIONS: The addition of TMZ to the EC solution increased the preservation quality and renal tubular function, and gave protection from reperfusion injury better than EC alone or UW. These results strongly suggest that TMZ has a cytoprotective effect and may therefore be useful for kidney preservation.

Adenosine↗
PubMed1997

When should expanded criteria donor kidneys be used for single versus dual kidney transplants?

BACKGROUND: To increase the utilization of cadaveric donor kidneys, we have recently expanded our acceptable criteria to include aged donors (frequently with a history of hypertension), by selectively using both donor kidneys (dual transplant) into a single recipient. METHODS: To define when these expanded criteria donor (ECD) kidneys should be used as a single versus a dual kidney transplant, we retrospectively reviewed 52 recipients of ECD kidneys that had been turned down by all other local centers between 1/1/95 and 11/15/96. Fifteen patients received dual transplants, whereas the remaining 37 received single kidneys. Of the dual kidney recipients, 14 of 15 ECD were > or = 59 years of age, 10 of 15 were hypertensive, and 9 of 15 were both. Of the single recipients, 11 of 37 ECD were > or = 59 years of age, 11 of 37 were hypertensive, and 7 of 37 were both. All patients received cyclosporine-based triple-drug therapy. We compared seven donor (D) and sixteen recipient outcome variables in single versus dual kidney transplants as subgrouped by: (1) donor admission creatinine clearance (D-AdC(Cr)) < 90 ml/min; (2) D-age > or = 59 years; and (3) cold storage (Cld Stg) < or > 24 hr. RESULTS: In the group with D-AdC(Cr) < 90, there was a significantly higher incidence of delayed graft function (DGF) in single versus dual recipients (9 of 20 [45%] vs. 1 of 11 [9%]; P=0.04) and worse early graft function based upon mean serum creatinine at 1 and 4 weeks (5.3+/-3.3 and 2.8+/-2.0 vs. 1.7+/-0.6 and 1.4+/-0.5 mg] dl; P<0.05). In the group with D-age > or = 59, recipients of single kidneys had significantly higher mean serum creatinine at 1, 4, and 12 weeks versus recipients of dual kidneys (5.1+/-3.3, 3.4+/-2.1, 2.8+/-1.5 versus 2.8+/-2.5, 1.5+/-0.6, 1.6+/-0.5 mg/dl; P<0.05). Cld Stg time also had an impact on DGF and early outcome. Recipients of dual kidneys stored less than 24 hr had a significantly lower incidence of DGF versus single kidneys stored more than 24 hr (10% vs. 46%; P<0.05) and better early graft function based on mean serum creatinine at 1, 4, and 12 weeks (1.9+/-0.8, 1.3+/-0.4, 1.5+/-0.2 vs. 6.6+/-3.4, 3.0+/-1.6, 2.9+/-1.9 mg/dl; P<0.05). The overall 1-year patient and graft survivals were 96% and 81% vs. 93% and 87% (P=NS) in recipients of single ECD versus dual ECD kidneys. CONCLUSIONS: In conclusion, we believe that kidneys from ECD with D-AdC(Cr) < 90 ml/min and D-age > or = 59 should be used as dual kidney transplants, keeping the Cld Stg time at < 24 hr to minimize the effect of Cld Stg on early graft function.

Adult↗
PubMed1998

Mycophenolate mofetil reduces the risk of acute rejection less in African-American than in Caucasian kidney recipients.

BACKGROUND: Multicenter clinical trials have shown that mycophenolate mofetil (MMF) reduces the risk of acute rejection, but it is unknown whether African-Americans constitute a subgroup of recipients less likely to benefit from MMF. METHODS: This study compared the acute rejection rates within 6 months of kidney transplantation in MMF-treated transplant patients with those on azathioprine (AZA) at a single center. The study population consisted of 353 consecutive recipients of cadaver or living donor kidney transplants. African-Americans constituted 43% of the patients on AZA and 49% of the patients on MMF. Variables used in a Cox regression analysis included MMF immunosuppression, recipient race, type of transplant, delayed graft function, postoperative immune induction, average cyclosporine trough level, and HLA mismatch. RESULTS: Significantly fewer patients on MMF experienced a biopsy-proven rejection episode than those treated with AZA (24% vs. 42%, respectively; relative risk [RR]=0.57, P=0.001). This decrease in risk was greater in Caucasian transplant recipients (MMF vs. AZA: 16% vs. 46%, RR=0.35, P < 0.001) than in African-American patients (32% vs. 36%, RR=0.88, P=0.6). Within each race stratum, the mean cyclosporine trough levels averaged over 2-week intervals were nearly identical for AZA- compared with MMF-treated patients. In the regression model, the effect of MMF on the incidence of rejection was again less in African-American than in Caucasian patients. CONCLUSIONS: Kidney recipients treated with MMF have a significantly lower risk of acute rejection within 6 months of transplantation than those given AZA. This reduction in risk is significantly less in African-American recipients than Caucasians.

Adult↗