The detection of renal allograft rejection by fine-needle intrarenal manometry

The causes of early renal allograft malfunction include rejection, acute tubular necrosis, cyclosporin nephrotoxicity and vascular complications. Fine-needle intrarenal manometry is a potential method of distinguishing rejection from the other causes of malfunction and has been used by Salaman and Griffin in patients' treated with cyclosporin. The technique involves inserting a fine-needle, which is connected to a specially designed manometer, into the substance of the transplant kidney. One hundred and six measurements of intrarenal pressure have been made in 28 patients immunosuppressed with either azathioprine and prednisolone or cyclosporin. Thirteen rejection episodes were identified and confirmed by biopsy. These were treated by pulse steroid (methylprednisolone) therapy. Seven episodes of cyclosporin toxicity were identified and there were fifteen episodes of acute tubular necrosis. The mean intrarenal pressure in the rejecting group was 52.8 mmHg compared with 22.3, 24.1 and 24.3 mmHg for the normal function, acute tubular necrosis and cyclosporin nephrotoxicity groups, respectively (P less than 0.01; Wilcoxon unpaired test). There were no differences within these groups related to the type of immunosuppression used. There were no clinical complications associated with the procedure. Thus in newly transplanted patients, fine-needle intrarenal manometry accurately identified rejection and distinguished it from normal function, acute tubular necrosis and cyclosporin nephrotoxicity in all the patients regardless of the immunosuppressants used.     

Intrarenal manometry in the diagnosis of acute rejection superimposed on acute tubular necrosis in renal transplantation

We used fine-needle intrarenal manometry as a guide for detection of acute rejection superimposed on protracted oliguric acute tubular necrosis occurring in the postoperative course of human renal transplantation. We followed intrarenal pressure (IRP) in 31 patients who received 32 renal transplants, 12 from living related donors and 20 from cadaveric donors. There were 19 rejection episodes and 10 episodes of transient cyclosporin A (CyA) nephrotoxicity. Nine patients had posttransplant acute renal failure. Levels of IRP (mmHg) in acute rejection were (mean +/- SD) 48.6 +/- 11.1, significantly higher (p less than 0.001) than the levels in CyA nephrotoxicity (28.2 +/- 5.21), acute tubular necrosis (24.5 +/- 5.5) and normal functioning grafts (26.4 +/- 6.63). Antirejection treatment was associated with return to normal of IRP after 10 days. Intrarenal manometry was performed routinely ever 2-3 days in patients who had postoperative acute renal failure. Increments in IRP were detected on the 7-10th postoperative day in 7 patients who had 10-25 days of post-transplant oliguria. Renal biopsy findings were compatible with acute rejection, and the patients responded to intravenous bolus of steroids. We suggest that fine-needle intrarenal manometry is a reliable test for the detection of acute rejection in circumstances when traditional parameters of altered renal function cannot be evaluated.     

An assessment of intrarenal hydrostatic pressure measurements in the diagnosis of acute renal allograft rejection

Postoperative intrarenal pressure measurements may be an aid to the diagnosis of acute renal transplant rejection, especially in patients treated with cyclosporine. Serial measurements of intrarenal pressure were made in 38 recipients using a fine-needle technique. Thirty-two intraoperative and 207 postoperative measurements were made, and 39 clinical rejection episodes (23 confirmed by biopsy) monitored. Intraoperative pressures in grafts with immediate function (37.4 +/- 4.0 mmHg, mean +/- SEM) were not significantly different from those with delayed function (30.9 +/- 4.8 mmHg), whereas postoperative pressures were greater (P less than 0.01) in kidneys with acute tubular necrosis (29.4 +/- 1.9 mmHg) than in functioning grafts (20.4 +/- 0.9 mmHg). Pressures recorded during clinical rejection episodes (44.3 +/- 2.3 mmHg) exceeded (P less than 0.001) those during quiescent periods (23.6 +/- 1.0 mmHg). During rejection episodes, higher pressures (P less than 0.01) were recorded from tender or palpably enlarged grafts (52.5 +/- 3.0 mmHg) than in the absence of these signs (36.3 +/- 3.1 mmHg), and patients whose transplants biopsies showed cellular rejection tended to have greater pressures (50.1 +/- 4.1 mmHg) than those with concomitant vasculopathy (36.4 +/- 3.9 mmHg), but the latter did not reach statistical significance. In 7 cases of cyclosporine toxicity the intrarenal pressure was 17.8 +/- 4.2 mmHg. Using a diagnostic cut off point of 40 mmHg, the investigation failed to recognize 26% of acute rejection episodes--and, in the presence of acute tubular necrosis, it wrongly categorized 21% of nonrejectors. While its predictive capacity was limited, the test may occasionally be helpful in the differentiation of cyclosporine toxicity and rejection in functioning kidneys.     

Combination fine-needle aspiration cytology and intrarenal manometry at the onset of renal dysfunction

Twenty-three consecutive cadaveric renal allograft recipients immunosuppressed with cyclosporin have been monitored three times a week by fine-needle aspiration cytology and intrarenal manometry until discharge from hospital or until 30 days post-transplant. Standard criteria were used to determine the cause of allograft dysfunction. The onset of allograft rejection was marked by an elevation of the total corrected increment score by fine-needle aspiration cytology in 80 per cent of rejection episodes whereas intrarenal pressure was raised in only 46.6 per cent. However, intrarenal pressure was greater than 40 mmHg on a single occasion in 16 measurements performed on allografts showing evidence of cyclosporin nephrotoxicity. By combining fine-needle aspiration cytology and intrarenal manometry the sensitivity of these tests for allograft rejection was increased to 93.3 per cent at the onset of renal dysfunction. Our results demonstrate that fine-needle aspiration cytology is more sensitive than intrarenal manometry as a single investigation. However, the combined test may have an important role in the differentiation of allograft rejection and cyclosporin nephrotoxicity in the early management of renal allograft recipients.     

Glutathione transferase in the urine: a marker for post-transplant tubular lesions

Basic glutathione transferase released from the proximal tubular epithelium in the kidney was monitored in the urine of 69 recipients of renal allografts. The enzyme was isolated from human liver and the urinary analysis performed with radioimmunoassay. Patients receiving cyclosporine A without toxicity or rejection did not excrete this enzyme in their urine; whereas the urine of patients with cyclosporine A-induced nephrotoxicity contained significant amounts of the transferase (P less than 0.001). Patients with allograft rejection also showed increased urinary concentrations of the basic glutathione transferase, but had significantly lower values than patients with cyclosporine induced nephrotoxicity (P less than 0.001). During aminoglycoside and co-trimoxazole treatment, the urinary concentration of this transferase also increased. Patients with renal infarction showed a sudden increase in urinary transferase to very high levels. The results indicate that quantitative analysis of the basic glutathione transferase in urine is useful for monitoring renal tubular lesions present in various complications following transplantation, such as cyclosporine and antibiotic induced nephrotoxicity and renal infarction.     

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.     

Primary immunosuppression with tacrolimus in kidney transplantation: three-year follow-up in a single center

INTRODUCTION: The 1-year results of the phase III US Multicenter Trial comparing tacrolimus- and cyclosporine (Sandimmun)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. This retrospective, nonrandomized, single-center study represented 3-year data for patient and graft survival and safety in the tacrolimus-treated patients. METHODS: Among 97 consecutive kidney transplant recipients 41 who received tacrolimus and 56 cyclosporine-based immunosuppression were followed for 3 years for patient and graft survivals and for the incidence of acute rejection episodes as well as serious adverse events. RESULTS: The 3-year patient and graft survival rates for tacrolimus and cyclosporine were similar (91.0% vs 90.2%, 96.5% vs 95.0%). However, the incidence of acute rejection episodes was significantly lower in the tacrolimus (17.1%) compared with the cyclosporine group (35.7%, P = .043). There was a higher incidence of headache, posttransplant diabetes, and alopecia reported in the tacrolimus group, whereas hypertension, hypercholesterolemia, and hirsutism were more frequent in the cyclosporine group. The incidences of hand tremor, hyperkalemia, and viral infections were comparable in both groups. Two patients in the tacrolimus group were converted to cyclosporine due to nephrotoxicity and posttransplant diabetes, respectively, whereas 12 patients in the cyclosporine group were converted to tacrolimus as rescue therapy for acute rejection (41.7%), gingival hyperplasia (33.3%), nephrotoxicity (8.3%), neurotoxicity (8.3%), and hirsutism (8.3%), respectively. CONCLUSION: The 3-year results of tacrolimus treatment show excellent efficacy and safety in kidney transplantation. Due to different side-effect profiles, it is necessary to develop individualized immunosuppressive strategies in kidney transplant recipients.     

Role of Resistive Index Measurement in Diagnosis of Acute Rejection Episodes Following Successful Kidney Transplantation

Objective

This study was performed to evaluate the role of resistive index (RI) in the diagnosis of rejection episodes following successful kidney transplantation.

Materials and Methods

One hundred and one unrelated living first kidney allograft adult recipients (75 males and 26 females) of overall mean age of 39 years were enrolled and prospectively followed for 6 months. The measurement of RI by Doppler ultrasonography was performed in all patients on days 3 and 7 as well as at months 1, 3, and 6 in addition to when there was graft dysfunction. We determined serum creatinine and cyclosporine levels.

Results

Twenty-seven patients (26.7%) experienced 33 acute rejection episodes during the follow-up. There were significant differences between mean RI among patients with normal function vs rejection: 0.606 ± 0.065 vs 0.866 ± 0.083 (P < .05), respectively. Overall, elevated levels of cyclosporine, ischemic acute tubular necrosis (ATN), and renal artery thrombosis were observed in 8, 5, and 3 patients, respectively. No association was observed between these factors and RI.

Conclusions

RI was significantly higher in patients with acute rejection episodes. It had no association with ATN or cyclosporine toxicity. Hence, RI may be useful to diagnose acute renal allograft rejection following renal transplantation.     

The role of C-reactive protein in graft dysfunction after renal transplantation

PURPOSE: We investigated whether serial daily measurements of serum C-reactive protein could help differentiate episodes of transplant dysfunction due to rejection, infection, cyclosporin A nephrotoxicity or acute tubular necrosis in renal allograft recipients. MATERIALS AND METHODS: Morning serum was obtained daily from 134 patients during the first 30 days after renal transplantation. All episodes of graft dysfunction were recorded and compared to transplant biopsies. C-reactive protein concentrations were correlated with postoperative graft function and the various causes of graft dysfunction. RESULTS: All patients demonstrated an increase in C-reactive protein in response to surgery and a maximum level was reached on day 2 after transplantation. Mean C-reactive protein concentration was significantly increased for delayed (61.50 microg./ml.) compared to primary (mean 38.01) graft function (p = 0.001, Mann-Whitney U test). There were significant increases in C-reactive protein for bacterial infections other than asymptomatic bacteriuria (33.98 microg./ml), interstitial graft rejection (16.43) and acute tubular necrosis (30.50) compared to uneventful courses. C-reactive protein was unchanged for viral infections or cyclosporin A toxicity. CONCLUSIONS: Serial C-reactive protein measurements help to identify renal transplant dysfunction of different origins. However, rejection, infection and acute tubular necrosis show similar patterns of C-reactive protein increase. Thus, C-reactive protein is unable to discriminate the causes of renal graft dysfunction. Biopsy remains the gold standard for the differential diagnosis of renal allograft dysfunction.     

老年患者肾移植围手术期的处理体会

目的总结老年患者肾移植围手术期处理的经验及教训。方法对１４例年龄为６０～７６岁的老年患者肾移植的资料进行回顾性分析。结果术后患者肾功能恢复正常的时间为３～３０天，平均（８．９±７．５）天；无移植肾功能丧失；术后未发生排斥反应；术后并发症有环孢素Ａ肝毒性、尿瘘、急性肾小管坏死、白细胞减少等。结论针对老年患者的特点做好围手术期各项工作，老年患者肾移植是可以取得较好效果的     

Impact of dialysis modality on posttransplantation results in kidney transplantation

Studies looking at the type of pretransplantation renal replacement therapy on graft and patient survivals after kidney transplantation have produced conflicting results. Therefore, we studied the effect of pretransplantation dialysis modality (peritoneal dialysis [PD] or hemodialysis [HD]) on transplant outcomes. We performed a retrospective study of 78 patients (39 PD and 39 HD) who had their first renal transplantation between January 1986 and December 2004. Comparisons between groups were made using chi-square tests for qualitative parameters and nonpaired Student t tests for continuous variables. Comparisons between actuarial curves of patient and technique survivals used log-rank tests. The percentages of recipient males, cadaveric donors, transplant-induced diabetes, mean period of dialysis, mean transplantation follow-up, mean duration of first hospital stay, first infection, acute tubular necrosis, and acute rejection episodes were not significantly different among PD versus HD patients, whereas recipient and donor mean ages were significantly higher in HD and PD patients, respectively. There were no differences in graft and recipient survivals among PD versus HD patients. After kidney transplantation, there was no difference between PD and HD patients concerning percentages of infection, acute tubular necrosis, acute rejection episodes or graft and recipient survivals.     

Evaluation of renal grafts in patients with lupus nephritis as cause of end-stage renal disease

INTRODUCTION: Kidney transplantation is the best option in end-stage renal disease (ESRD). For many years patients affected with lupus nephritis have had poor graft results. However, this has been changing over recent years with the development of new immunosuppressive drugs and a better comprehension of the natural evolution of the entity. METHODS: We studied 20 patients with lupus nephritis who received 22 kidney grafts: 15 women and five men (n = 11) who were treated with cyclosporine or with tacrolimus (n = 11). Secondary immunosuppression included mycophenolate match (MMF) (n = 13) or azathioprine (n = 9). We analyzed human leukocyte antigen, cold ischemia time, acute tubular necrosis, creatinine, cholesterol, triglycerides, glucose, blood pressure, acute rejection episodes, immunosuppression, infections, disease recurrences, as well as graft and patient survival. RESULTS: After a mean cold ischemia time of 22 +/- 4 hours, nine patients displayed delayed graft function of an average duration 9 +/- 4 days. At 36 +/- 35 months nine grafts were lost: two due to acute rejection; five to chronic allograft nephropathy; and two to venous thrombosis. One patient died of hemorrhagic shock. There were five cytomegalovirus infections. Graft survival was dependent on the type of secondary immunosuppression, incidence of acute rejection episodes and occurrence of delayed graft function. CONCLUSIONS: We found no clinical recurrence of lupus nephritis after transplantation and a low incidence of complications, although there was a trend toward thrombosis. The presence of delayed graft function, episodes of acute rejection, and receiving azathioprine instead of MMF as secondary immunosuppression were associated with poorer graft survival.     

Enzyme-linked immunosorbent assay for serum renal tubular antigen in kidney transplant patients

A mouse monoclonal antibody, specific for binding with the epithelial surface antigen in human renal proximal tubules, was produced by hybridoma culture. Using this antibody, an enzyme-linked immunosorbent assay was developed to measure the human renal tubular epithelial antigen (HRTE) concentrations in serum samples from 25 normal subjects and 66 consecutive renal allograft recipients. In 46 patients treated with azathioprine and prednisone, serum HRTE was elevated more than two-fold in 56 of 62 rejection episodes 2-5 days before the clinical diagnosis was made. Of the 56 rejection episodes, the antigen level fell to baseline after treatment in 44 steroid-responsive episodes, but it remained elevated in 8 steroid-resistant rejections, and it became undetectable 3-4 days after the initial elevation in 4 episodes in which allografts were lost to rejection. In 20 patients treated with cyclosporine and prednisone, all 25 rejection episodes demonstrated a greater than two-fold increase of serum HRTE 1-6 days prior to the diagnosis of rejection. The antigen level fell to baseline in 23 reversible rejection episodes, however serum HRTE remained elevated in 2 steroid-resistant patients whose grafts were lost to rejection. Cyclosporine nephrotoxicity without rejection was confirmed in 6 episodes, each of which demonstrated a more than two-fold increase in HRTE 2-4 days before toxicity was diagnosed. When the cyclosporine dose was reduced, the antigen level decreased as the serum creatinine declined. Serial determinations of serum HRTE in renal transplant recipients can provide valuable information for the early diagnosis and management of allograft rejection and cyclosporine nephrotoxicity.     

A comparison of duplex Doppler ultrasonography and intrarenal manometry in the diagnosis of acute renal transplant rejection

Renal transplant rejection is frequently difficult to differentiate from other causes of renal dysfunction. This study examined the use of duplex Doppler ultrasound and intrarenal manometry in a consecutive series of 73 patients who underwent renal transplantation. Altogether 327 duplex scans were analyzed and, for each, a resistive index (RI) was calculated. A raised RI predicted rejection in patients with grafts that functioned immediately, but not in those that had delayed function. A rise in intrarenal pressure ( greater than or equal to 40 mmHg) indicated the presence of rejection in both groups. However, neither test had a sensitivity of more than 71% and this was not improved by combining the results of the two tests for each patient. Although both tests have a place in transplantation, renal biopsies may still be required to confirm rejection.     

Flow-cytometric measurement of cellular changes in urine: a simple and rapid method for perioperatively monitoring patients after kidney transplantation.

OBJECTIVE: In renal transplant patients having graft dysfunction, it is usually difficult to obtain the accurate diagnosis, such as acute rejection, acute tubular necrosis, infection, or cyclosporin nephrotoxicity. An accurate diagnosis can provide the proper treatment of these patients, thereby lessening the chance of kidney loss. METHODS: A total of 42 patients were enrolled. By using the flow-cytometric technique, the white cell populations of urine in these patients were analyzed and linked to their clinical course. All patients underwent sonography-guided biopsy of the transplanted kidney with a definitive diagnosis. RESULTS: When 10% lymphocytes and 15% granulocytes in urine were set as the cutoff point of a normal ratio threshold, the flow-cytometric analysis presented the highest sensitivity and the highest negative predictive rate for acute tubular necrosis. However, a lower sensitivity and positive predictive rate was found in acute rejection cases. CONCLUSIONS: Our results suggest that flow-cytometric analysis of the urinary cell population can be used as an adjunct in patient follow-up after kidney transplantation.     

Serum C-reactive protein concentrations in cyclosporine-treated renal allograft recipients

Acute or persistent elevations in serum C-reactive protein (CRP) concentration have been shown to be of value in diagnosing acute rejection episodes in azathioprine (AZA)-treated renal transplant recipients. To assess whether changes in serum CRP level might assist in differentiating nephrotoxicity from acute rejection in cyclosporine (CsA)-treated renal transplant recipients, we measured changes occurring in serum CRP concentrations in 74 CsA patients in response to transplant operation, acute rejection, cyclosporine nephrotoxicity, and serious infection, and compared these values with changes in AZA patients. Serum CRP concentration rose in response to operation in virtually all patients, regardless of immunosuppressive regimen, from mean baselines of 5.9 +/- 2.7 mcg/ml (AZA) and 6.8 +/- 6.5 mcg/ml (CsA) to mean peak levels of 43.8 +/- 33.4 mcg/ml and 65.1 +/- 39.5 mcg/ml, respectively. CRP rose during 76% of acute rejection episodes in AZA patients by a mean of 29.7 +/- 37.4 mcg/ml. In contrast, in 80% of acute rejection episodes of CsA patients, CRP remained undetectable or failed to rise above a stable, minimally elevated baseline. Similarly, there was no elevation in CRP in 9 of 10 episodes of nephrotoxicity. In 14 CSA patients with serious infections (8 pulmonary, 3 intraabdominal, 3 genitourinary), CRP rose by a mean of 67.7 +/- 50.7 mcg/ml. Thus, although CRP rises significantly with operation or serious infection in CsA patients, CRP fails to rise with nephrotoxicity or acute rejection.     

Renal expression and urinary concentration of EGF and IL-6 in acutely dysfunctioning kidney transplanted patients

Background: Despite marked improvements in the success of solid organ transplantation, a significant percentage of transplanted organs is lost due to recurrent episodes of acute cellular rejection. The mechanisms that govern allograft rejection likely include a complex regulatory network of multiple cytokines and growth factors. Design and Method: This study investigated the kidney gene (in situ hybridization) and protein (immunohistochemistry) expression and the urinary excretion rate of IL-6 and EGF in 29 renal transplant recipients: 16 with acute cellular rejection (AR) and 13 with acute tubular damage/cyclosporine toxicity (ATD). Results: AR patients displayed a 4-fold increase of renal IL-6 expression, which localized chiefly to proximal tubular cells and monocytes/macrophages, whereas EGF signal was extremely weak or even absent. In ATD patients, EGF expression was markedly reduced, while IL-6 specific signal was unchanged. In all the patients examined the renal expression of IL-6 and EGF strictly correlated with their urinary excretion rate (r:0.459, P:0.001). Thus, urinary IL-6/EGF ratio was markedly increased in the former group (>20-fold at day 1), where it parallelled the modifications of plasma creatinine over time (r:0.603, P <0.0001), and was only slightly increased in the latter group (<3-fold). Conclusion: Kidney transplanted patients with acute cellular rejection or acute tubular damage/CyA nephrotoxicity exhibit a distinctly different pattern of intragraft expression of IL-6 and EGF, which is closely reflected by their rate of urinary excretion.     

Renal allograft rupture caused by acute tubular necrosis

Renal allograft rupture is a rare but potentially lethal complication of kidney transplantation. A renal allograft recipient receiving quadruple immunosuppressive therapy developed a spontaneous allograft rupture 13 days after kidney transplantation. Warm ischaemia time during the transplant was 80 minutes. The ruptured kidney graft could not be salvaged because of the patient's haemodynamic instability. The histopathological examination showed interstitial oedema with severe acute tubular necrosis with no signs of acute rejection. The most common causes of renal graft rupture are acute rejection and vein thrombosis, while acute tubular necrosis may only rarely be responsible for this complication. Renal graft rupture may be the result of interstitial damage attributed both to the prolonged warm ischaemia time during the transplant and to post-transplant acute tubular necrosis in the absence of graft rejection. In those patients whose haemodynamic status cannot be stabilized by appropriate aggressive haemodynamic support therapy, graft nephrectomy should be considered the only definitive treatment.     

Is acute rejection the key predictor for long-term outcomes after renal transplantation when comparing calcineurin inhibitors?

In the context of modern immunosuppressive regimens, the overall incidence of acute rejection may no longer be the most accurate surrogate marker for long-term kidney graft survival. The type, severity, timing, and clinical course of acute rejection each influence the impact of a rejection episode, and if renal function recovers fully, there appears to be no survival disadvantage. Randomized clinical trials in renal transplant patients have generally shown that there are fewer acute rejection episodes with tacrolimus compared with cyclosporine, although with contemporary regimens, including mycophenolate acid, this difference is less marked than previously. In randomized trials, kidney graft survival rates with cyclosporine and tacrolimus have proven similar. Large-scale registry analyses have consistently shown no graft survival benefit with tacrolimus vs cyclosporine, and indeed, 2 such analyses have reported significantly higher graft survival with cyclosporine-based immunosuppression compared with tacrolimus in living-donor kidney transplant patients receiving mycophenolate mofetil. There are no reports of improved patient survival with either calcineurin inhibitor after kidney transplantation. In conclusion, the perception of better efficacy with tacrolimus vs cyclosporine based on the incidence of acute rejection is not supported by a difference in graft or patient survival after kidney transplantation.     

Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity

BACKGROUND: Long-term treatment with cyclosporine (CsA) or tacrolimus (Tac) results in chronic nephrotoxicity. Transforming growth factor-beta (TGF-beta) and other pro-fibrogenic molecules have been known to contribute to this side effect. A comparison of intrarenal expression of TGF-beta and other fibrogenic genes in biopsies from patients with either CsA or Tac nephrotoxicity have not been documented. This study compared the expression of TGF-beta, collagen, fibronectin, metalloproteinases (MMP-2, -9), tissue inhibitors of metalloproteinases (TIMP-2) and osteopontin in renal biopsies obtained from renal transplant recipients treated with either CsA or Tac as primary immunosuppressive agents. METHODS: Using RT-PCR, intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, MMP-9 and TIMP-2 were studied in renal biopsies from patients with histological diagnosis of CsA or Tac nephrotoxicity and acute rejection. TGF-beta protein expression was studied by staining section of biopsies with anti-TGF-beta antibody. RESULTS: Intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, TIMP-2, and osteopontin were significantly increased in patients treated with Tac nephrotoxicity compared with CsA nephrotoxicity. The intrarenal mRNA expression of these genes was higher in patients diagnosed with Tac/CsA nephrotoxicity compared to acute rejection. CONCLUSIONS: This study compares the intrarenal expression of TGF-beta and profibrogenic genes in renal transplant recipients treated with Tac and CsA. The results show that patients diagnosed with Tac nephrotoxicity exhibit increased expression of profibrogenic genes compared to CsA nephrotoxicity.