Effect of cyclosporine and delayed graft function on posttransplantation erythropoiesis

The effect of delayed graft function and immunosuppressive drugs on posttransplant erythropoiesis was studied prospectively in 18 living-related (LR) and 84 cadaver-donor (CD) recipients. Eight of 18 LR and 20 of 84 CD recipients received antilymphoblast globulin (ALG) in addition to azathioprine and prednisone. Sixty-four CD recipients received cyclosporine (CsA) with prednisone. In the absence of rejection reticulocytosis began 6.7 +/- 0.2 days following graft implantation in azathioprine-only-treated LR recipients. This was lengthened by ALG to 9.4 +/- 0.3 and 9.9 +/- 0.7 days in LR and CD recipients, respectively, whose grafts functioned immediately. Delayed graft function prolonged onset of reticulocytosis to 15.9 +/- 0.9 days in ALG-treated but not in CsA-treated recipients (5.8 +/- 0.4 days). The shortest latency was noted in CsA-treated recipients (4.9 +/- 0.5 days) with immediately functioning grafts. The earlier onset of reticulocytosis of CsA-treated recipients was followed by statistically significant blunting of peak reticulocytosis, which correlated with a slower rate of correction of anemia (delta Hct = 0.19/day) compared with non-CsA-treated recipients (delta Hct = 0.34/day). Early rejection was associated with abrogation of reticulocytosis and correction of anemia without regard to immunosuppressive regimen) until rejection was reversed. Erythropoietin (EPO) was measured sequentially in 5 patients with immediate function. In 4 of 5 cases changes in EPO preceded those in reticulocytosis. EPO rose from a mean of 13 mU/ml pretransplant to a peak of 50 within 3 weeks and decreased to 18 mU/ml within 6 weeks of graft implantation. At six months posttransplant, normalized reticulocyte counts were only 55% higher (1.75 vs. 1.13%) but hematocrit had increased from 26 +/- 1% to 42 +/- 1%. Hematocrit varied inversely with serum creatinine, which was highest in CsA-treated patients with initial delayed graft function. We conclude that correction of anemia posttransplantation is driven by EPO but other factors may also be important, that neither ATN nor ALG-therapy have clinically important effects on erythropoiesis, and that CsA reduced "effective" erythropoiesis and influences correction of anemia--particularly if delayed graft function complicates the initial course posttransplantation.     

Peritoneal dialysis versus hemodialysis in patients with delayed graft function

Delayed graft function (DGF) in kidney transplantation affects adverse outcomes. It remains unclear whether the post‐transplant dialysis modality alters perioperative or long‐term graft outcomes. We performed a retrospective observational quality initiative at two Canadian renal transplant centers, in which DGF occurred in the recipient, necessitating one of peritoneal dialysis (PD) or hemodialysis (HD). There was no difference in baseline factors between patients with post‐transplant PD (n = 14) or HD (n = 63). The use of PD was associated with an increased risk of wound infection/leakage (PD 5/14 vs. HD 6/63, p = 0.024), shorter length of hospitalization (13.7 vs. 18.7 d, p = 0.009) and time requiring dialysis post‐operatively (6.5 vs 11.0 d, p = 0.043). There were no differences in readmission to hospital within 6 months (4/14 vs. 23/63, p = 0.759), graft loss (0/14 vs. 2/63, p = 1.000) or acute rejection episodes (1/14 vs. 4/63, p = 1.000) at one yr, and GFR did not differ between the PD or HD groups at 30 d (35.7 vs. 33.8 mL/min/m², p = 0.731), six months (46.9 vs. 45.5 mL/min/m², p = 0.835) or one yr (46.6 vs. 44.5 mL/min/m², p = 0.746). Further research is needed to determine which transplant patients are most appropriate to undergo PD catheter removal at the time of transplantation.     

Addition of sirolimus to cyclosporine delays the recovery from delayed graft function but does not affect 1-year graft function

Delayed graft function (DGF) has long been identified as one of the main correlates of poor graft survival in cadaveric renal transplantation, but the factors that affect its onset and duration are not fully elucidated. The impact of two immunosuppressive protocols on the incidence and length of DGF among kidney transplant recipients of a suboptimal organ was evaluated. Patients were randomly treated with corticosteroids (CS); low-dose cyclosporine (CsA) and sirolimus (SRL; group 1; n = 42); or CS, full-dose CsA, and mycophenolate mofetil (group 2; n = 48). All recipients received immunoprophylaxis with basiliximab. After 3 mo, group 1 discontinued CsA and continued with SRL, whereas group 2 continued the same treatment. The incidence of DGF was similar in the two groups (group 1 = 52.4%; group 2 = 58.3%), whereas its duration was significantly higher in the group 1 (19.0 +/- 6.0 versus 10.3 +/- 3.2 d; P = 0.001). Both groups showed 100% actuarial graft and patient survival at 1-yr. Among DGF patients, serum creatinine (sCr) at discharge was significantly worse in group 1 (sCr, 3.0 +/- 1.0 versus 1.5 +/- 0.2 mg/dl; calculated creatinine clearance, 31.2 +/- 9.3 versus 61.1 +/- 10 ml/min; P = 0.001). During the first year, the former group displayed a significant improvement of graft function, such that at 1-yr, no difference could be measured between groups (sCr, 1.8 +/- 0.5 versus 1.7 +/- 0.4 mg/dl; calculated creatinine clearance, 51.5 +/- 10.2 versus 53.3 +/- 9.4 ml/min). In conclusion, in de novo renal transplanted patients, the administration of SRL, in combination with low-dose CsA, is associated with a delayed recovery from DGF but does not worsen 1-yr graft function.     

Highly sensitized patients with delayed graft function: a management protocol

The postoperative management of the highly sensitized renal transplant recipient with delayed graft function on cyclosporine is complicated. Allografts with delayed graft function are reported to have a 20 to 30% poorer 1-year survival than allografts without delayed graft function. Several factors may be implicated in this poorer 1-year survival. A decrease in or cessation of cyclosporine dosage frequently is used in an attempt to minimize nephrotoxicity. Such under-immunosuppression can result in irreversible rejection. Occasionally, a pessimistic view of the prognosis for the transplant may result in early abandonment of the allograft with discontinuation of immunosuppression and allograft nephrectomy. We report on 3 highly sensitized patients whose kidneys had delayed graft function and were deliberately maintained on high doses of cyclosporine throughout the period of delayed graft function. Each graft achieved function (2, 4 and 5 months) after transplantation. The serum creatinine levels 20, 28 and 38 months after transplantation were 2.7, 2.0 and 1.0 mg./dl., respectively. We suggest that the maintenance of high cyclosporine levels throughout the delayed graft function period is useful in highly sensitized recipients and was an important factor in their successful outcome. A management protocol for such patients is proposed.     

Impact of the delayed graft function in hypersensitized kidney transplant patients

AIM: The aim was to study the incidence, impact, and association of pretransplantation anti-HLA antibodies and delayed graft function (DGF) on the outcome of cadaver kidney transplants independent of the immunosuppressive therapy. METHODS: Data from 1325 cadaver donor kidneys (February 1975 to December 2002) included the variables of current and peak anti-HLA antibodies, presence of DGF, acute rejection (AR) episodes, patient survival, and graft half-life. RESULTS: DGF (need for dialysis in the first week posttransplantation) ranged between 15% and 40% with a mean of 30% in last 5 years. Eighty-five percent of the candidates on the waiting list for kidney transplants displayed <25% panel reactive antibody (PRA) at transplantation with 4.6% between 26% and 50%, 7.7% between 51% and 75%, and 1.5% >75%. Among the patients who developed DGF, 47% displayed AR compared an incidence of 30% among patients without DGF (P=.0026). The patients displaying >50% PRA (either current or maximum) showed a worse graft survival compared with patients with <50% PRA (log rank, P=.0000). DGF reduced graft survival (P=.04), the difference appearing in the early phase after transplantation. The best outcome was observed in the no DGF-no AR group (half-life, 11.6 years) and the worst results were in the hypersensitized patient groups: peak and current PRA >50% (half-lives of 2.4 and 2.2 years). A multivariate analysis showed that the presence of peak or current PRA >50% is the most important risk factor for graft loss. CONCLUSION: Sensitization is the key factor in graft outcome. Presensitization increases the risk of DGF and DGF increases the incidence of AR and both together produce the worst graft survivals.     

Basiliximab improves graft survival in renal transplant recipients with delayed graft function

The aim of this study was to evaluate the use of basiliximab in first renal transplant recipients with delayed graft function, defined by the need for dialysis in the first week posttransplantation. Among 148 patients in the study, 90 received basiliximab (60.8%) with 58 comprising the control group. There were no significant differences between the 2 groups related to the evaluated variables, except that the control group received more blood transfusions pretransplantation. There was a lower incidence of steroid-resistant rejection (6% vs 20.9%; P = .017) and humoral rejections (0% vs 7%; P = .038) in the basiliximab group. Also, graft survival was significantly higher in basiliximab group compared with the control one (92.8% vs 80.4%; P = .028). There were no significant differences in the other outcomes. In conclusion, this study confirmed the beneficial effects of addition of basiliximab to the immunosuppressive schema of patients with delayed graft function.     

Association of graft neutrophil sequestration with delayed graft function in clinical renal transplantation

BACKGROUND: The authors studied the impact of neutrophil activation, detected in experimental models, on reperfusion injury in clinical renal transplantation. METHODS: Forty-five patients from a larger trial comparing three immunosuppressive protocols were recruited: perioperative antithymocyte globulin (ATG) with low initial cyclosporine A (CsA) triple therapy (group A, n=15); two-dose basiliximab with low initial CsA triple therapy (group B, n=16); and conventional triple therapy (group C, n=14). Blood samples were obtained preoperatively, before reperfusion, and at 1 and 5 min after reperfusion. During reperfusion, samples were collected from the iliac artery and the graft vein for calculation of transrenal differences (Delta) of study parameters. Leukocyte differential counts, plasma lactoferrin concentration, and neutrophil CD11b and L-selectin expressions were assessed. Graft blood flow was measured at 2 and 30 min after reperfusion. RESULTS: ATG induced neutrophil activation already before reperfusion. Thus, group A was excluded, but groups B and C were pooled for analysis of reperfusion-induced neutrophil activation. At 1 min after reperfusion, lactoferrin concentration was higher in graft vein than iliac artery, yielding Delta=15 microg/L (P<0.05). Concomitantly, Delta neutrophil count correlated with both Delta L-selectin expression (R=0.49, P=0.012) and graft blood flow at 2 min (R=0.51, P=0.007). At 5 min after reperfusion, 0.17 (-1.0-0.24)x10 cells/L neutrophils were sequestered in the graft (P<0.001). This sequestration correlated with graft blood flow at 30 min (R=0.53, P=0.005) and was stronger in patients with delayed graft function (DGF) (Delta = -0.38 [-1.45 to -0.2]) than those without (Delta = -0.12 [-0.41-0.24], P<0.001). In multiple regression analysis, sequestration was the most important parameter associated with DGF. CONCLUSIONS: Neutrophils are activated and sequestered in the reperfused graft during clinical renal transplantation. Neutrophil sequestration is a powerful independent factor explaining the incidence of DGF.     

Outcomes of DCD kidneys with CIT-induced delayed graft function

Donation after circulatory death (DCD) kidneys are exposed to warm ischemia, which, coupled with cold ischemia time (CIT) exacerbates delayed graft function (DGF) and is possibly associated with worse graft survival. To analyze the risk of CIT-induced DGF on DCD kidney outcomes, we evaluated national data between 2008 and 2018 of adult kidney-only recipients of paired DCD kidneys where one kidney recipient experienced DGF and the other did not. Of 5602 paired DCD kidney recipients, multivariate analysis between recipients with higher CIT relative to lower CIT showed that increasing CIT differences had a significant dose-dependent effect on overall graft survival. The graft survival risk was minimal with CIT differences of ≥1-h (adjusted hazard ratio [aHR] 1.07, 95% CI .95– 1.20, n = 5602) and ≥5-h (aHR 1.09, 95% CI .93–1.29, n = 2710) and became significant at CIT differences of ≥10-h (aHR 1.37, 95% CI 1.05–1.78, n = 1086) and ≥15-h (aHR 1.78, 95% CI 1.15–2.77, n = 1086). Between each of the four delta-CIT levels of shorter and longer CIT, there were no statistically significant differences in the proportion of acute rejection. These results suggest that in the setting of DCD kidney transplantation (KTX), DGF, specifically mediated by prolonged CIT, impacts long-term graft outcomes.     

Mycophenolate mofetil, with cyclosporine and prednisone, reduces early rejection while allowing the use of less antilymphocytic agent induction and cyclosporine in renal recipients with delayed graft function

Antilymphocytic agent induction (ALAI), with antithymocyte globulin or monoclonal antibody, is generally used in renal transplantation (TX) to spare renal allografts with poor initial function from the toxic effects of cyclosporine (CsA) and/or to augment immunosuppression (IS) in the patient at a high risk for early rejection. ALAI, unfortunately, increases the cost of TX and the risk to the patient, having been associated with many adverse side effects. An IS protocol, which results in a low incidence of early rejection while using less CsA and ALAI, is a worthwhile goal.
We compare our experience with mycophenolate mofetil (MMF), CsA, and prednisone (MMFCP; n=62) to our azathioprine (AZA), CsA, and prednisone (AZACP; n=50) triple‐drug IS, with and without ALAI. The patient characteristics for age, race, first TX, cadaveric donor, pediatric recipient, and dialysis in the first post‐op week (DGF) were not different for the MMFCP versus AZACP groups. There were more females in the MMFCP group (51.6% versus 30.0%, p=0.022).
We report that rejection‐free survival at 6 months (RF6) was better in the MMFCP versus AZACP group (83.9% versus 60.0%, p=0.005). Less ALAI and CsA were used in the MMFCP patients. At 1 year, actuarial graft survival was 91.9% in the MMFCP group and 81.9% in the AZACP group (p=0.116). Actuarial 1‐year patient survivals were not different in the two patient groups. In the sub‐population of patients with DGF, the RF6 in the MMFCP (n=13) group was 92.3% versus 57.1% in the AZACP (n=14) group (p=0.041). The reduction in early rejection episodes in the patients on MMFCP with DGF was accomplished while using half as much ALAI and lower CsA doses and levels. The African‐American recipient sub‐population on MMFCP also demonstrated an improvement in RF6 while using less ALAI and CsA (78.6% versus 48.0%, p=0.022).
We conclude that the use of MMF‐based triple‐drug IS results in fewer rejection episodes while allowing for lower CsA levels and less ALAI, even in patients with delayed graft function.     

Acute rejection in kidney grafts with delayed onset of graft function

Forty-five kidney transplant recipients with delayed onset of diuresis due to acute tubular necrosis (ATN) were examined with duplex ultrasonography (DU). Resistive index (RI) was measured on the 4th post-transplant day. Eleven grafts (24%) developed acute rejection. Mean RI prior to rejection of the 4th postoperative day in these grafts was 0.97 and in the 34 grafts which did not develop rejection mean RI was 0.82. There were 2/26 rejections (8%) in the group of grafts with an initial RI below 0.9 and 9/19 rejections (47%) in the group of grafts with RI of 0.9 or above on the 4th post-transplant day. Six months postoperatively there were 2/26 nonfunctioning grafts in the group with lower initial RI values (<0.9) and 6/19 nonfunctioning grafts in the group with higher indices (0.9). In nonfunctioning grafts a high initial RI (0.9) indicates that these grafts will be prone to developing actute rejection.     

Risk factors for delayed kidney function and impact of delayed function on patient and graft survival in adult graft recipients

The influence of delayed kidney graft function on allograft outcome is described controversially in the literature. The aim of the study was to evaluate possible risk factors for delayed graft function (DGF) and investigate the impact of DGF on short- and long-term renal allograft function. Two groups were formed: the first one consisted of patients who gained immediate graft function (IGF) (n = 64) after transplantation and the second group included patients with DGF (n = 31; with at least one dialysis needed in first week after transplantation). The DGF group had a statistically significant longer duration on dialyses prior to transplantation (DGF 54 vs. IGF 33 months; p < 0.05), on average more frequently a re-transplantation (DGF 1.7 vs. IGF 1.3; p < 0.01), a longer re-anastomosis time (DGF 52.9 vs. 44.2 min; p < 0.01), a lower systolic (DGF 136 +/-24 mmHg vs. IGF 158 +/- 25; p < 0.001) and diastolic blood pressure (DGF 78 +/- 14 vs. IGF 89 +/- 16 mmHg; p < 0.01) at admission to the hospital and a higher serum (S)-creatinine at discharge (DGF 2.5 +/- 1.6 vs. IGF 1.6 +/- 0.4 mg/dL; p < 0.01). Prior to transplantation the DGF group had more often advanced vascular diseases (DGF 29.0 vs. IGF 12.5%; p < 0.01) and these patients incurred more frequently new ones during the next 3 yr after transplantation (DGF 22.6 vs. IGF 6.3%; p < 0.001). After 3 yr the graft survival tended to be lower in the DGF group (DGF 74.2 vs. IGF 84.4%; NS), but this difference was not statistically significant.     

Endocrine-metabolic function in remission-phase IDDM during administration of cyclosporine

We have studied the endocrine-metabolic status of patients in non-insulin-receiving (NIR) remission of insulin-dependent diabetes mellitus (IDDM) within 6-60 mo of diagnosis during administration of cyclosporine, in comparison with nondiabetic subjects. IDDM patients in NIR remission were recognized when target glycemic control (plasma glucose and mean capillary blood glucose levels less than 7.8 mM before meals) was maintained without administration of insulin for at least 2 wk. In so-called isoglycemic tests, 50 g glucose was administered orally, and the glycemic curve was simulated in a subsequent study by programmed intravenous infusion of glucose. Under these conditions, the subjects with diabetes exhibited obvious glucose intolerance: acute beta-cell responses to intravenous glucose were virtually absent but significant, although subnormal responses were present after oral glucose. The responses of plasma immunoreactive gastric inhibitory polypeptide to oral glucose were normal. After bolus intravenous injections of glucose, the patients with diabetes again exhibited glucose intolerance; acute responses of immunoreactive insulin (IRI) and C-peptide were present, although grossly obtunded. On intravenous infusion of arginine (30 g in 30 min), the patients with diabetes showed substantial but subnormal increases in plasma IRI and C-peptide. Intravenous infusion of arginine elicited increments of plasma immunoreactive glucagon (IRGI) in both groups, and this response was slightly exaggerated in the patients with diabetes. On ingestion of a standard mixed meal (Sustacal) delivering 600 cal, there was a modest but significantly greater increase in plasma glucose levels in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Three-year posttransplant graft survival in renal-transplant patients with graft function at 6 months receiving tacrolimus or cyclosporine microemulsion within a triple-drug regimen

BACKGROUND: Registry data can provide valuable information about possible treatment effects; however, pretreatment differences in patient characteristics may influence treatment assignment. Careful analysis must therefore be undertaken when evaluating treatment differences in the context of nonrandomized studies so that the impact of treatment selection bias is minimized. METHODS: A multivariable risk factor analysis of adult patients registered in the US Renal Data System who received a primary renal allograft during 1995 to 1998 was undertaken to compare 3-year graft survival using tacrolimus or Neoral with mycophenolate mofetil (MMF) and steroids. RESULTS: In total, 9,449 patients were included (cadaveric donor n=6,011; living donor n=3,438). Patients (2,130) received tacrolimus, and 7,319 received Neoral. At 3 years posttransplant, the proportion of cadaveric donor recipients experiencing all causes of graft loss was 10.0% for tacrolimus and 10.6% for Neoral; for living donor recipients these figures were 6.5% and 6.7%, respectively (unadjusted Kaplan-Meier analysis). The incidence of graft failure excluding death was also similar between the two groups. With Cox proportional hazards modeling, the adjusted relative hazard of 3-year graft failure for cadaveric donor patients taking tacrolimus versus Neoral was 1.02 (95% confidence interval [CI] 0.8-1.3), and for living-donor recipients it was 1.15 (95% CI 0.8-1.8). CONCLUSIONS: These results indicate excellent 3-year graft survival for both cadaveric and living-donor renal-transplant patients receiving either Neoral or tacrolimus with MMF and steroids, with no significant differences between treatment groups. On the basis of these results, relative cost-effectiveness may become increasingly important in selection of tacrolimus or Neoral as primary immunosuppressant for renal-transplant patients.     

Long-term renal outcomes after delayed graft function

Delayed graft function (DGF) describes dysfunction of the kidney allograft immediately after transplantation and is the most common complication in the immediate posttransplantation period. Although a standardized definition for DGF is lacking, it is most commonly defined as the need for dialysis within the first week after transplant. DGF is caused by a variety of factors related to the donor and recipient as well as organ procurement techniques. The occurrence of DGF affects both allograft and patient outcomes. In addition to prolonging hospital stay and increasing the costs associated with transplantation, DGF is associated with an increased incidence of acute rejection after transplantation and is associated with poorer long-term graft outcomes. Both immunologic and nonimmunologic mechanisms contribute to DGF. The risk factors for DGF that have been identified are reviewed as well as the impact of DGF on long-term outcomes.     

Sub‐clinical acute rejection detected using protocol biopsies in patients with delayed graft function

Abstract Acute rejection in renal transplants is difficult to diagnose when patients have delayed graft function (DGF) in the early post‐transplant period. In this study protocol, renal transplant biopsies were performed in an attempt to detect sub‐clinical acute rejection episodes. Eighty‐three patients were eligible for the study, of whom 33 had DGF. All had protocol renal transplant biopsies performed under ultrasound control at 7 days post‐transplant, and those with DGF had further biopsies weekly until the graft functioned. All histologically confirmed acute rejection episodes were treated. Sub‐clinical acute rejection was detected in 6/33 (18%) patients with DGF compared to 2/50 (4 %) in the other patients (P < 0.05). Borderline rejection was present in 4/33 (12 %) and 4/50 (8 %) patients, respectively. Because of the high detection rate of sub‐clinical acute rejection and the low morbidity of renal transplant biopsies, their use is recommended in patients with DGF.