Is mycophenolate mofetil less safe than azathioprine in elderly renal transplant recipients?

BACKGROUND: Mycophenolate mofetil (MMF) is a potent immunosuppressive agent that has been shown to be superior to azathioprine in preventing early acute rejection in the general renal transplant population. However, it is uncertain whether these benefits also apply to older renal transplant recipients, who are known to be more susceptible to infectious complications and have considerably lower rates of rejection and immunological graft loss. METHODS: A retrospective analysis was undertaken of all elderly (> or =55 years old) renal transplant recipients who underwent renal transplantation at the Princess Alexandra Hospital (1994-2000) and received either MMF (n=60) or azathioprine (n=55) in combination with prednisolone and cyclosporin. Data were analyzed on an intention-to-treat basis using a multivariate Cox proportional hazards model. RESULTS: The azathioprine- and MMF-treated groups were well matched at baseline with respect to demographic characteristics, end-stage renal failure causes and transplant characteristics. Compared with the MMF cohort, azathioprine-treated patients experienced a shorter time to first rejection [hazard ratio (HR) 4.47, 95% CI 1.53-13.1, P<0.01]. However, azathioprine-treated patients were also less likely to develop opportunistic infections (HR 0.11, 95% CI 0.03-0.41, P=0.001). No differences were observed between the two groups with respect to hospitalization rates, intensive care admissions, hematological complications, or posttransplant malignancies. Actuarial 2-year survival rates for the azathioprine- and MMF-treated patients were 100 and 87%, respectively (P<0.001). The principal cause of death in the MMF cohort was infection. Using a multivariate Cox regression analysis of patient survival, an adjusted hazard ratio of 0.01 (95% CI 0.001-0.08, P=0.001) was calculated in favor of azathioprine. Overall graft survival also tended to be better in patients receiving azathioprine (HR 0.27, 95% CI 0.06-1.33, P=0.11), CONCLUSIONS: In elderly renal transplant recipients, the combination of MMF, cyclosporin, and prednisolone appears to result in a worse outcome compared with the less potent combination of azathioprine, cyclosporin, and prednisolone. Future prospective studies need to specifically evaluate the risk/benefit ratios of newer, more potent immunosuppressive protocols, such as MMF-based regimens, in this important and sizeable patient subgroup.     

Is uric acid a predictive factor for graft dysfunction in renal transplant recipients?

Hyperuricemia is a common complication in renal transplant recipients, and uric acid (UA) may play a role in renal dysfunction. The aim of this study was to evaluate the effects of UA on chronic allograft nephropathy (CAN) in renal transplant recipients. The 133 study subjects included 34 women and 99 men of overall mean age of 34.7 +/- 9.9 years. They underwent renal transplantation between 1998 and 2000. Serum UA levels were measured in the first month after transplantation and then at yearly intervals throughout a 3-year follow-up. In the first month after transplantation, 55.3% of recipients had hyperuricemia (UA >7 mg/dL in men; UA >6 mg/dL in women), but, 3 years after transplantation, 84.6% of the subjects had that disorder (P<.001). CAN was diagnosed in 31.5% of the patients at a mean onset of 31.8 +/- 14.3 months after transplantation. Fifty-two percent of these individuals experienced graft failure within 43.3 +/- 20.8 months after transplantation. UA levels were recorded before the development of CAN. There was no association between UA levels and CAN according to a Cox regression analysis (P>.05; relative risk, 1.082; 95% confidence interval [CI] 0.9-1.3). We concluded that the prevalence of hyperuricemia was higher among recipients than in healthy individuals, but that the UA level did not affect the development of CAN during first 3 years after transplantation.     

C2 monitoring in maintenance renal transplant recipients: is it worthwhile?

Presently, there is little knowledge regarding cyclosporine (CsA) concentration at 2 hr post-dose (C2) monitoring in maintenance patients. This study evaluates the actual C2 range in stable renal transplant recipients (who underwent transplantation >12 months ago). In addition, we investigated whether underexposure or overexposure to CsA (assessed by C2) affects graft function (as measured by serum [S]-creatinine). All renal transplant recipients in Norway receiving CsA were asked to participate; 1447 fulfilled the criteria. Valid C2 and CsA trough concentration (C0) measurements were performed in 1032 renal transplant recipients (71%) monitored by C0. Target C0 level was 75 to 125 mumol/L. CsA levels were measured using a Cloned Enzyme Donor Immunoassay method, and all analyses were performed in the same laboratory (overall mean [+/-standard deviation] CsA C0=112+/-31 mug/L, CsA C2=697+/-211 mug/L [range 81-1580 mug/L], CsA dose [mg/day]=208+/-61, CsA dose [mg/kg/day]=2.8+/-1.1, and S-creatinine=141+/-58 mumol/L). A univariate analysis of variance showed that patients with C2 levels between 700 and 800 mug/L (n=203, S-creatinine=136+/-49 mumol/L) had significantly lower S-creatinine levels compared with patients with C2 levels greater than 950 mug/L (n=94, S-creatinine=152+/-56 mumol/L) (P<0.02). The same was true for patients with C2 levels less than 450 mug/L (n=95, S-creatinine 141+/-72 mumol/L) (P<0.05) when compared with patients with C2 levels greater than 950 mug/L. There was no significant difference in S-creatinine between patients in the low and intermediate C2 group; 666 patients had C0 levels in the therapeutic range (75-125 mumol/L). A linear regression showed a significant relation between S-creatinine and C2 for these patients (P=0.03). The corresponding relation between S-creatinine and C0 was nonsignificant (P=0.3). Monitoring of C2 in maintenance patients is a valuable tool to detect overexposure to CsA. Until results from prospective studies are available, we recommend C0 in the therapeutic range and reduction in CsA in overexposed patients, aiming at a C2 value between 700 and 800 mug/L.     

Withdrawal of immunosuppression in liver transplant recipients: Is this as good as it gets?

Background: Some reported studies have indicated the possibility of immunosuppression withdrawal in cadaveric liver transplantation. The aim of this study was to evaluate the possibility and feasibility of weaning living donor liver transplant recipients from immunosuppression. Methods: From June of 1990 to October of 1999, 63 patients were considered to be weaned from immunosuppression. They consisted of 26 electively weaned patients and 37 either forcibly or incidentally weaned patients (nonelective weaning) due to various causes but mainly due to infection. Regarding elective weaning, we gradually reduced the frequency of tacrolimus administration for patients who survived more than 2 years after transplantation, maintained a good graft function, and had no rejection episodes in the preceding 12 months. The frequency of administration was reduced from the conventional b.i.d. until the start of weaning of q.d., 4 times a week, 3 times a week, twice a week, once a week, twice a month, once a month, and finally, the patients were completely weaned off with each weaning period lasting from 3 to 6 months. The reduction method of nonelective weaning depended on the clinical course of each individual case. When the patients were clinically diagnosed to develop rejection during weaning, then such patients were treated by a reintroduction of tacrolimus or an additional steroid bolus when indicated. Results: Twenty-four patients (38.1%) achieved a complete withdrawal of tacrolimus with a median drug-free period of 23.5 months (range, 3-69 months). Twenty-three patients (36.5%) are still being weaned at various stages. Sixteen patients (25.4%) encountered rejection while weaning at median period of 9.5 months (range, 1-63 months) from the start of weaning. All 16 were easily treated with the reintroduction of tacrolimus or additional steroid bolus therapy. Conclusions: We were able to achieve a complete withdrawal of immunosuppression in some selected patients. Although the mechanism of graft acceptance in these patients has yet to be elucidated, we believe that a majority of long-term patients undergoing living donor liver transplantation may, thus, be potential candidates to be successfully weaned from immunosuppression.     

Does subclinical rejection contribute to chronic rejection in renal transplant patients?

Renal allograft biopsies have traditionally been performed in the setting of acute graft dysfunction. However, several groups have performed graft biopsies at times of stable graft function, and more recently, after treatment of rejection episodes. Surprisingly, unequivocal histologic criteria for acute rejection have been demonstrated in a high proportion of these protocol biopsies. The Winnipeg Transplant Group has documented the high prevalence of clinically silent inflammatory infiltrates in early protocol biopsies, and demonstrated their inflammatory and cytotoxic potential by immunohistochemical and molecular biological techniques. Furthermore, in a randomized trial, our group has demonstrated that subclinical rejection, if untreated, is associated with the development of early chronic pathology and late graft dysfunction. In this overview, we will summarize the early data on subclinical allograft inflammation, present the experience of the Winnipeg Transplant Group, and discuss the possible implications of subclinical rejection on the development of chronic rejection.     

Is there any effect of compliance on clinical parameters of renal transplant recipients?

Noncompliance with regard to diet, medications and routine physician visits is frequently observed among some patient groups. This results in late graft dysfunction and behavior loss. In the present study, we defined compliance as attendance at 80% or more outpatient visits. The study included 63 cadaveric and 158 living-related renal transplant recipients namely, 150 men and 76 women of 8 to 70 years of age (median 38 +/- 12) who were operated between 1986 and 2001. Demographic data, number of visits attended per month, cigarette smoking, and alcohol intake were probed with a questionnaire that was delivered to the patients, 8 of whom died; hemophagocytic syndrome (n = 4), cardiovascular disease (n = 2), Kaposi' sarcoma (n = 1), and cerebrovascular bleeding (n = 1). Twenty-three patients had lost their graft. Compliance among men was lower than among women, a result that trended toward statistical significance (P =.087). Compliance was not related to marital status (P =.297), but tended to increase with educational background (P =.059). Graft loss (P =.546) and aging (P =.509) were not related to compliance. There was no relationship between compliance and mortality rate (P =.526). Interestingly, living-related kidney transplant recipients showed lower compliance than cadaveric kidney recipients, a result that was statistically significant (P =.04). Noncompliance was also related to cigarette smoking during the pre- and posttransplant periods (P =.008 and P =.03, respectively), as well as alcohol intake (P =.000). In conclusion, male gender and living-related donation are related to noncompliance, but (in contrast with literature) not young age, graft loss, or mortality. Compliance increases with educational status of the patients. Smoking and alcohol intake are closely related to noncompliance.     

Is low pre-transplant parathyroid hormone a risk marker for cardiovascular disease in long-term follow-up of renal transplant recipients?

Background

Secondary hyperparathyroidism and altered levels of parathyroid hormone (PTH) are associated with vascular events in chronic kidney disease. After renal transplantation, this association is not clear. Pre-transplant parathyroidectomy (PTX) is common, but post-transplant data are scarce. We aimed to study the effect of PTH at the time of transplantation on risk of post-transplant vascular events in renal transplant recipients with and without pre-transplant PTX.

Methods

258 patients from two Swedish transplant units were followed for 6 years. Separate analyses were made for patients with or without pre-transplant PTX. Patients with no pre-transplant PTX were stratified by quartiles of PTH at time of transplantation and patients with pre-transplant PTX were stratified by above and below median levels of PTH at time of transplantation. Hazard ratios for vascular events, mortality, and graft failure were calculated in adjusted Cox regression models.

Results

In patients with no pre-transplant PTX, the lowest quartile of PTH at transplantation had a higher risk of cardiovascular events compared to quartile 3 with an adjusted hazard ratio (95% CI) of 2.63 (1.04–6.67). In patients with pre-transplant PTX, the group below median of PTH had a higher risk of cardiovascular events with an adjusted hazard ratio (95% CI) of 18.15 (1.62–203.82) compared to patients above median of PTH.

Conclusion

Low levels of parathyroid hormone before transplantation were associated with increased risk of post-transplant vascular events both in patients with and without pre-transplant parathyroidectomy. Any conclusions on causal or direct effect of PTH on outcome cannot be drawn from this observational study.

     

Elevated urinary angiotensinogen a marker of intrarenal renin angiotensin system in hypertensive renal transplant recipients: does it play a role in development of proteinuria in hypertensive renal transplant patients?

The aim of this study was to evaluate the relationship of local intrarenal renin angiotensin system (RAS) with hypertension and proteinuria in renal transplant recipients. Sixty-nine nondiabetic renal transplant recipients (39 male, mean age: 36.3 ± 11.5 years) were included in this study. All patients were in stable condition with GFR greater than 30 ml/min/1.73 m(2); (MDRD). Hypertension was defined to be present if there was a recorded diagnosis of hypertension, systolic blood pressure >130 mmHg and/or diastolic blood pressure >80 mmHg according to ambulatory blood pressure monitoring. None of the hypertensive patients were receiving RAS blockers. Spot urine samples were obtained to measure urinary angiotensinogen (AGT) using human AGT-ELISA, urinary creatinine and protein levels. The demographic properties and laboratory findings were similar between hypertensive and normotensive transplant recipients. Urinary AGT-creatinine ratio (UAGT/UCre) was significantly higher in hypertensive patients compared with the normotensives (8.98 ± 6.89 μg/g vs. 5.48 ± 3.33 μg/g; P = 0.037). Importantly, a significantly positive correlation was found between UAGT/Ucre levels and proteinuria in hypertensive patients (P = 0.01, r = 0.405). Local intrarenal RAS probably plays an important role in the development of hypertension and proteinuria in renal transplant recipients.     

Treatment of recurrent hepatitis C in liver transplant recipients: Is there any histologic benefit?

The benefit of antiviral treatment in recurrent hepatitis C after liver transplantation remains unclear. The aim of this study was to determine whether antiviral treatment improved histologic outcome in recurrent hepatitis C. All patients who were transplanted for hepatitis C from January, 1998 to December, 2000 were offered treatment with interferon alpha 2b (3 million units three times per week) and ribavirin (800 mg/d) for 1 year. All patients underwent liver biopsy before and after treatment. Virologic assay was performed at 3 months and at 1 year. Among the 33 patients, 13 managed 80% of total doses of both interferon and ribavirin. Dose reduction or discontinuation was necessary in others. In an intention to treat analysis, the overall virologic response at 3 months and 1 year was 27% and 12%, respectively. On an intention to treat basis, the overall histologic response showed little benefit. In the subgroup of patients who received full treatment, there was a trend towards benefit in regard to inflammation (per histologic activity index [HAI] score). However, the fibrosis score was comparable in both groups, and complete antiviral treatment did not improve the fibrosis score or prevent progression of fibrosis. In the posttransplant setting, it is often extremely difficult to give a full course of treatment with existing antiviral regimes. In an intention to treat analysis, the overall benefit of antiviral treatment in recurrent hepatitis C is disappointing, with little impact on the progression of fibrosis. (Liver Transpl 2003;9:354-359.)     

Does etiology of end-stage renal disease affect sleep quality in kidney transplant recipients?

BACKGROUND: That hypertension (HTN) as a leading cause of end-stage renal disease (ESRD) is linked to sleep disorders in the general population can be the basis of a hypothesis that HTN may be a contributing factor to the poor quality of sleep in some kidney transplant recipients. This study was designed to investigate the correlation between ESRD secondary to HTN and sleep quality among kidney transplant recipients. METHODS: In this case control study, 201 kidney transplant recipients were divided into group I (ESRD) secondary to HTN, (n=82) and group II (ESRD secondary to other causes, n=119). The groups were matched for medical comorbidities, demographic and clinical data, and symptoms of anxiety and depression. Sleep quality assessed by means of the Pittsburgh Sleep Quality Index (PSQI) was compared between the study groups. RESULTS: The mean (SD) of the total PSQI score was significantly high in group I compared with group II (7.42 +/- 2.36 vs 6.60 +/- 3.07, P=.042). Similar results were observed for the sleep duration scores in the groups (1.22 +/- 1.12 vs 0.86 +/- 1.12, P=.026). In group I, all the other PSQI components were higher than those in group II, difference that were statistically significant. CONCLUSION: Sleep quality and duration was poorer among our kidney transplant recipients with ESRD secondary to HTN compared with the controls. Further studies, however, are required to investigate whether HTN is responsible for the reported poor quality of sleep in some kidney transplant recipients.     

Do cyclosporin proffles provide useful information in the management of renal transplant recipients?

BACKGROUND.: This study investigated the relationships between cyclosporinA (CsA) blood levels and episodes of renal allograft rejectionand nephrotoxicity following renal transplantation, with theaim of establishing whether CsA profiles provided more usefulinformation than single CsA blood levels in respect of theserelationships. METHODS.: One hundred and sixty-two profiles were performed over 16 monthsin 40 patients and analysed retrospectively. Blood samples weretaken at 0, 2, 4, 6 and 8 h after the morning CsA dose. Rejectionepisodes were diagnosed by renal biopsy and CsA nephrotoxicityby a fall in serum creatinine 1 week after a cut in CsA dose. RESULTS.: The mean area under the curve (AUC) was lower for profiles performedat the time of rejection (3821 h.ng/ml) than that of a matchedgroup of non-rejecting profiles (5479 h.ng/ml; P0.02). An AUCabove 6400 h.ng/ml significantly discriminated rejection fromnon-rejection, whereas pre-dose and peak CsA concentrationsdid not have such discriminating cut-off values. A comparisonof CsA-toxic and non-toxic profiles showed that there were nosignificant differences between mean CsA concentrations norbetween the mean AUCs of these groups. CONCLUSION.: We conclude that basing CsA dosing on CsA profiles could helpto avoid some early episodes of rejection without increasingthe risk of nephrotoxicity.     

Are heart transplant recipients more likely to develop skin cancer than kidney transplant recipients?

Abstract Non‐melanoma skin cancer is frequent in organ transplant recipients. The risk of post‐transplant cutaneous squamous cell carcinoma in Norwegian heart transplant recipients (n = 148) and kidney transplant recipients (n = 1020) on triple immunosuppressive therapy with cyclosporine, azathioprine, and prednisolone, transplanted between 1983 and 1992, were studied. After adjustment for age at transplantation in multivariable Cox models, heart transplant recipients had a significantly 2.8‐times higher risk of developing squamous cell carcinoma relative to kidney transplant recipients. The risk relative to the general population (standardized incidence ratio) was higher in heart transplant recipients than in kidney transplant recipients. The results indicate that heart transplant recipients are more likely to be diagnosed with skin cancer than kidney transplant recipients, probably due to the higher doses of cyclosporine and azathioprine after heart transplantation used at our center in the study period.     

Should living-unrelated renal transplant recipients receive antibody induction? Results of a clinical experience trial

BACKGROUND: Living-donor kidney transplant recipients generally do not receive antibody induction. Induction avoidance may not be appropriate, particularly for living-unrelated renal transplant (LURT) recipients, in whom matching may not be optimal. We compared the incidence of acute rejection and graft outcome of LURT recipients who were administered no induction and cadaveric renal transplant (CRT) recipients who were administered anti-CD25 antibody. These groups both had immediate graft function and similar maintenance immunosuppression. METHODS: This retrospective analysis included patients who received kidney transplants between 1999 and 2000. CRT recipients received basiliximab, corticosteroids, mycophenolate mofetil (MMF), and delayed tacrolimus (serum creatinine <3 mg/dL). LURT recipients received tacrolimus (initiated pretransplantation), MMF, and corticosteroids. RESULTS: The analysis included 136 LURT recipients and 126 CRT recipients. CRT recipients included more African Americans (52.4% vs. 30.9%, P<0.01). LURT recipients included more patients with at least one human leukocyte antigen mismatch (97.8% vs. 85.7%, P<0.01). A higher acute rejection rate was observed in LURT recipients at both 6 months (LURT recipients 19.1% vs. CRT recipients 3.2%, P<0.01) and 1 year (21.3% vs. 4.0%, P<0.0004); a higher rate also was observed in African American LURT recipients compared with African American CRT recipients (35.7% vs. 4.5%, P<0.0015) at 1 year. LURT recipients demonstrated a threefold greater rejection risk than CRT recipients who were administered basiliximab (relative risk: 3.6, P<0.002). Graft survival was similar at 1 year. CONCLUSION: The higher rejection rates in LURT recipients (no induction) compared with CRT recipients (basiliximab induction), despite similar chronic immunosuppression (tacrolimus, MMF, and steroids) and immediate graft function, indicate the potential advantage of anti-CD25 induction in LURT protocols to reduce the risk of acute rejection.