Post-transplant hyperglycaemia: a study of risk factors.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) has several identifiable pre- and post-transplant risk factors. The link to nutritional status pre-transplant has not been explored previously. This study was conducted to identify risk factors for the development of PTDM, with emphasis on pre-transplant nutritional status and glucose tolerance. METHODS: Non-diabetic adult end-stage renal failure patients awaiting renal transplantation were studied prospectively. Their nutritional status was assessed as body mass index (BMI), serum albumin, and the evolution of these parameters over time prior to transplantation. An oral glucose tolerance test (OGTT) was performed pre- and serially post-transplant until 6 months. Pre- and post-transplant risk factors such as age, nutritional status, glucose tolerance parameters and immunosuppression were related to the development of PTDM or impaired glucose tolerance (IGT) post-transplant. RESULTS: The mean age of 174 patients studied over a 2-year period was 32.9 +/- 9.7 years. The mean post-transplant follow-up was 25.6 +/- 12.8 months. The mean BMI at recruitment was 18.3 +/- 2.4 kg/m(2). The rate of increase in BMI pre-transplant showed an inverse correlation with the baseline BMI (r = -0.34, P = 0.000) and formed an independent marker of nutritional status. PTDM developed in 21.4% patients and 24.1% had IGT. On univariate and multivariate analyses, the factors significantly associated with the development of PTDM were greater age, more rapid increase in dry weight after starting haemodialysis (HD), elevated pre-transplant OGTT responses and cyclosporin (CsA) and prednisolone doses early post-transplant. Additionally, on multivariate analysis, higher CsA trough level > 300 ng/ml at 3 months increased the risk for the development of PTDM. Of patients who developed PTDM, 57% had impairment of glucose tolerance pre-transplant (> 140 mg/dl at 2 h). Patients with a 1-h glucose value greater than the 50th percentile on pre-transplant OGTT had a 3.9-fold greater risk for the development of PTDM (P = 0.05, 95% CI = 1.03-11.1). In those patients with higher 1-h glucose (> 50th percentile) who also gained in dry weight rapidly pre-transplant, the risk increased to 5.3 (P = 0.02). Of 76 patients with abnormal OGTT early post-transplant, only 68% continued to have PTDM or IGT post-transplant, the remainder reverting to normal glucose tolerance. CONCLUSIONS: Persistent abnormal glucose tolerance after transplantation was seen in 45% of the patients. Pre-transplant factors including greater age, abnormal glucose tolerance parameters, and rapid gain in dry weight on HD, along with higher prednisolone and CsA doses early post-transplant were the important factors associated with the development of PTDM. Identification of patients with pre-transplant risks might allow modification of post-transplant immunosuppression with non-diabetogenic agents.     

A 6-year prospective study on new onset diabetes mellitus, insulin release and insulin sensitivity in renal transplant recipients.

BACKGROUND: It is well known that both insulin resistance and insulin deficiency are involved in the pathogenesis of post-transplant diabetes mellitus (PTDM), but the relative importance of the two different mechanisms is still under debate. The present prospective longitudinal study was performed over 6 years to investigate the impact of impaired insulin secretion (ISec) and insulin sensitivity (IS) in the development of PTDM in renal transplant recipients. METHODS: A total of 95 non-diabetic patients underwent a 75 g oral glucose tolerance test (OGTT) 10 weeks post-transplant. Six years later, 63 of these recipients were re-examined, the majority (n = 58) with an OGTT. Fasting, 1- and 2-h insulin and glucose levels were measured and used to estimate the insulin secretory response and IS both at baseline and at follow-up. RESULTS: The proportion of recipients with normal glucose tolerance (NGT) rose from 46% (baseline) to 65% (follow-up) (P = 0.008), and median fasting and 2-h serum glucose were reduced by 0.7 mmol/l (P < 0.001) and 1.3 mmol/l (P = 0.039), respectively. The recipients with PTDM at follow-up had a significant decline in the estimated median first and second phase ISec (-58 and -47%, respectively, P = 0.005 for both). The patients who normalized their glucose tolerance from PTDM or IGT at baseline to NGT at follow-up increased their IS significantly (68%, P = 0.002) without significant alterations in ISec. CONCLUSIONS: Impaired ISec seems to be the dominant mechanism in the development of PTDM after renal transplantation. In contrast, normalization of glucose intolerance is associated with improved IS.     

The impact of impaired insulin release and insulin resistance on glucose intolerance after renal transplantation

The current knowledge of the pathogenesis of post-transplant glucose intolerance is sparse. This study was undertaken to assess the relative importance of insulin secretion (ISec) and insulin sensitivity (IS) in the pathogenesis of post-transplant diabetes mellitus (PTDM), impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) after renal transplantation. An oral glucose tolerance test (OGTT) was performed in 167 non-diabetic recipients 10 wk after renal transplantation. Fasting, 1-h and 2-h insulin and glucose levels were used to estimate the insulin secretory response and IS. One year after transplantation 89 patients were re-examined with an OGTT including measurements of fasting and 2 h glucose. Ten weeks after transplantation the PTDM-patients had significantly lower ISec and IS than patients with IGT/IFG, who again had lower ISec and IS than those with normal glucose tolerance (NGT). One year later, a similar difference in baseline ISec was observed between the three groups, whereas baseline IS did not differ significantly. Patients who improved their glucose tolerance during the first year, were mainly characterized by a significantly greater baseline ISec, and they received a significantly higher median prednisolone dose at baseline with a subsequent larger dose reduction during the first year, than the patients who had their glucose tolerance unchanged or worsened. In conclusion, both impaired ISec and IS characterize patients with PTDM and IGT/IFG in the early course after renal transplantation. The presence of defects in insulin release, rather than insulin action, indicates a poor prognosis regarding later normalization of glucose tolerance.     

Metabolic cardiovascular syndrome after renal transplantation.

BACKGROUND: Cardiovascular disease (CVD) is the major cause of death in renal transplant recipients. Traditional risk factors like hypertension, dyslipidaemia and diabetes mellitus are common, but cannot completely account for the high prevalence of CVD in this population. The aim of the present study was to assess whether post-transplant glucose intolerance, defined as post-transplant diabetes mellitus, impaired glucose tolerance, or impaired fasting glucose, is associated with metabolic disturbances known to increase risk of cardiovascular disease, similar to what has been observed in the general population. METHODS: One hundred and seventy-three consecutive patients were prospectively examined 10 weeks after transplantation. An oral glucose tolerance test was completed in 167 patients. Questionnaires, medical records, and the results of various blood tests were used to evaluate a number of known cardiovascular risk factors in all patients. RESULTS: Glucose intolerance was present in about one-half the recipients and was associated with age, a positive family history of ischaemic heart disease, acute rejection, higher levels of serum triglycerides, apolipoprotein B and 2-h insulin, and lower levels of serum HDL cholesterol. After adjustment for age and sex, lower HDL cholesterol (P=0.005), higher serum triglycerides (P<0.001), apolipoprotein B (P=0.039) and 2-h insulin (P<0.001) were still associated with post-transplant glucose intolerance. CONCLUSIONS: Ten weeks after renal transplantation glucose intolerance is associated with a clustering of cardiovascular risk factors and metabolic abnormalities, consistent with a post-transplant metabolic cardiovascular syndrome.     

Bilateral nephrectomy simultaneously with renal allografting does not alleviate hypertension 3 months following living-donor transplantation

Severe hypertension prior to renal transplantation has traditionallybeen an indication for bilateral nephrectomy. The reasons forhypertension after successful renal transplantation are howevermany, and the impact of simultaneous bilateral nephrectomy (BN)in this setting has not been well documented. We retrospectivelyevaluated 158 living-donor renal graft recipients. BN had beenperformed in 76 patients at the time of the transplantationand 82 were not nephrectomized (controls). All received a tripleimmunosuppressive drug regimen. Before transplantation, patientsin the BN group used 1.8±0.9 (mean±SD) antihypertensivedrugs/day, significantly more than in the control group (1.3±0.8;P<0.05). Three months after renal transplantation no differencewas found (0.9±1.0 drugs/day in the BN group vs 1.0±0.8drugs/day in the control group). No difference was found withrespect to serum creatinine, whole blood cyclosporin A (CsA)concentration or blood pressure between the groups. The numberof blood transfusions during the first week after transplantationwas significantly increased in the BN group (66 SAG units vs4 SAG units). The median hospitalization length was also longerin the BN group (21 days vs 16 days). In order to circumscribethe pre-transplant difference in use of antihypertensive medicationwe studied a subgroup of 62 hypertensive recipients (BN/control= 31/31) matched for number of antihypertensive drugs at thetime of transplantation (2.3±0.5 drugs/day in the BNgroup, 2.1±0.3 drugs/day in the control group). Threemonths after transplantation the use of antihypertensive drugsremained the same in the two groups (1.3±1.0 drugs/dayin the BN group vs 1.3±0.9 drugs/day in the control group).At 3 months no difference was found between the two hypertensivesubgroups regarding serum creatinine, whole blood CsA and haemoglobinconcentration or systolic blood pressure. However, the BN patientswere younger than the control group (38±10 years vs 49±11years, P<0.05) and this may explain the marginally lowerdiastolic blood pressure observed in the BN group (82±10mmHg vs 87±7 mmHg, P<0.05). It is concluded that,in recipients of living-donor grafts, bilateral nephrectomyperformed at the time of transplantation did not influence thenumber of antihypertensive drugs used 3 months after a successfultransplantation. Bilateral nephrectomy did however increasethe need of blood transfusions during the first week after transplantationand also the hospitalization length.     

Hypertension after renal transplantation. A comparison of cyclosporine and conventional immunosuppression

Hypertension is a common complication after renal transplantation and is associated with increased mortality. Cyclosporine is known to be nephrotoxic and raises blood pressure in recipients of cardiac and bone marrow transplants, but there is conflicting data on the role of cyclosporine after renal transplantation. We have examined this question in patients entered into the second Oxford prospective randomized comparison of short-term cyclosporine treatment alone with conversion to azathioprine and prednisolone at 90 days (CsA group), and conventional therapy with azathioprine and prednisolone throughout (AP group). Blood pressure and antihypertensive medication were similar in the CsA and AP treatment groups during the first 90 days. Following conversion from cyclosporine, mean blood pressure fell from 155/94 to 142/81 within 7 days, and this fall correlated with the change in plasma creatinine over the same period (r = 0.44, P less than 0.05). Blood pressure was subsequently lower in the converted patients than in those treated with AP throughout. Six months after transplantation patients converted from cyclosporine not only had lower blood pressure but also required fewer antihypertensive drugs than AP patients. This study demonstrates that cyclosporine may elevate the blood pressure in recipients of renal transplants. This effect may either be direct or mediated through the effect of cyclosporine on renal function. Administration of corticosteroids during the first three months after transplantation is implicated as a possible cause of persisting high blood pressure.     

Renal function after kidney transplantation in children. A comparison of conventional immunosuppression with cyclosporine

Clearance studies were performed in 32 transplanted children treated with CsA in combination with low-dose prednisolone (CsA group), and the results were compared with those of 29 children transplanted earlier and treated with azathioprine and prednisolone (CIS group). Serum creatinine and urea levels 6 weeks and 1 year after transplantation (Tx) were significantly higher in the CsA than in the CIS group. Clearance studies 6 weeks after Tx exhibited significantly lower rates in the CsA group: Cin = 47 +/- 16.5 versus 83 +/- 25 ml/min/1.73 sqm, CPAH = 271 +/- 110 versus 503 +/- 181 ml/min/1.73 sqm (P less than 0.001). The filtration fractions were not different (19.1 versus 17.1%). The tubular phosphate reabsorption per ml GFR (Tp/Cin) was only slightly lower in the CsA group (0.76 +/- 0.23 mumol/ml versus 0.93 +/- 0.29; P = 0.09). The endogenous glucose clearance rates were equally elevated in both groups and returned to normal after 1 year. The creatinine clearance (Ccr) had dropped in both groups by a mean for 13 ml/min/1.73 sqm between 6 weeks and 1 year after Tx. No correlation was found between the Ccr and the CsA blood levels, but Ccr was inversely correlated with the number of rejection episodes (r = -0.72, P = 0.001). In conclusion, renal allografts in CsA-treated children exhibited a significantly lower function than in CIS-treated children. The effect was related to the global kidney function without any signs of additional tubular toxicity and was apparent within the first weeks after Tx. Thereafter, the decline in graft function was comparable in both groups and could not be related to CsA treatment.     

Amelioration of chronic renal allograft dysfunction in cyclosporine-treated patients by addition of azathioprine

Management of chronic renal allograft dysfunction in cyclosporine-prednisone treated renal allograft recipients remains problematic. We therefore initiated a protocol of azathioprine addition (1.0-1.5 mg/kg/day) to ongoing CsA/Pred therapy. Three groups were treated. Group A (n = 21) had chronic progressive renal dysfunction (serum creatinine greater than or equal to 2.5 mg/dl or more than 15% above baseline) four or more months after transplantation. Group B (n = 8) had frequent or severe rejection episodes occurring despite adequate CsA levels. Group C (n = 7) had constitutional side effects of CsA with or without renal dysfunction persisting despite drug taper or financial difficulty in affording CsA. Aza was initiated 17.8 +/- 2.8 months after transplantation in group A, the mean serum creatinine having risen from 2.55 +/- 27 mg/dl to 3.04 +/- .20 mg/dl (P = .07) over the six months preceding Aza initiation, despite stable and low therapeutic range HPLC whole-blood CsA levels (118 +/- 10 ng/ml vs. 133 +/- 11 ng/ml, P = NS). Renal function declined at a rate of -0.20 +/- .06 Cr1/year in the six-month period before addition of Aza, and then improved at a rate of 0.09 +/- .04 Cr-1/year after addition of Aza (P = .002). These changes in renal function occurred without a decrease in CsA levels (118 +/- 10 six months before Aza vs. 126 +/- 26 six months after Aza, P = NS). In group B Aza was initiated at 58 +/- 8 days after transplantation when mean sCr was 3.56 +/- .29 mg/dl and mean CsA level was 222 +/- 17 ng/ml. At least follow-up 12.7 +/- 2.0 months after addition of Aza, all group B grafts were functioning, mean sCr was 2.69 +/- .31 mg/dl (P = .09 compared with baseline), and mean CsA level was 128 +/- 34 ng/ml (P = .07 compared with baseline). Group C patients had addition of Aza at 43 +/- 19 months after transplantation when mean sCr was 2.97 +/- .60 and mean CsA level was 125 +/- 30 ng/ml; addition of Aza had no influence on the rate of decline in renal function in this group. Of these 36 patients, 6 received therapy for acute rejection over the entire follow-up period of 12.3 +/- 1.4 months after addition of Aza; 4 of these retain graft function. Infectious complications consisted of 2 urinary tract infections, 1 bacterial pneumonia, and one case of otitis media.(ABSTRACT TRUNCATED AT 400 WORDS)     

环孢素A和他克莫司在高危肾移植患者中的应用比较

目的　比较高危肾移植患者术后应用环孢素 A(CsA)和他克莫司(FK506)的疗效和安全性。方法　将58例高危肾移植患者随机分为CsA组(30例)和FK506组(28 例),观察肾移植后 1年内两组的急性排斥发生率和药物逆转率、药物毒副作用及感染发生情况。结果　 FK506组和 CsA组的人/肾存活率分别为100%/100%和93.3%/86.7%;急性排斥反应发生率分别为14.3%和16.7%;抗排斥治疗的逆转率分别为100%和60%。FK506组药物毒副作用也较 CsA组小。结论　在高危肾移植患者的免疫抑制治疗中FK506应为首选。     

Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients

In cyclosporine (CsA)-treated renal transplant recipients complete corticosteroid withdrawal followed by CsA monotherapy has been associated with severe rejection episodes in a significant proportion of patients. We report the results of replacement of steroids by azathioprine (AZA) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone (MP). MP taper was started 8.8 +/- 5.6 months posttransplant when the MP dose was either 10 mg/day or 20 mg every other day. MP was tapered off over a 5-month period. At the initiation of MP taper, AZA was added at 1 mg/kg/day and increased to 1.5 mg/kg/day after two months. The CsA dose was adjusted to maintain trough serum levels as measured by radioimmunoassay (RIA) of 50-75 ng/ml, during and after MP withdrawal. Seventeen patients have remained continuously off MP for 14.6 +/- 5.0 months with stable renal function. Reinstitution of MP at 10 mg/day was required in 8 patients, 6 for rejection (1.8 +/- 0.7 months after MP withdrawal), 1 for AZA-induced leukopenia, and 1 for de novo glomerulopathy. Renal function returned to baseline in all 6 patients with rejection after reinstitution of MP. Two of these patients have again been successfully retapered off MP. In the patients withdrawn from MP, body weight and mean arterial blood pressure had decreased by 2.1 +/- 1.3 kg (P less than .05) and 11 +/- 7 mmHg (P less than .05), respectively, at the time of the most recent follow-up compared with values at the initiation of steroid withdrawal. The number of blood pressure medications per patient decreased by 38% (P less than .05) and 6 patients were able to discontinue all antihypertensive drugs after cessation of steroids. Discontinuation of MP also resulted in a decrease in serum cholesterol concentration from 248 +/- 50 to 217 +/- 55 mg/dl (P less than .05). We conclude that steroids can be replaced by AZA in the majority of CsA-treated primary cadaveric renal transplant recipients by the end of the first posttransplant year without an adverse effect on graft survival. This protocol resulted in significant reductions in serum cholesterol, mean arterial blood pressure, and body weight, and may avoid the long-term side effects of steroid therapy.     

肾移植术后应用他克莫司的临床观察

目的 观察他克莫司（ＦＫ５０６）作为免疫抑制剂的有效性和安全性。方法 将首次接受同种异体肾移植的３５例患者随机分为２组,一组给予他克莫司,硫唑嘌呤（或霉酚酸酯）和泼尼松（ＦＫ５０６组）,另一组给予环孢素Ａ、硫唑嘌呤（或霉酚酸酯）及泼尼松（ＣｓＡ组）,观察２个组的免疫抑制效果及药物的副作用。结果 ＣｓＡ组和ＦＫ５０６组的人／肾１年存活率分别为１００．０％／９３／３％和９５．０％／９５．０％;两组肝和     

Short-term treatment with rosiglitazone improves glucose tolerance, insulin sensitivity and endothelial function in renal transplant recipients.

BACKGROUND: Insulin resistance (IR) contributes to the development of glucose intolerance (post-transplant diabetes mellitus or impaired glucose tolerance) following renal transplantation. Furthermore, endothelial dysfunction (ED) is associated with IR. Glucose intolerance, IR and ED are all independent risk factors for cardiovascular disease. Therefore, treatment with insulin sensitizers may benefit glucose-intolerant renal transplant recipients. The main objectives of the present study were to investigate the effect of 4 weeks' treatment with the PPAR-gamma agonist rosiglitazone on insulin sensitivity, plasma glucose and endothelial function in renal transplant recipients with glucose intolerance. Safety parameters were also addressed. METHODS: A total of 10 glucose-intolerant renal transplant recipients were treated with rosiglitazone (initially 4 mg/day increasing to 8 mg/day after 1 week). A hyperinsulinaemic euglycaemic glucose clamp, an oral glucose tolerance test and endothelial function assessment with laser Doppler flowmetry were performed both at baseline and at follow-up. RESULTS: Treatment with rosiglitazone was followed by a significantly improved mean glucose disposal rate (from 6.5 to 9.1 g/kg/min; P = 0.02) and a significant decline in fasting and 2 h plasma glucose (from 6.4 to 5.8 mmol/l, P = 0.01 and from 14.2 to 10.6 mmol/l, P = 0.03, respectively). Furthermore, a significant improvement in endothelial function was demonstrated (AUC(ACh); from 389 to 832 AU x min, P = 0.04). No serious adverse events or hypoglycaemic episodes were observed. CONCLUSIONS: Four weeks' treatment with rosiglitazone was associated with increased insulin sensitivity, lowered fasting and 2 h plasma glucose and improved endothelial function in renal transplant recipients with glucose intolerance. The drug was well tolerated and may be a good alternative for treating these patients.     

肾移植受者将环孢素A转换为他克莫司治疗的三年疗效分析

目的 评价肾移植受者将环孢素A(CsA)转换为他克莫司(Tac)治疗的有效性和安全性。方法 回顾将CsA转换为Tac治疗的97例肾移植受者的资料,转换治疗的原因分别为慢性移植肾肾病62例,难治性排斥反应21例,肝功能异常8例,齿龈增生、多毛6例。观察转换治疗后3年内的肾功能、肝功能、血脂、血压、血糖、急性排斥发生率、人/肾存活率以及药物不良反应等指标。结果 与转换前相比较,慢性移植肾肾病及难治性排斥反应患者转换治疗1年后肾功能明显好转(P＜0.01),患者第2、3年肾功能稳定。转换治疗后,肝功能异常者的肝功能明显改善,齿龈增生和多毛患者的症状也明显改善。97例转换治疗后第1年的人/肾存活率分别为100％和97.9％,第3年为100％和92.8％,患者血浆胆固醇、低密度脂蛋白、甘油三酯和血压均下降(P＜0.05)。转换治疗后,13例需用药物控制血糖(13.4％),另发生腹泻和食欲不振2例(2.1％),震颤5例(5.2％)。观察期内患者均未发生严重肺部感染和肿瘤。结论 使用CsA行免疫抑制治疗的肾移植受者发生相关并发症后转换为Tac治疗是安全和有效的。     

Malignant tumors after renal transplantation

Abstract: The rate of certain malignancies in renal transplant recipients is 14 to 500 times higher than the rate in the general population. The reported prevalence rates for malignant tumors in various kidney recipient series range from 4% to 18% with an average of 6%. The tumors occur in patients who are younger than individuals affected in the general population, and the incidence rates rise with each year after transplantation. Since 1975, we have recorded 52 cases of malignancy development in 50 (3.7%) patients who were treated with P + AZA, P + CsA + AZA, or P + CsA + MMF therapy (P, prednisolone; AZA, azathioprine; CsA, cyclosporin A; MMF, mycophenolate mofetil). In this article, 50 renal transplant recipients who developed malignancy and were followed by the Transplantation Center at Ba?kent University Faculty of Medicine were analyzed. Analysis revealed that patients who received CsA had a higher incidence of Kaposi's sarcoma than those who received the standard regimen. Regarding other tumor types, our results showed no statistical differences among the incidence rates in the different treatment groups.     

Impact of long-term immunosuppression with cyclosporin A on serum lipids in stable renal transplant recipients

Abstract. To determine the impact of long-term immunosuppression on serum lipids in stable renal graft recipients we measured serum lipids and apolipoprotein B concentrations in 20 patients receiving therapy with cyclosporin (CsA) and low-dose prednisolone (CsA/P) and in 18 patients on therapy with azathioprine and maintenance steroids (Aza/P). The patients were matched for age, body mass index, primary renal disease and dose of prednisolone, but not for the duration in transplantation and serum creatinine concentration. Triglyceride concentrations were significantly higher in the CsA/P group than in Aza/P-treated patients: 2.62 ± 0.35 vs 1.62 ± 0.23 mmol/l ( P < 0.05). Similarly, total cholesterol (C) levels were significantly more elevated in the CsA/P recipients than in the other group: 7.4410.32 vs 5.84 ± 0.25 (F<0.02). CsA/P patients had higher serum levels of LDL-C (4.79 ± 0.20 vs 3.43 ± 0.19 mmol/l ( P < 0.001) and apolipoprotein B concentrations (191 ± 13 vs 128 ± 9 mg/dl; P < 0.001). CsA/P and Aza/P recipients had similar concentrations of HDL-C (1.73 ± 0.13 vs 1.52 ± 0.09 mmol/l; NS). We conclude that in stable renal graft recipients with good transplant function long-term immunosuppression with CsA/P is associated with a more atherogenic lipid status than therapy with Aza/P.     

Who should be converted from cyclosporine to conventional immunosuppression in kidney transplantation, and why

Twenty-three cadaveric renal allograft recipients with stable but compromised kidney function were electively converted from cyclosporine to azathioprine one year after transplantation. Within a few weeks glomerular filtration rate (GFR) rose by 40% and serum creatinine fell from 171 +/- 12 (mean +/- SEM) to 129 +/- 7 mumol/L. The increase in GFR was due to an increase in effective renal plasma flow of 21%. This suggests that one year of continuous cyclosporine (CsA) therapy does not result in irreversible structural renal damage. Although antihypertensive treatment was not changed, blood pressure fell from 142 +/- 4/90 +/- 3 to 123 +/- 3/77 +/- 2 mmHg. In addition a significant drop in serum cholesterol and triglycerides and an improvement in glucose tolerance were found. The beneficial effects on renal function, blood pressure, and metabolic indices were, however, outweighed by a high incidence of postconversion rejection in recipients of a second allograft. For these patients conversion from CsA to azathioprine seems therefore contraindicated. Recipients of a first kidney allograft can be converted safely, as long-term CsA administration in these patients induced a solid engraftment. The sequelae of the mode of treatment--impaired renal function, hypertension, and metabolic disturbances--are reversible even after late conversion.     

Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a serious complication of transplantation caused by immunosuppressive drugs. In this study, we assessed the incidence of PTDM and the factors that are associated with the development of this complication. METHODS: The study population included 2078 non-DM renal allograft recipients, transplanted since 1983 in one institution. PTDM was diagnosed by the requirement of hypoglycemic medications, starting more than 30 days after transplantation. Post-transplant, all patients received cyclosporine (CsA) and prednisone, but none of these patients received tacrolimus. RESULTS: At 1, 3, 5, and 10 years after transplantation, 7, 10, 13, and 21% of patients developed PTDM. By multivariate Cox, the following variables correlated with a more rapid increase in the number of PTDM cases: (1) older age (RR = 2.2 comparing patients younger or older than 45 years, P < 0.0001), (2) transplant done after 1995 (RR = 1.7, P = 0.003), (3) African American race (RR = 1.6, P = 0.003), and (4) higher body weight at transplant (RR = 1.4, P < 0.0001). Compared with before 1995, since 1995, the percentage of patients with PTDM has increased from 5.9 to 10.5% at one year and from 8.8 to 16.9% at three years. This increase was statistically independent from all other variables tested. However, since 1995, recipients have become significantly heavier (P < 0.0001) and older (P < 0.0001), and the average CsA level has increased significantly (P < 0.0001). Also, since 1995, the cumulative dose of corticosteroids has declined (P < 0.0001); patients received a newer, better absorbed preparation of CsA and received mycophenolate mofetil. CONCLUSIONS: The risk of PTDM increases continuously with time post-transplant. There has been an increase in the incidence of PTDM in patients transplanted recently, and that increase can be explained only partially by changes in the recipients' characteristics. We postulate that this increase may be due to the introduction of better absorbed CsA formulations that result in higher blood levels and higher cumulative exposure to this diabetogenic drug.     

Mycophenolate mofetil for the prophylaxis of acute GVHD in HLA-mismatched bone marrow transplant patients

Mycophenolate mofetil (MMF), a new immunosuppressive drug successfully used in renal and heart transplant recipients, was used in combination with cyclosporin A (CsA), methotrexate (MTX) and prednisolone for the prophylaxis of acute graft-versus-host disease (aGVHD) after bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen (HLA)-mismatched, unrelated (n = 9) and related donors (n = 4) in an open single-centre phase II study. Thirteen patients, transplanted from HLA-mismatched donors of 18-57 yr of age, received 1 g MMF daily, starting at day 10, in addition to CsA and prednisolone for aGVHD prophylaxis. All patients were engrafted between days 13 and 15. Four of the 13 patients experienced aGVHD grade I/II (n = 2) and grade III (n = 2). All patients except 3 were alive on day 100 post-transplantation. No severe adverse effects of MMF were recorded. In our pilot study, we demonstrated that MMF can be used safely for the prophylaxis of aGVHD.     

Reduced incidence of new-onset posttransplantation diabetes mellitus during the last decade

BACKGROUND: A previous study (1995-1996) of 173 nondiabetic renal transplant recipients (historical cohort; HC) revealed a 20% incidence of new-onset posttransplantation diabetes mellitus (PTDM) and 32% with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). We examined whether glucose tolerance has improved after recent changes in our immunosuppressive protocol and a switch from deferred to preemptive cytomegalovirus (CMV) therapy. METHODS: A total of 321 consecutive, nondiabetic patients (new cohort; NC) were examined 10 weeks after kidney transplantation with an oral glucose tolerance test (n=301) between January 2004 and December 2005. RESULTS: Although recipients in the NC were on average 3 years older [mean (SD): 50.3 (14.6) vs. 47.4 (16.0), P=0.038] and had a higher mean body mass index [24.5 (3.6) vs. 23.5 (3.8) kg/m(2), P=0.003], a significantly lower incidence of both PTDM (13%) and IGT/IFG (18%) was observed in the NC (P<0.001) as compared to the HC. The patients in the NC received a significantly lower mean daily oral prednisolone dose [13.2 (4.7) vs. 15.3 (6.6) mg/day, P<0.001], and had lower frequencies of rejections (36% vs. 57%, P<0.001) and CMV infection (54% vs. 63%, P=0.071). Patients in the NC had significantly lower odds of developing PTDM, even after adjustment for age, prednisolone dose, HLA-B27 status and CMV infection (odds ratio: 0.42, 95% CI: 0.23-0.77, P=0.005). CONCLUSIONS: The odds of developing PTDM are more than halved over the last decade. Possible explanations are changes in immunosuppressive therapy, fewer rejections, and lower doses of steroids.     

Cardiovascular risk factors in renal transplant patients: cyclosporin A versus tacrolimus

The hypertensive and hyperlipidemic effects of cyclosporin A (CsA) may contribute to the high cardiovascular morbidity in renal transplant patients and to the development of chronic transplant nephropathy. Tacrolimus is reported to have less effect on BP and lipids, but steroids, other drugs, and renal function may confound this. This study assessed 24-h BP and lipid profile in stable renal transplant recipients (n = 17) while they were receiving CsA, after 4 wk of receiving tacrolimus, and again after 4 wk of receiving CsA. Antihypertensives were stopped at least 3 wk before. A few patients used low-dose steroids and lipid-lowering drugs, which were not changed during the study. Mean daytime BP decreased from 149 +/- 12 and 95 +/- 8 mmHg to 138 +/- 13 and 87 +/- 9 mmHg (P: < 0.001) after patients were switched to tacrolimus. Mean nighttime BP also decreased, from 140 +/- 12/86 +/- 7 mmHg to 132 +/- 17/79 +/- 10 mmHg (P: < 0.05). Total and low-density lipoprotein cholesterol decreased from 6.1 +/- 0.7 and 3.84 +/- 0.79 mmol/L to 5.1 +/- 0.8 and 2.98 +/- 0.75 mmol/L (P: < 0.001). Return to CsA caused an increase in BP and cholesterol to values similar as during the first CsA period. The conclusion is that tacrolimus has fewer unfavorable effects on BP and lipids than does CsA. Elective conversion from CsA to tacrolimus in stable renal transplant recipients may lead to attenuation of cardiovascular morbidity and chronic transplant nephropathy in the long term.