Glomerulotubular function in long-term renal allograft recipients. A comparison of conventional therapy with cyclosporine

Glomerular and tubular function were assessed, using a lithium clearance technique, in two groups of renal allograft recipients at least one year after transplantation. Group 1 comprised 14 patients receiving low-dose prednisolone and cyclosporine, and group 2, 14 patients receiving low-dose prednisolone and azathioprine. There were no significant differences in creatinine clearances between the two groups, although the clearances of lithium (which is absorbed almost exclusively from the proximal tubule) and sodium were significantly lower in the cyclosporine-treated group. Fractional lithium excretion was also significantly lower in group 1 than in group 2, but there was no significant difference in fractional sodium excretion. The absolute proximal reabsorption of sodium and water did not differ between the groups, although the fractional proximal reabsorption of sodium and water was significantly higher in group 1. In contrast, the distal reabsorption of sodium and of water was significantly lower in the cyclosporine-treated patients than in the azathioprine-treated patients; there were, however, no significant differences in the distal fractional reabsorptions of sodium and water between the two groups. In addition there was no correlation in group 1 between whole-blood cyclosporine levels or time since transplantation and any of the assessed parameters of renal function. These results indicate that tubular concentrating abnormalities in cyclosporine-treated renal allograft recipients are similar to those observed in rodent models of cyclosporine nephrotoxicity. They suggest that the pathogenesis of cyclosporine nephrotoxicity may be similar in renal allograft recipients to that in experimental models.     

Renal function and tubular phosphate handling in long-term cyclosporine- and tacrolimus-based immunosuppression in kidney transplantation

The aim of the study was to assess impaired tubular phosphate reabsorption and renal function among patients on cyclosporine- or tacrolimus-based immunosuppression for 2 years after kidney transplantation. Among 60 cadaveric kidney allograft recipients observed for 48 months, 40 received cyclosporine, azathioprine, and prednisone (group A and B). Group C consisted of 20 patients receiving tacrolimus with steroid withdrawal at 3 months after transplantation. Renal function and calcium-phosphate metabolism-iPTH, 25-OHD, 1,25(OH)(2)D concentration, phosphate reabsorption (TRP; mmol/L), and tubular maximum phosphate reabsorption per glomerular filtration rate (TmPO(4)/GFR; mmol/L)-were assessed at 1, 6, 12, 18, and 24 months (groups A and C) or 24, 30, 36, 42, and 48 months (group B). Renal function after 24 months of observation was significantly better among tacrolimus-treated patients (serum creatinine concentration mumol/L; C: 94.6 +/- 16.8 vs A: 110.5 +/- 22.1 vs B: 121.1 +/- 30.9; P < .05). Among tacrolimus-treated recipients, TRP and TmPO(4)/GFR remained within normal values during the whole observation period. In groups A and B, TRP improved during the first year of observation; after 2 years it reached values observed in group C (TRP: A: 0.67 +/- 0.1; B: 0.72 +/- 0.13; C: 0.76 +/- 0.07; P = NS), whereas TmPO(4)/GFR remained low in group A after 2 years (A: 0.78 +/- 0.19; B: 0.91 +/- 0.25; C: 0.94 +/- 0.15; P < .05). Tacrolimus-treated patients exhibit significantly faster recovery from tubular phosphate reabsorption impairment compared with cyclosporine-treated recipients. Tacrolimus-based immunosuppression led to better kidney allograft function during 2-year observation.     

Conventional immunosuppression after deliberate third party transfusions versus cyclosporine in living related renal transplant recipients

A total of 93 recipients of either HLA-identical (34) or 1-haplotype matched (59) living related donor renal transplants was assigned prospectively into immunosuppressive treatment groups on the basis of transfusion histories obtained at the initial evaluation for transplantation. Patients who received 0 to 2 third party transfusions were given no further transfusion, and received cyclosporine and prednisone immunosuppression after transplantation (cyclosporine group). Patients who received 3 or 4 third party transfusions were given additional transfusions until 5 had been received, and were managed with azathioprine and prednisone after transplantation (azathioprine group). Patients who already received 5 or more third party transfusions had no additional transfusions and were assigned to the azathioprine group. No patient had a positive crossmatch to the potential donor after initial evaluation and confirmation of a negative crossmatch. The number of rejection episodes per patient after transplantation was significantly higher in the azathioprine group for HLA-identical (p equals 0.001) and 1-haplotype (p equals 0.003) recipients. One-year patient survival rats for the HLA-identical cyclosporine and azathioprine groups were 100 and 94 per cent, respectively, with respective 1-year allograft survivals of 100 and 89 per cent in the 2 groups. In the 1-haplotype group 1-year patient survival rates were 95 and 94 per cent for the cyclosporine and azathioprine groups, respectively; allograft survival was 81 per cent for the cyclosporine group and 91 per cent for the azathioprine group. None of the observed differences in graft or patient survival between the 2 groups was statistically significant. Deliberate third party transfusions with conventional immunosuppression and cyclosporine immunosuppression are effective methods to treat recipients of living related donor renal transplants.     

A comparison of prednisolone and methylprednisolone for renal transplantation

A large difference in immunosuppressive potency between methylprednisolone and prednisolone has been suggested in vitro . However, the selection of the best glucocorticoid for renal transplantation has been seldom considered so far. Thus, the present study was undertaken to compare therapeutic efficacy between prednisolone and methylprednisolone in renal transplantation. We studied 42 renal transplant recipients who were operated on between 1990 and 1994. The patients were divided into two treatment groups: a methylprednisolone/cyclosporine group (n=19) and a prednisolone/cyclosporine group (n=23). Clinical outcome and drug side effects were compared retrospectively between the treatment groups 24–84 months after transplantation. The overall graft survival time in patients treated with methylprednisolone/cyclosporine was superior to that in patients treated with prednisolone/cyclosporine (p<0.05). Among the recipients from cadaver donors, 5/16 (31.3%) treated with prednisolone required nephrectomy, whereas none of the 10 patients treated with methylprednisolone received nephrectomy (p<0.01). An examination of the recipients from living related donors revealed that serum creatinine levels 24–36 months after operation were significantly lower in the methylprednisolone group (p<0.05). Cyclosporine trough levels and glucocorticoid side effects were similar between the treatment groups. The results raised the possibility that methylprednisolone is superior to prednisolone when combined with cyclosporine for maintenance immunosuppressive therapy in renal transplantation.     

Tacrolimus decreases tubular phosphate wasting in renal allograft recipients

The aim of the study was to elucidate whether cyclosporine- and tacrolimus-based immunosuppression impairs tubular reabsorption of phosphate after kidney transplantation. Sixty cadaveric allograft recipients were included in the study. Forty patients receiving triple immunosupression with cyclosporine, azathioprine, and prednisone were studied for 1, 6, 12 months (groups A1 and A2, 20 patients) and for 24, 30, and 36 months (groups B1 and B2, 20 patients) after transplantation. Twenty patients who received tacrolimus with steroid withdrawal after 3 months were included in the study (group C). Recipients from groups A2 and B2 were treated additionally with vitamin D and calcium carbonate. Serum iPTH, 25-OHD, 1.25(OH)(2)D concentrations were determined, and TRP (mmol/L) and TmP/GFR (mmol/L) were calculated using Walton-Bijvoet nomogram. Higher values of total calcium serum concentration in group A were detected. Lower inorganic phosphate serum concentrations were detected in groups A and C, in contrast to group B where they remained within normal values. TmP/GFR values were significantly higher in group C in the first and third examination in comparison with patients of group A. Moreover, TRP index values were significantly higher than analogous values of groups A and B. Tacrolimus-treated patients exhibit significantly faster recovery from tubular phosphate reabsorption impairment compared to cyclosporine-treated recipients. No correlation between iPTH, 25-OHD, 1,25(OH)(2)D concentration, and tubular dysfunction parameters was observed. Amelioration of phosphate handling, in spite of hyperparathyroidism intensity, can follow early steroid avoidance.     

Clinical experience of mycophenolate mofetil in the treatment of chronic allograft nephropathy in kidney transplantation: three-year follow-up

BACKGROUND: Mycophenolate mofetil (MMF) in conjunction with calcineura antagonists has been shown to prevent acute rejection in renal allograft recipients. Its role in treatment of chronic rejection or allograft nephropathy is still controversial. We initiated the study to investigate the effect of adding MMF to a cyclosporine plus prednisolone regimen in renal recipients with chronic allograft nephropathy. MATERIALS AND METHODS: We retrospectively studied 36 patients with chronic allograft nephropathy, defined clinically as increased of serum creatinine, proteinuria, and hypertension. Renal function, cyclosporine level, renal biopsy, and renal scan were regularly done as indicated. MMF was added to 20 recipients after initial treatment with cyclosporine and prednisolone. The other 16 recipients were managed without adding MMF. Serum creatinine was monitored for 3 years. RESULTS: The demographic characteristics of the patients in the two groups were comparable. The average dose of prednisolone was unchanged throughout the study and the trough level of cyclosporine was maintained in the range of 100 to 150 ng/mL. The serum creatinine decreased initially in the group on MMF, but renal function deteriorated progressively after 6 months. There was a difference in serum creatinine between the two groups but this did not reach statistical significance. CONCLUSION: MMF therapy tender to improve renal function initially but did not attenuate significantly the impairment in chronic allograft nephropathy.     

Treatment of oropharyngeal cancer in renal transplant recipients without cessation of immunosuppressive therapy

INTRODUCTION: Renal transplantation and immunosuppression are associated with an increased incidence of malignancy. Reduction or cessation of immunosuppressive therapy has been advocated in these cases to prevent tumor progression and recurrence. We evaluated the outcome of treatment of oropharyngeal cancer (OC) after renal transplantation without cessation of immunosuppressive therapy. METHODS: The database of patients with OC after renal transplantation was analyzed with respect to age, sex, type of immunosuppression, interval between transplantation and diagnosis of cancer, as well as method of treatment and survival. RESULTS: Thirty one (2.06%) renal transplant recipients developed malignancy including 6 (20%) with OC. Lingual cancer was seen in three, and one each showed an isolated tonsillar lymphoma, a parotid carcinoma, or a carcinoma of the larynx with only the last having had two other malignancies in the past. Three subjects were on immunosuppression with azathioprine and prednisolone, and the others were prescribed cyclosporine and prednisolone. Average time from transplantation to diagnosis of OC was 106 months. The interval was the shortest (2 years) for tonsillar lymphoma in an 18-year-old patient who received cyclosporine and showed features of left follicular tonsillitis. The patient with advanced carcinoma of the larynx did not receive any treatment and succumbed within 3 months. The dose of cyclosporine was reduced in the lymphoma case but immunosuppression was not altered in the other patients. All subjects were treated with a standard protocol. During a mean follow-up of 33 months, one had local recurrence of parotid carcinoma and the others showed well functioning renal grafts. CONCLUSION: Comprehensive treatment of OC after renal transplantation without withdrawing the immunosuppression prolonged the life of these patients with functioning grafts.     

Effect of basiliximab on renal allograft rejection within 1 year after transplantation

Basiliximab is widely used in clinical practice for initial immunosuppressive treatment of renal transplant recipients, seeking to reduce the incidence of acute rejection episodes without adverse events. This retrospective study included 123 renal allograft recipients transplanted at a single center. All were followed for longer than 1 year after transplantation and treated with calcineurin inhibitor and steroid (methylprednisolone) for prophylactic immunosuppression, but basiliximab and mycophenolate mofetil were optional. We compared the outcomes of renal transplant recipients who were versus treated were not with basiliximab as initial immunosuppressive therapy. Basiliximab was used for initial immunosuppression in 42 patients. Their maintenance immunosuppressive treatment included triple (n = 44) or double (n = 79) regimens, including a calcineurin inhibitor (cyclosporine [n = 87] or tacrolimus [n = 36]), methylprednisolone with or without mycophenolate mofetil. Twenty-six (21.1%) patients had a rejection episode within 1 year after transplantation and 22 (17.9%) had infections. Within the first year after transplantation the patients who were treated with basiliximab showed fewer rejection episodes (n = 6, 14.3%) than the patients without this therapy (n = 20, 24.7%), which was not statistically significant (P = .245). However, basiliximab significantly affected the occurrence of rejection episodes among the double immunosuppressive regimen group (P = .006), but not the triple regimen group (P = .098) without an impact on infection episodes (P value of double, triple = .291, .414) within 1 year after transplantation. We concluded that basiliximab was more useful for the recipients treated with double immunosuppression with a calcineurin inhibitor and steroid than for those on a triple regimen including mycophenolate mofetil.     

Cyclosporine Withdrawal Improves Renal Function in Heart Transplant Patients on Reduced-Dose Cyclosporine Therapy

Renal failure is a major cause of morbidity after heart transplantation. It is unclear whether calcineurin inhibitor (CNI) free immunosuppression provides more nephroprotection than low-dose CNI therapy. Thirty-nine patients with renal failure on low-dose cyclosporine A (CsA) were studied (62.9 +/- 8.7 years, five female, 8.2 +/- 4.3 years posttransplant, serum creatinine: 1.9 +/- 0.3 mg/dL, calculated GFR (cGFR): 48.2 +/- 18.3 mL/min, CsA C0 level: 64.0 +/- 19.9 ng/mL). All patients had been treated with low-dose CsA >6 months, renal function was stable or slowly decreasing (creatinine 1.7-3.5 mg/dL). Nineteen patients were randomized to discontinuation of CsA and overlapping rapamycin therapy initiation (RAPA), 20 patients continued low-dose CsA (control). Three patients (16%) discontinued rapamycin medication for side effects (diarrhea, skin rash), two patients developed pneumonia and pulmonary embolism, respectively, no rejection or other infectious complications were seen. After 6 months, renal function in the control group was unchanged. In the RAPA group, renal function markedly improved (creatinine: 2.08 +/- 0.15 to 1.67 +/- 0.13 mg/dL, cGFR: 48.5 +/- 21.4 to 61.7 +/- 21.4 mL/min (p < 0.001 within and between groups)). In carefully selected late survivors following heart transplantation who are at low risk of rejection, CNI-free rapamycin-based immunosuppression improves cGFR even in those already receiving low-dose CsA therapy. The results of this study warrant further confirmation in larger clinical trials that are powered to assess clinical outcomes.     

Polyomavirus nephropathy after renal transplantation: a single centre experience

BACKGROUND: Polyomavirus associated nephropathy (PVN) in renal transplant recipients has been observed with increasing frequency recently and has emerged as a cause of allograft failure linked to highly potent new immunosuppressive regimens containing tacrolimus or mycophenolate mofetil (MMF). METHODS: Polyomavirus associated nephropathy was identified in nine out of 182 patients who received renal transplantation between October 1998 and July 2003. PVN was confirmed by allograft biopsy. The clinical records of these nine patients were reviewed, as were all of the allograft biopsies. Electron microscopy was performed in all nine cases. After the diagnosis of PVN, maintenance immunosuppression was reduced. The clinical course and outcome of the PVN patients were reviewed in relation to manipulation of immunosuppressive agents. RESULTS: There were nine cases of PVN in renal transplant recipients and the incidence of PVN was 4.9%. All patients with PVN were under triple immunosuppression comprising tacrolimus and MMF. The mean time to a diagnosis of PVN was 7.8 months after transplantation. Three of the nine patients received antirejection therapy prior to PVN. Seven out of nine PVN patients presenting acute allograft dysfunction were initially treated with high-dose intravenous steroid pulse or OKT3 before reduction of the immunosuppression. After reduction of the immunosuppression, seven patients stabilized their renal function. Two (22%) lost their grafts due to persistent PVN and chronic rejection. Two (22%) patients later developed acute rejection after reduction of the immunosuppression. CONCLUSION: PVN can cause allograft dysfunction and graft loss. Renal allograft recipients who are at risk of PVN should be routinely screened with urine cytology and quantitative measurements of viral load in the blood, particularly patients who had graft dysfunction. Early diagnosis and judicious alteration of immunosuppressive agents might permit a superior prognosis and reduce the graft loss from PVN in renal transplant recipients.     

Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy

Rapamycin is a new immunosuppressive agent approved for maintenance therapy after kidney transplantation. It may allow calcineurin-inhibitor-free, non-nephrotoxic immunosuppression. We report, however, on four kidney-transplant recipients who developed post-transplantation glomerulonephritis after conversion from a calcineurin-inhibitor-based immunosuppression to rapamycin. In all four patients nephrotic-range proteinuria occurred 2–9 months after conversion to rapamycin. Renal biopsy confirmed membrano-proliferative glomerulonephritis type 1 in one case, membranous glomerulonephritis in another and IgA-nephropathy in two cases, respectively. Calcineurin-inhibitor-based immunosuppression was reintroduced and resulted in complete remission of proteinuria and in stabilised renal function in all patients. We conclude that in the case of rapamycin-associated post-transplantation glomerulonephritis an attempt should be made to replace rapamycin by a calcineurin inhibitor.     

Conversion to rapamycin immunosuppression for malignancy after kidney transplantation: case reports

INTRODUCTION: Malignancies are a well-known complication of immunosuppressive therapy among renal transplant recipients, representing an important cause of long-term morbidity and mortality. Rapamycin has been shown to limit the proliferation of a number of malignant cell lines in vivo and in vitro. METHODS: Eight patients developed the following malignancies after kidney transplantation (mean 102.6 months; range 12 to 252): metastatic gastric cancer (n = 1), metastatic colon cancer (n = 1), bilateral nephrourothelioma (n = 1), skin cancer (n = 1), Kaposi's sarcoma (n = 2), posttransplant lymphoproliferative disorder (PTLD) (n = 2). After the diagnosis of malignancy, the patients were switched from calcineurin inhibitor-based immunosuppression to rapamycin (monotherapy, n = 2), associated with steroids (n = 4) or mycophenolate mofetil (n = 2). RESULTS: Both patients with metastatic cancer underwent chemotherapy and then succummbed after 6 and 13 months. After a mean follow-up of 20.3 months (range 2 to 47), the remaining six patients are free from cancer disease. Renal graft function was unchanged from diagnosis throughout the follow-up. CONCLUSION: Our observations suggested that rapamycin-based immunosuppression offered the possibility of regression of nonmetastatic tumors. Nevertheless, it is difficult to assess whether tumor regression was attributed to Rapamycin treatment or to the reduced immunosuppression.     

Enhanced in vitro hemostasis and reduced thrombolysis in cyclosporine-treated renal transplant recipients

In vitro hemostatometry and assessment of thrombolysis was carried out in three groups of 72 renal transplant recipients. In one (triple, n = 21) immunosuppression was with cyclosporine, azathioprine, and prednisolone, while a second group (CsA, n = 29) received cyclosporine and prednisolone alone, and the third group (Aza, n = 22) azathioprine and prednisolone. Results were compared with those in 30 normal controls. A statistically significant increase in hemostasis compared with controls was seen in the triple group and in patients in the CsA group studied within 2 years of transplantation. Hemostasis in the Aza group did not differ from normal. All patients in this group had been transplanted more than 2 years before study. Thrombolysis times were significantly prolonged compared with controls in all three groups. Cyclosporine treatment is associated with enhanced hemostasis and reduced thrombolysis, especially during the first 2 years after renal transplantation. If these in vitro findings reflect events in vivo, this may throw light upon the pathogenesis of the obliterative arteriolopathy that is a feature of cyclosporine nephrotoxicity.     

Lipid profile before and after renal transplantation--a longitudinal study

BACKGROUND: The data on lipid profile in renal transplant recipients from the Indian subcontinent is scant. METHODS: Lipid profile was studied in 30 consecutive patients of end stage renal disease before renal transplantation (0 month) and prospectively posttransplantation at 1, 3, and 6 months. The results were compared with 30, age and sex matched, healthy controls. All the patients received triple immunosuppression (prednisolone, azathioprine and cyclosporine). RESULTS: Pretransplantation, the hypertriglyceridemia and hypercholesterolemia was present in 20% and 7% of the patients and the difference (elevation) in the mean values of various lipid fractions was not significant compared to healthy controls except a fall in HDL (p < .01). After renal transplantation, there was a significant elevation in the mean values of total cholesterol, triglycerides, VLDL, and LDL cholesterol at 1, 3, and 6 months. HDL cholesterol levels remained significantly lower as compared to healthy controls. Although, the mean values of serum triglycerides and cholesterol were significantly higher in diabetic end stage renal disease compared to nondiabetic ESRD, however there was insignificant difference in the lipid profile amongst diabetic and nondiabetic renal allograft recipients. CONCLUSION: Our data shows distinct elevation in the lipids and lipoproteins after renal transplantation and immunosuppressive drugs seem to be the culprit.     

Effects of and predictors for tacrolimus rescue therapy among renal transplant patients under cyclosporine-based immunosuppression

BACKGROUND: Though cyclosporine has dramatically decreased rejection rates and improved graft survival rates of renal allografts, there is still a remarkable rate of acute rejection and progressive deterioration of renal function after transplantation. Rescue therapy with tacrolimus has been used for allografts failing under cyclosporine-based treatment in order to get some renal functional recovery or stabilization. The aim was to evaluate tacrolimus rescue therapy for failing allografts under cyclosporine-based immunosuppression for possible prediction factors for success. PATIENTS AND METHODS: Thirty-five renal allograft recipients with failing transplants under cyclosporine-based immunosuppression were enrolled into this study. Renal function was evaluated by reciprocal serum creatinine level (1/Cr) and calculated CCr. The slope of changes in 1/Cr and CCr were calculated before and after tacrolimus therapy. The possible risk factors that affect the outcome of tacrolimus rescue therapy were analyzed. RESULTS: Nineteen patients showed improved renal function (group 1) and 16 patients, persistent deterioration (group 2) after rescue therapy. Group 1 showed positive slopes of changes of 1/Cr and CCr after rescue therapy. Group 2 patients showed persistent negative slopes although less negative than before rescue therapy. Only the posttransplant time was the significant predictive factor for successful tacrolimus therapy (P = .018). CONCLUSION: Tacrolimus rescue therapy improved or stabilized renal function in some patients with failing grafts under cyclosporine-based immunosuppression. To assure a successful rescue effect, it should be given early after transplantation, if there is a tendency toward deterioration of renal function.     

The influence of immuosuppressive therapy on the development of CD4+CD25+ T cells after renal transplantation

A growing number of studies suggest that CD4(+)CD25(+) T regulatory (Treg) cells play a significant role to downregulate the immune response to alloantigens. In this study, we investigated the possible influence of immunosuppressive therapy, including cyclosporine (CsA) or rapamycin (sirolimus), on the level of CD4(+)CD25(+), CD4(+)CD25(+)FOXP3(+), and CD4(+)CD25(+)CTLA-4(+) T cells in the peripheral blood of renal allograft recipients. The study was performed on renal allograft recipients who displayed uneventful stable courses (RAR-S; n = 15) versus biopsy-proven chronic rejection (RAR-CH; n = 12). The patients were divided based on the immunosuppressive protocol: group 1 (prednisone+CsA+Aza) and group II (prednisone+sirolimus). The control group consisted of 10 healthy blood donors. We examined the expression of CD4, CD25, CTLA-4, and Foxp3 in peripheral blood T cells. Flow cytometry was performed with a FACSCalibur (BD Biosciences) instrument with data analyzed using Cell Quest software. The percentage of CD4(+)CD25(+)Foxp3(+) T cells in rapamycin (sirolimus) treated patients did not differ from that observed in healthy individuals, but was significantly higher compared with CsA-treated patients. CsA therapy resulted in a reduction in the percentage of CD4(+)CD25(+)CTLA-4(+) and CD4(+)CD25(+)Foxp3(+) regulatory T cells after renal transplantation in both groups (RAR-S and RAR-CH) compared with patients treated with rapamycin or to healthy donors. The type of immunosuppressive therapy (with or without calcineurin inhibitors) may have an important role in tolerance induction and graft function.     

6例心脏移植围手术期的处理

目的总结6例心脏移植围手术期处理经验。方法6例晚期心肌病患者接受同种体原位心脏移植术。围术期免疫抑制剂采用赛尼哌诱导方案。维持治疗为环孢素A＋吗替麦考酚酯（或硫唑嘌呤）＋泼尼松三联方案,术后保持低水平的中心静脉压。随访23～30个月,平均（25．6＋4．2）个月。结果6例受者均存活。1例因牙髓感染并发败血症致胸部伤口延期愈合．1例出现硬膜外血肿、脑疝形成行开颅手术。所有患者围术期及随访期间受者均无急性排斥反应、移植物功能不全、肝肾功能不全等并发症。结论围术期适当强度的免疫抑制治疗,合理应用强心利尿,密切监测血流动力学和重视受者的个体化治疗是防治心脏移植术后并发症的有效方法。     

Delayed acute rejection episodes in cyclosporine-treated renal transplant recipients.

Of 109 cyclosporine-treated cadaveric renal allograft recipients, 45 were free of acute rejection in the first 4 weeks after transplantation. Eleven of 45 (24%) subsequently had delayed, biopsy-proven first rejection episodes 34-61 days after grafting, often after discharge from the hospital. Delayed rejectors had significantly higher plasma creatinine levels at all times during the first posttransplant month than 34 nonrejectors. Trough serum cyclosporine levels were similar in the two groups, although by the 4th week oral cyclosporine dose was significantly lower in the delayed rejection group. Two-thirds of those patients who had serum creatinine levels greater than or equal to 260 mumol/l at 2 weeks and greater than or equal to 225 mumol/l at 3 weeks had a delayed acute rejection episode. Renal transplant recipients treated with cyclosporine who have serum creatinine levels at or above these levels should be aggressively worked up and closely followed for the development of delayed acute rejection.     

The effect of cyclosporine on mortality and renal function in living related pediatric kidney transplant recipients

The outcome, incidence of acute rejection episodes, complications and cyclosporine (CyA) induced nephrotoxicity were studied in 10 pediatric kidney transplant recipients who were grafted from one-haplotype indentical parent with immunosuppression of CyA and prednisolone (Pred). Excellent patient and graft survival could be achieved in this population with low incidences of acute rejection or serious complications as when compared with the results of azathioprine (AZ) treated pediatric patients. With a mean follow-up of 12.9 months (range 1 to 50 months), the patient survival rate was 100 per cent and the graft survival rate was 100, 84, 84 and 84 per cent at 1, 2, 3 and 4 years post transplantation, respectively. Serum creatinine levels in the group were 0.97, 1.17, 1.14 and 1.2 mg/dl at 3, 6, 12 and 24 months post transplantation, respectively. The incidence of treated acute rejection episodes was 20 per cent (2 out of 10) in the CyA-treated children, whereas it was 53 per cent (9 of 17) in the Az-treated children. Five children who had undergone transplant surgery before they were 11 years old displayed linear growth in height after their transplantation. There have been no opportunistic infections, aseptic necrosis or peptic ulcers in this group and cyclosporine nephrotoxicity has not been a serious problem in the pediatric recipients. Only 10 per cent (1 out of 10) of the recipients displayed acute nephrotoxicity and only one recipient has converted from CyA+Pred to CyA+AZ+Pred (Three drug therapy) due to persistent nephrotoxicity. Cyclosporine and prednisolone have therefore constituted a relatively safe, effective immunosuppressive regimen for pediatric renal allograft recipients. This paper was presented at the 7th international congress of pediatric nephrology.     

Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation

Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor for graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data from multicenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not nephrotoxic and they do not have any hypertensive effect. New immunosuppressive combinations including mycophenolate mofetil in a triple therapy regimen (associated with corticosteroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even eliminated. Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression, associated with azathioprine or mycophenolate mofetil, could reduce the incidence of post-transplant arterial hypertension. Also, in renal transplant patients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood pressure is achieved. In summary, new protocols with mycophenolate mofetil and/or rapamycin may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation.