Long-term graft survival after conversion from cyclosporin to azathioprine 1 year after renal transplantation. A prospective, randomized study from 1 to 6 years after transplantation

Cyclosporin has improved graft survival after renal transplantation,but cyclosporin nephrotoxicity is a severe clinical problem.Conversion from cyclosporin to azathioprine 1 year after transplantationmight improve long-term graft survival by avoidance of cyclosporinnephrotoxicity. After treatment with cyclosporin and prednisoloneduring the first year after renal transplantation, 106 patientswere consecutively randomized to treatment with either azathiprineand prednisolone or cyclosporin and prednisolone in a prospective,controlled study during the following 5 years, i.e. 6 yearsafter transplantation. Actuarial estimates of graft survivalrates after inclusion in the study were obtained by the product-limitmethod of Kaplan-Meier, and the Mantel-Cox log rank test wasused to compare the two treatment regimens. When the end-pointsin the analyses were cessation of graft function or withdrawalof immunosuppressive treatment due to side-effects, and whenpatients alive with graft function or who had died with a functioninggraft were treated as censored observations, graft survival5 years after inclusion in the study was 57.7±5.2% inthe total material and was the same in both the azathioprinegroup (52.4±7.7%) and the cyclosporin group (63.3±6.7%)(log rank=0.40, P=0.53). When cessation of graft function wasthe only end-point, graft survival 5 years after inclusion inthe study was 73.7±5.2% for the total material with nosignificant differences between the two groups (log rank=0.58,P=0.45). Assuming that cyclosporin and prednisolone were usedduring the first year after renal transplantation, it can beconcluded that conversion to treatment with azathioprine andprednisolone does not deviate from continued treatment withcyclosporin and prednisolone with regard to long-term graftsurvival for the following 5 years.     

The beneficial effects of oral nifedipine on cyclosporin-treated renal transplant recipients — a randomised prospective study

The aim of this study was to test the hypothesis that nifedipine will improve graft survival in cyclosporin A (CyA)-treated renal transplant recipients. One hundred and forty-seven patients were randomised to one of three regimens. Group A received CyA, 7 mg/kg per day, and prednisolone; group B followed the same regimen as group A plus oral nifedipine and group C received CyA, 4 mg/kg per day, prednisolone and azathioprine. Calcium channel blockers were avoided in groups A and C. The crude 2-year (P=0.0223) and 4-year (P=0.0181) graft survival was significantly better in group B (86% and 81%, respectively) than in group A (75% and 63%, respectively). Delayed initial function was seen least frequently in group B (10.2%) compared to groups A (31%) and C (28%; P<0.01). Group B also experienced fewer rejection episodes than groups A and C (P<0.05). We conclude that the combination of oral nifedipine and CyA significantly improves initial graft function, rejection frequency and long term graft survival.     

Influence of diltiazem on renal function and rejection in renal allograft recipients receiving triple-drug immunosuppression: a randomized, double-blind, placebo-controlled study

In a prospective, randomized and placebocontrolled study weevaluated the influence of treatment with the calcium-channelblocker diltiazem on the course and results of cadaveric kidneytransplantation in 39 graft recipients. The grafts were reperfusedwith Euro-Collins solution containing diltiazem 20 mg/l. Allrecipients except those in chronic treatment with a calcium-channelblocker received preoperatively a bolus of diltiazem or placebo0.3 mg/kg and in all an infusion of diltiazem or placebo 3 mg/kg/24h was started preoperatively. After that, diltiazem or placebowas given orally for 3 months. Donors were not treated. Immunosuppressivetherapy consisted of prednisone, azathioprine and CsA. Therewere no significant differences between the groups concerningdonor or recipient characteristics, HLA-mismatching, and ischaemictime. Thrombosis leading to graft loss occurred in 3 recipients(diltiazem:2, placebo:1) and one graft was lost due to septicaemia(diltiazem). For the remaining 35 grafts no beneficial effectof treatment with diltiazem was found for the rate of delayedgraft function, the rate of rejections, time to first rejection,whole blood CsA concentration, or graft function. The CsA doseneeded to reach target whole blood concentration was significantlyless in the diltiazem group. In conclusion, our results do notindicate any beneficial effects of treatment with diltiazemin cadaveric kidney transplantation, except a reduction of costsbecause of a significant reduction of the CsA dosage.     

Long-term renal allograft outcome after simultaneous kidney and pancreas transplantation.

BACKGROUND: In selected young patients with type 1 diabetes mellitus and end-stage renal failure, simultaneous pancreas and kidney (SPK) transplantation is the treatment of choice. We conducted a retrospective, case-controlled study to compare the function, survival and pathology of renal allografts after SPK and kidney-alone (KA) transplantations. METHODS: We studied 26 consecutive SPK patients and 67 KA controls matched for time of transplantation. Renal function was assessed by routine evaluation of serum creatinine and its course by the 1/serum creatinine vs time curve. Histologic evaluation of early biopsies (0-3 months post-transplantation, n=63), intermediate biopsies (3 months-1 year, n=75) and late biopsies (after 1 year, n=35) were performed by two independent reviewers. RESULTS: SPK and KA recipients differed significantly with regard to donor and recipient age, time on the waiting list, HLA sensitization, renal cold ischaemia time (CIT) and the incidence of delayed graft function. Acute rejection was more frequent after SPK than KA (54 vs 27%; P=0.01), despite higher trough levels of calcineurin inhibitors. After SPK and KA, actuarial patient and renal allograft survival and renal function were comparable at 1 and 4 years. Severe chronic lesions, especially vascular lesions, and calcineurin-inhibitor nephrotoxicity were more frequent in intermediate and late biopsies in the SPK group. CONCLUSIONS: We confirmed that patient and graft survival is comparable between SPK and KA recipients. Despite the use of optimal organs and shorter CIT in SPK, renal graft function was not different in the two groups. Histologic chronic lesions were more severe in SPK than in KA recipients. This might be caused by acute rejection episodes or be due to more severe nephrotoxicity after SPK, because of higher doses of calcineurin inhibitors, or higher sensitivity to calcineurin-inhibitor nephrotoxicity.     

Impact of patterns of proteinuria on renal allograft function and survival: a prospective cohort study

Suhail SM, Kee TSY, Woo KT, Tan HK, Yang WS, Chan CM, Foo MWY, Li HH, Siddique MM, Wong KS. Impact of patterns of proteinuria on renal allograft function and survival: a prospective cohort study.
Clin Transplant 2011: 25: E297–E303. © 2011 John Wiley & Sons A/S. Abstract: Background: Proteinuria is an important complication in renal transplant recipients. The aim of this prospective study was to evaluate the long‐term impact of transplant proteinuria patterns on allograft function and survival. Methods: We analyzed urinary protein of a cohort of 83 renal transplants with proteinuria ≥0.5 g/d by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and radial immunogel diffusion assay. After initial stratification and analysis, the cohort was followed up for 16 yr. The graft outcome and survival were analyzed using Cox regression model to determine their association with different patterns of initial transplant proteinuria. Results: Group with predominantly glomerular (middle‐ and high‐molecular‐weight with or without low‐molecular‐weight) proteinuria (61%) had higher serum creatinine (p < 0.001) than the group with predominantly tubular (low‐molecular‐weight) proteinuria (39%). The incidences of chronic graft dysfunction and graft loss had increased in the glomerular proteinuria group (p < 0.001, hazard ratio 3.6, 95% confidence interval 1.7–7.5 and p < 0.001, hazard ratio 4.9, 95% confidence interval 1.9–12.1, respectively). Patient death did not differ (p = 0.434, hazard ratio 1.5, 95% confidence interval 0.5–4.5). Conclusion: Proteinuria in renal transplants can be differentiated into glomerular and tubular types based on molecular weight. Glomerular proteinuria is associated with significant increase in graft dysfunction and graft loss.     

A randomized placebo-controlled study of enalapril in the treatment of erythrocytosis after renal transplantation

BACKGROUND: Erythrocytosis is a common complication of renal transplantationwith an incidence of up to 17%. It is associated with an increasedrisk of complications due to thromboembolic events and has traditionallybeen treated by intermittent venesection. More recently, angiotensin-convertingenzyme inhibitors have been shown to cause a fall in haematocritin a number of groups of subjects and some uncontrolled studieshave shown these drugs to be of possible therapeutic benefitin post renal transplant erythrocytosis. METHODS: We performed a randomized double-blind placebo-controlled studyin 25 patients with post-transplant erythrocytosis. Subjectsreceived either 2.5 mg of enalapril daily or a placebo for 4months and all patients completed the study period without anyserious adverse effects. RESULTS: Haematocrit fell from 52.7 (±SEM 0.7) to 47.1 (±1.8) at 1 month and 46.1 (± 1.2) after 4 months in patientsreceiving enalapril, with no change in the placebo group (P=0.004).We did not demonstrate any change in serum erythropoietin ineither group. CONCLUSION: Angiotensin-converting enzyme inhibitors are a safe and effectiveform of treatment for erythrocytosis developing after renaltransplantation. The mechanism of action, however, is not mediatedby changes in erythropoietin production and remains uncertain.     

The importance of early renal graft function

Onset of function and consequent graft and patient survivalin 7923 cadaveric kidney transplants (Tx) were analysed; 42.3%of grafts had early function, 43.6% delayed function, definedas a temporary need of dialysis postoperatively, and 14.1% graftsnever functioned. Multivariate analysis of 1743 cases showed that important riskfactors for delayed function were of non-immune origin, i.e.length of pre-Tx dialysis, or warm and cold ischaemia. The significantrisk factors for non-functioning were of immune origin i.e.panel-reactive antibodies, DR mismatches, immunosuppres-sionwithout cyclosporin A and previous Tx. Five-year survival rates of early function and delayed functiongrafts were identical when non-functioning grafts were excluded.Comparison of early function with delayed function grafts dividedaccording to the length of the function delay showed worse (p<0.05)survival in grafts with delayed function > 20 days only (50.6%grafts had delayed function < 10 days, 32.7% 10–20days, and 16.7% >20 days). Survival of recipients with non-functioninggrafts was worse (P<0.01) than those with early functionand delayed function grafts. There was no difference in recipients'survival between early function and delayed function groups. When comparing early function and delayed function graft outcome,the problem is not so much a question of how as when to defineearly function. A statement that delayed function is prognosticallya bad sign is not correct, as most delayed function grafts recoverspontaneously without any effect on long-term graft and patientsurvival. The poorer survival of grafts with delayed function > 20days and the risk of non-functioning stresses the need to takeprecautionary measures to ensure early function. Kidneys withrisk factors for delayed function should not be used in thepresence of immune factors associated with non-function.     

Effect of moderately intense perioperative glucose control on renal allograft function: a pilot randomized controlled trial in renal transplantation

Recipient diabetes accounts for ~34% of end‐stage renal disease in patients awaiting renal transplantation and has been linked to poor graft function. We conducted a single‐center, open‐label, randomized controlled trial to determine whether moderately intense glucose control during allograft reperfusion would reduce the incidence of poor graft function. Adult diabetics undergoing deceased donor renal transplant were randomized to moderately intense glucose control (n=30) or standard control (n=30). The primary outcome was poor graft function (dialysis within seven days of transplant or failure of serum creatinine to fall by 10% for three consecutive days). Recipients with moderately intense glucose control had less poor graft function in the intention‐to‐treat (43.3% vs 73.3%, P=.02) and per‐protocol analysis (43.2% vs 81%, P<.01). Recipients with moderately intense control also had higher glomerular filtration rate (GFR) at 30 days after transplant in the per‐protocol and intention‐to‐treat analyses. There were no episodes of severe hypoglycemia in either group and no differences in mortality, seizures, stroke, graft loss, or biopsy‐proven rejection. Moderately intense glucose control at the time of allograft reperfusion reduces the incidence of poor graft function in diabetic renal transplant recipients and improves glomerular filtration rate at 30 days.     

Effect of renal transplantation on endothelial function in haemodialysis patients.

BACKGROUND: Haemodialysis patients (HD) have been characterized by a high incidence and prevalence of atherosclerotic cardiovascular disease. Based on the traditional cardiovascular risk factors in this population, we cannot explain this high incidence and prevalence. One of the mechanisms contributing to cardiovascular risk in HD patients may be to uraemic toxins. Cardiovascular risk factors and uraemic toxins themselves may cause endothelial dysfunction, which may play a pivotal role in the development and progression of atherosclerosis in this population. We hypothesized that elimination of uraemic toxins in response to renal transplantation (RTx) can improve endothelial function as assessed by flow-mediated dilatation of brachial artery in haemodialysis (HD) patients. METHODS: Endothelial function measured by flow-mediated dilatation of the brachial artery (FMD) and glyceryltrinitrate-induced dilatation of the brachial artery (NMD) were assessed twice, during haemodialysis treatment and after RTx in 30 chronic haemodialysis patients. All patients were characterized by absence of known atherosclerotic disease and traditional cardiovascular risk factors. We also studied age- and gender-matched 20 normotensive healthy controls. RESULTS: FMD values significantly improved after RTx (6.69+/-3.1% vs 10.50+/-3.0%, P<0.001) in HD patients. FMD of patients both during haemodialysis and after RTx was lower than in healthy controls (6.69+/-3.1%, 10.50+/-3.0% vs 14.02+/-2.3%, P<0.001 and P<0.01, respectively). There was no change in NMD values after RTx in HD patients (16.27+/-1.9% vs 16.30+/-1.8%, P>0.05). Also, NMD values in all patients were similar to healthy control values. CONCLUSIONS: There is an improvement of endothelial function as assessed by FMD of the brachial artery after RTx in HD patients. This may be attributed to the elimination of uraemic toxins by successful RTx.     

A prospective,double-blind,randomized study of high-versus low-dose OKT3 induction immunosuppression in cadaveric renal transplantation

We undertook a prospective, double-blind study of high-(5-mg) versus low-(2-mg) dose OKT3 for induction immunosuppression (12 days) in cadaveric renal allograft transplantation. Maintenance immunosuppression was identical in both groups and consisted of azathioprine and prednisone initially, with cyclosporine beginning on the 5th postoperative day. Twenty-six patients were randomized. The groups were similar in terms of age, kidney ischemia time, peak PRA, and latest PRA. There were more diabetics and women in the high-dose group. Patient survival at 12 months was 100% in both groups. Graft survival at 12 months was 92% and 100% in the high- and low-dose groups, respectively. Infections were mostly minior and equal in frequency in the two groups. All patients receiving high- or low-dose OKT3 had manifestations of the cytokine release syndrome; these were delayed in onset in the low-dose group. Eleven patients (85%) in each group produced anti-OKT3 andtibodies. Lymphocyte depletion after 1 day was major (>98%) and identical in both groups. CD3 antigens were removed more slowly in the low-dose group but eventually at equal rates in both groups. Cost was significantly lower in the low-dose group. We conclude that while both doses of OKT3 were effective and safe for induction immunosuppression, it may be prudent to use a lower dose of OKT3 for induction immunosuppression because of its potential to reduce cytokine-mediated effects and to avoid the complications of overimmunosuppression and because of the lower costs associated with it.     

Major effects of delayed graft function and cold ischaemia time on renal allograft survival.

BACKGROUND: There is mounting evidence from experimental and clinical studies that the quality of organs from cadaver donors may be influenced by events occurring around the time of brain death, and that these may affect transplant outcome. The aim of this study is to investigate the influence of donor factors on renal allograft outcome in a homogeneous cohort of 518 patients transplanted in a single centre over a 9 year period. METHODS: Endpoints of the study were delayed graft function (DGF), acute rejection (AR), 1 year graft survival and long-term survival of those grafts that reached 1 year. Multivariate analysis was performed to determine factors that may have influenced the graft outcome indicators. RESULTS: DGF was the major predictor of graft failure overall with cold ischaemia time (CIT) as an important independent factor. The level of histocompatibility did not influence graft survival. DGF was the major factor affecting 1 year graft survival (P<0.0005) with effects persisting beyond 1 year. DGF was significantly influenced by CIT, donor age, female kidney into male recipient and donor creatinine (P<0.05). Other donor factors and factors associated with donor management were not risk factors for DGF, rejection episodes or graft survival. The risk factors for a number of AR episodes were HLA-DR mismatch and DGF (P<0.005). When grafts surviving for 1 year were considered, only CIT, recipient age and creatinine at 1 year (P<0.05) were found to affect graft survival significantly. CONCLUSIONS: The results of this analysis of well-matched transplant recipients show that CIT and DGF are the most important predictors of poor short and long-term graft survival. Therefore, in order to improve the long-term survival of renal allografts efforts should focus on limiting CIT and the damage that occurs during this period and on improving our understanding of DGF.     

Predictors of graft survival at diagnosis of antibody-mediated renal allograft rejection: a retrospective single-center cohort study

Antibody-mediated rejection (ABMR) is a major cause of graft loss in renal transplantation. We assessed the predictive value of clinical, pathological, and immunological parameters at diagnosis for graft survival. We investigated 54 consecutive patients with biopsy-proven ABMR. Patients were treated according to our current standard regimen followed by triple maintenance immunosuppression. Patient characteristics, renal function, and HLA antibody status at diagnosis, baseline biopsy results, and immunosuppressive treatment were recorded. The risk of graft loss at 24 months after diagnosis and the eGFR slope were assessed. Multivariate analysis showed that eGFR at diagnosis and chronic glomerulopathy independently predict graft loss (HR 0.94; P = 0.018 and HR 1.57; P = 0.045) and eGFR slope (beta 0.46; P < 0.001 and beta −5.47; P < 0.001). Cyclophosphamide treatment (6× 15 mg/m²) plus high-dose intravenous immunoglobulins (IVIG) (1.5 g/kg) was superior compared with single-dose rituximab (1× 500 mg) plus low-dose IVIG (30 g) (HR 0.10; P = 0.008 and beta 10.70; P = 0.017) and one cycle of bortezomib (4× 1.3 mg/m²) plus low-dose IVIG (HR 0.16; P = 0.049 and beta 11.21; P = 0.010) regarding the risk of graft loss and the eGFR slope. In conclusion, renal function at diagnosis and histopathological signs of chronic ABMR seem to predict graft survival independent of the applied treatment regimen. Stepwise modifications of the treatment regimen may help to improve outcome.     

Effect of donor source on renal allograft function in children on triple immunosuppression

Results of renal transplantation using cadaver donors (CAD)are usually inferior to those using living related donors (LRD).We have previously reported 100% 1-year CAD and LRD graft survivalusing adult cadaver donors and triple immunosuppression. Inthe present study glomerular and tubular function of 23 LRDand 22 CAD grafts (median ages 3.5 and 2.6 years) were comparedduring 3 years after transplantation. Glomerular filtrationrate (GFR) and renal plasma flow were lower in CAD grafts butremained stable in both groups. The mean GFRs were 87.3 and63.2 ml/min/l.73 m² at discharge and 82.8 and 72.5 ml/min/1.73m² at 36 months in LRD and CAD grafts respectively. No significantdifferences were found after 6 months. Tubular function wasgood in both groups. The only significant difference was inurate handling at 36 months (mean serum urate 396 µmol/lin CAD, 301 in LRD grafts, P<0.05). Cyclosporin nephrotoxicitymanifested as hyperkalae mia due to reduced distal potassiumsecretion and/or adrenal suppression. In conclusion, donor source had little effect on the developmentof progressive allograft dysfunction using adult CAD graftsand triple immunosuppression with CsA administered in threedaily doses to preschool children.     

DTPA renal scan assessment of renal allograft dysfunction in rats

The precise cause of allograft dysfunction after renal transplantation often cannot be established by non-invasive means. In clinical practice, radionuclide scans form an integral part of the clinician's armamentarium in the assessment of these patients [1, 2]. Unfortunately, in the clinical setting more than one pathological process may be responsible for the impaired function, making it difficult to correlate the scan appearances with the pathology. In this study in rats we compared the renal DTPA scan appearances of the various pathological processes which may cause renal allograft dysfunction in the immediate post-transplant period.     

肾移植与血液透析治疗对尿毒症患者阴茎勃起功能影响的临床对照研究

目的:研究对比男性尿毒症患者接受肾移植与接受血液透析治疗勃起功能的变化及与生殖激素水平变化的关系。方法:收集2009年5月至2012年1月在我院门诊进行随访的肾移植男性患者35例、血液透析治疗的尿毒症患者30例,应用国际勃起功能指数(IIEF-5)调查表、夜间勃起功能(NEVA)测定仪评估阴茎勃起功能,同时测定生殖激素水平。结果:接受肾移植手术者勃起功能障碍(ED)患病率为51.4%,血液透析者ED患病率为73.3%(P<0.05);肾移植后的ED患者发病情况要明显轻于单纯血液透析的ED患者;肾移植中重度ED患者(25.7%)要明显少于单纯血液透析者(46.6%);肾移植组中ED患者夜间阴茎勃起次数、勃起强度及持续时间均强于单纯血液透析组ED患者(P<0.05);接受肾移植患者较单纯血液透析血清睾酮水平上升[(4.32±1.37)vs(2.53±1.12)ng/ml,P<0.05],雌二醇[(19.57±2.29)vs(43.38±5.58)pg/m)]和催乳激素[(8.59±1.19)vs(17.22±3.31)mIu/ml]明显下降(P均<0.05)。结论:肾移植受者肾功能良好时其总体勃起功能要优于单纯血液透析的尿毒症患者。     

Incidence and outcome of Levitronix CentriMag support as rescue therapy for early cardiac allograft failure: a United Kingdom national study

Objective: Primary graft failure is the most common cause of mortality early after heart transplantation. The availability of relatively low-cost short-term mechanical support devices has altered the management of primary graft failure but there are few data on clinical outcome. Here, we describe the UK experience with Levitronix CentriMag support following heart transplantation across multiple centres. Methods: Data for all adult heart transplants and all CentriMag devices used within 30 days of heart transplantation in the UK between November 2003 and July 2008 were collected. Transplant characteristics were compared for those who did and did not receive CentriMag support, and device outcomes and survival rates were summarised. Results: A total of 572 heart transplants were performed in this period. As many as 38 patients (6.6%) were implanted with CentriMag devices for primary graft failure. Four patients received extracorporeal membrane oxygenation concurrently and were excluded from further analysis. There were no significant differences in transplant characteristics between the patients who received CentriMag support and those who did not. Twelve patients were explanted; nine survived but three died shortly afterwards. Five underwent acute retransplantation; two survived and three died. Seventeen patients died on support. The 30-day and 1-year survival rates were 50% (95% confidence interval (CI) 32–65%) and 32% (95% CI 18–48%), respectively. Patients who previously had a bridge-to-transplant ventricular assist device (VAD) had significantly better survival than those who did not (1-year survival 71% vs 22%, p = 0.029). Conclusions: Primary graft failure remains an important early complication of heart transplantation. Levitronix CentriMag support led to the salvage of 32% of patients with severe allograft failure.     

Delayed graft function is not associated with an increased incidence of renal allograft rejection

Delayed graft function (DGF) is considered as a risk factor for renal allograft rejection, but this association might be confounded by diagnostic biases (e.g., higher biopsy frequency in patients with DGF, inclusion of clinically diagnosed rejection episodes, and limited details on the rejection phenotype). This retrospective study including 329 deceased donor transplantations aimed to clarify a causal relationship between DGF and rejection. DGF occurred in 93/329 recipients (28%), whereas immediate graft function (IGF) in 236/329 recipients (72%). The percentage of patients with ≥1 allograft biopsy within the first year post‐transplant was similar between the DGF and IGF group (96% vs. 94%; p = 0.60). The cumulative one‐yr incidence of biopsy‐proven clinical (35% vs. 34%; p = 0.62) and combined (sub)clinical rejection (58% vs. 60%; p = 0.79) was not different between the two groups. Furthermore, there were no differences regarding rejection phenotypes/severities and time frame of occurrence. By multivariable Cox regression analysis, donor‐specific HLA antibodies, younger recipient age, and immunosuppressive regimens were independent predictors for clinical rejection, while DGF was not. These results in an intermediate sized, but thoroughly investigated patient population challenge the concept that DGF is a risk factor for rejection and highlights the need for additional studies in this regard.