Cancer after kidney transplantation and immunosuppression

Between 1977-1998 we followed up 115 patients with renal allograft. Seventy patients had received a graft from a living donor, while 45 had received a graft from a cadaver donor. The immunosuppressive therapy included azathioprin (AZA), prednisolone (PRED) and cyclosporin A (CyA) in 90 patients and AZA and PRED in 25 patients. Nine patients showed skin malignancies (7.3%), three of these patients had Kaposi's sarcoma and the other six patients squamous or basal cell carcinoma. All cases were clinically and histologically confirmed. Squamous or basal cell carcinoma occurred mostly on the head and was radiosensitive, though recurrences might be observed. Kaposi's sarcoma was localized on either the lower extremities or the face. The condition of two patients treated by radiotherapy only partially improved. Due to chronic renal allograft rejection immunosuppressive therapy was withdrawn in two patients and dialysis was restarted without any other recurrence of the sarcoma. The rate of cancer occurrence in patients with renal allograft is consistent with the findings of other authors. Reduction or withdrawal of immunosuppressive therapy may have a beneficial effect on malignancy, but incurs the risk of losing the allograft.     

Stable kidney function in the second decade after kidney transplantation while on cyclosporine-based immunosuppression

BACKGROUND: Calcineurin inhibitors (CNIs) have been the mainstay of immunosuppressive protocols in kidney transplantation over the past 20 years. However, in some recipients, the adverse effects of CNIs contribute to chronic allograft nephropathy and death with function--the two leading causes of late graft loss. Other recipients maintain stable graft function. METHODS: We studied the impact of continuing CNI-based immunosuppression in the second decade after kidney transplantation. From 1984 through 1996, a total of 1,263 patients underwent a primary kidney transplant at the University of Minnesota and received cyclosporine-based immunosuppression. Antibody induction was used only in deceased donor recipients. RESULTS: The actuarial 20-year patient survival rate was 38%; graft survival, 30%; and death-censored graft survival, 60%. The annual mean serum creatinine level for recipients whose grafts survived > or =1 year remained stable, although recipients with a history of > or =1 acute rejection episode had a higher serum creatinine level vs. recipients who were rejection-free. The annual mean calculated creatinine clearance was also stable over time. In addition, for recipients who were acute rejection-free, chronic allograft nephropathy/chronic rejection was only responsible for 9% of graft losses. CONCLUSIONS: Our study suggests that some kidney transplant recipients tolerate long-term CNI-based immunosuppression with stable creatinine levels. Identifying certain recipients' predisposition to CNI toxicity and individualizing immunosuppressive therapy may be important in order to improve long-term kidney function, while simultaneously preserving low short-term acute rejection rates.     

New-onset diabetes mellitus after kidney transplantation: the role of immunosuppression

BACKGROUND: Complications related to posttransplantation immunosuppressive therapy remain common. New-onset diabetes mellitus after transplantation (PTDM) is a well-recognized complication associated with reduced graft and patient survival. The type of immunosuppression may be responsible for more than two thirds of PTDM. We retrospectively reviewed our experience in a population of 284 kidney transplant recipients, evaluating the incidence of PTDM with regard to the type of immunosuppression. PATIENTS AND METHODS: From January 2001 to December 2005, 284 kidney transplantations were performed using tacrolimus-based (TAC) immunosuppression in 192 patients and a cyclosporine-based (CyA) regimen in 62 patients, whereas 30 patients received sirolimus-based immunosuppression. RESULTS: The overall incidence of PTDM was 4.9%. Among the immunosuppression protocols, 8 patients (4.1%) received TAC and 6 patients (9.6%) received CyA, whereas no patients treated with sirolimus developed PTDM. Graft and patient survival rates were 93% and 100%, respectively. CONCLUSIONS: The overall risk of PTDM with recent immunosuppressive protocols is low, but it is increased among calcineurin inhibitor (CNI)-treated kidney transplant recipients. Sirolimus did not increase the risk of PTDM, allowing potential clinical application in diabetic recipients and in patients affected by PTDM.     

Long-term immunosuppression, without maintenance prednisone, after kidney transplantation

BACKGROUND: Concern exists that prednisone-free maintenance immunosuppression in kidney transplant recipients will increase acute and/or chronic rejection. METHODS: From October 1, 1999, through February 29, 2004, at our center, 477 kidney transplant recipients (341 living donor, 136 cadaver) discontinued prednisone on postoperative day 6, per our protocol. Immunosuppression consisted of polyclonal antibody (Thymoglobulin) for 5 days, prednisone intraoperatively and for 5 days, a calcineurin inhibitor, and either sirolimus or mycophenolate mofetil. We compared outcome with that of historical controls who did not discontinue prednisone. RESULTS: The recipients on prednisone-free maintenance immunosuppression had excellent 4-year actuarial patient survival (92%), graft survival (90%), acute rejection-free graft survival (86%), and chronic rejection-free graft survival (95%). The mean serum creatinine level (+/- SD) at 1 year was 1.6 +/- 0.6; at 4 years, 1.6 +/- 0.6. We noted that 8% of recipients had cytomegalovirus (CMV) disease; 4.5%, fractures; 2.8%, cataracts; 1%, posttransplant diabetes; 0.2%, avascular necrosis; 0.2%, posttransplant lymphoproliferative disease; and 0%, polyomavirus. In all, 85% of kidney recipients with functioning grafts remain prednisone-free as of April 1, 2004.As compared with historical controls, the recipients on prednisone-free maintenance immunosuppression had better patient (P = 0.02) and graft survival (P < 0.0001) and lower rates of acute (P = 0.0004) and chronic (P = 0.02) rejection. In addition, they had a significantly lower rate of CMV disease (P < 0.0001), cataracts (P < 0.0001), posttransplant diabetes (P < 0.0001), and avascular necrosis (P = 0.0003). CONCLUSIONS: Prednisone-related side effects can be minimized without maintenance immunosuppression; our prednisone-free recipients do not have increased acute or chronic rejection.     

Minimization of immunosuppression in kidney transplantation

PURPOSE OF REVIEW: In an effort to reduce the long-term toxicities of immunosuppressant drugs, corticosteroid and calcineurin inhibitor-sparing immunosuppression protocols have become increasingly popular in managing kidney transplant recipients. This article focuses on outcomes of these strategies described in recently published trials. RECENT FINDINGS: The use of induction antibody therapy and potent residual immunosuppressants has increased the safety of steroid-free regimens, resulting in a paradigm shift towards earlier elimination of steroids after kidney transplantation. Even in the modern era, results of randomized trials generally indicate that steroid elimination increases the risk of rejection compared with maintenance steroid therapy. Among calcineurin inhibitor-sparing strategies, withdrawal of these agents after their initial use in stable patients, or conversion to either mycophenolate mofetil or sirolimus in patients with early renal dysfunction appears to yield the greatest benefit in preserving renal function. The outcomes of calcineurin inhibitor avoidance protocols have been mixed and have fallen into disfavor. SUMMARY: The benefits of minimizing immunosuppression in kidney transplant recipients must be weighed against the risks of precipitating acute rejection or chronic allograft dysfunction. Additional research is needed to identify clinical and immune parameters that will enable selection of patients for whom the benefits outweigh the risks.     

Decreased effect of immunosuppression on immunocompetence in African--Americans after kidney and liver transplantation

Several studies indicate that the poorer outcomes for African--Americans after transplantation may be due to decreased effectiveness of immunosuppressive agents. Using an in vitro test of immunocompetence (IMC), we measured the effects of immunosuppression on African-American, compared with Caucasian, kidney or liver transplantation recipients. The IMC result was the highest of three mixed lymphocyte culture responses using validated stimulator cell pools. A total of 293 tests were done in Caucasians and 144 in African--Americans. Overall, the IMC for African--Americans was 38, compared with 19 for Caucasians (p<0.01). This decreased effect of immunosuppression (higher IMC) was the same for liver as for kidney transplant recipients, occurred at the 2--3-yr interval, and was largely in patients of tacrolimus (FK506), with a strong but not significant trend in cyclosporine (CYA) recipients. The two groups were on the same nominal immunosuppression and FK506 and CYA levels were not different. We conclude that African-Americans retain more immune responsiveness on equivalent dose immunosuppression, notable particularly in years 2--3 after transplantation when earlier graft loss occurs in this group.     

Ageing and immunosuppression in kidney transplantation

Modern approaches to tailor-made, individualized immunosuppressive therapy for patients receiving organ transplantation require a rethinking of therapeutic strategies when it comes to older persons receiving kidney transplants, especially from deceased older donors. This review article makes the case for the use of calcineurin-inhibitor-free immunosuppressive induction/maintenance protocols in this "worst-case scenario" and discusses the theoretical and clinical data that support this recommendation. We will discuss modern theories of ageing, emphasizing the free-radical theory in relation to new insights into the mechanisms of innate immunity. In this context, a new, modified theory of ageing is presented. Increased generation of reactive oxygen species during ageing, via increased leakage of these oxidizing molecules from mitochondria, may contribute to senescence and age-related diseases by direct damage to intracellular DNA, proteins, and lipids. In addition, free-radical-mediated tissue injury, accompanied by induction of damage-associated molecular patterns, may result in activation of both inflammatory and vascular cells of the innate immune system, contributing (via inflammatory processes) to ageing and age-related diseases such as atherosclerosis. Calcineurin-inhibiting agents have been shown to induce oxidative stress and are thus defined as "proageing" drugs. Their use in older patients may aggravate the preexisting oxidized intracellular state and therefore should be avoided. In contrast, inosine-monophosphate dehydrogenase-inhibiting agents such as mycophenolate mofetil have been shown to even ameliorate oxidative stress and are thus defined as "antiageing" drugs. Therefore, their use for immunosuppression in older patients receiving kidney transplantation is suggested. This recommendation is supported by data from a prospective trial on the application of a calcineurin inhibitor-free, mycophenolate-mofetil--based induction/ maintenance immunosuppressive protocol in older recipients of kidneys from deceased older donors: the 5-year patient and 5-year allograft survival rates are currently 87% and 70%, respectively.     

Calcineurin inhibitor-free immunosuppression in kidney transplantation

The introduction of calcineurin inhibitors (CNI) revolutionized kidney transplantation (KTx). Exceptionally low acute rejection rates and excellent graft survival could be achieved with CNI-based (cyclosporine and tacrolimus) immunosuppressive protocols. However, despite short-term success, long-term graft attrition continues to be a significant problem, thus leaving clinicians looking for possible interventions. CNI nephrotoxicity is but one of numerous factors that may be contributing to long-term damage in transplant kidneys. Therefore, newer immunosuppressive agents such as mycophenolate mofetil and sirolimus (Rapa) have raised the possibility of withdrawing or avoiding CNIs altogether. Protocols exploring these options have gained greater attention over the last few years. Herein, we review studies addressing either CNI withdrawal or CNI avoidance strategies as well as discuss the risks versus benefits of these protocols. Given the accumulated experience to date, in our opinion, the use of CNIs as a part of immunosuppressive regimens remains the proven standard of care for renal transplant patients. The long-term safety and efficacy of CNI withdrawal and avoidance strategies need to be further validated in controlled clinical trials.     

Steroid withdrawal for pancreas after kidney transplantation in recipients on maintenance prednisone immunosuppression

Steroid withdrawal from patients taking prednisone for their renal allograft at the time of reinduction of immunosuppression for subsequent pancreas after kidney (PAK) transplantation has not been explored. Our expectation was that lymphocyte depletion, in conjunction with an augmentation of immunosuppression at the time of pancreas transplantation would protect the recipient from rejection of the renal allograft when chronic maintenance steroids are withdrawn. METHODS: Pancreas transplantation was performed using systemic venous drainage and enteric exocrine drainage. Regardless of preoperative immunosuppression, all patients received induction with antithymocyte globulin, a brief taper of intravenous solumedrol over four to five days, maintenance therapy with tacrolimus and sirolimus and either resumption of chronic maintenance steroids or complete withdrawal of steroids. RESULTS: A total of 30 PAK transplants were performed in 29 recipients and divided into two groups: continuation of chronic steroids (n = 10) or steroid-free (n = 19). One pancreas allograft was lost and there was a single mortality in the steroid free group. There was no significant difference in renal function or incidence of infections. CONCLUSION: Steroids can be safely withdrawn following pancreas after kidney transplantation for recipients already on maintenance prednisone in the setting of rabbit antithymocyte globulin induction and tacrolimus and sirolimus maintenance immunosuppression.     

Epidemiologic study on the origin of cancer after kidney transplantation

BACKGROUND: Subjects who underwent solid organ transplantation are at higher risk for a wide variety of cancers. METHODS: The authors investigated the origin of cancer in a cohort of 2,526 patients followed up for 60.7 +/- 35.6 months after kidney transplantation between 1990 and 2000 in seven transplant centers. RESULTS: One hundred four of them developed cancer. All subjects who developed solid cancer within 6 months after transplantation (n=10) and a group of subjects who developed solid cancer after 6 months posttransplant (n=10) were selected. Short tandem repeat analysis was performed on paraffin-embedded biopsy specimens of tumors and on both donor and recipient pretransplant peripheral blood. Biologic material was obtained in 17 of the 20 selected patients (85.0%). The analysis showed that 16 of 17 tumors were genetically identical to the recipient. CONCLUSIONS: The authors' results suggest that donor transmission of solid cancer is an unlikely event in their population.     

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.     

Strategies for minimizing immunosuppression in kidney transplantation

Immunosuppression remains the cause of most morbidity following organ transplantation. However, its use is also responsible for the outstanding graft and patient survival rates commonplace in modern transplantation. Thus, the predominant challenge for transplant clinicians is to provide a level of immunosuppression that prevents graft rejection while preserving immunocompetence against environmental pathogens. This review will outline several strategies for minimizing or tailoring the use of immunosuppressive drugs. The arguments for various strategies will be based on clinical trial data rather than animal studies. A distinction will be made between conventional immunosuppressive drug reduction based on over-immunosuppression, and newer induction methods specifically designed to lessen the need for chronic immunosuppression. Based on the available data we suggest that most patients can be transplanted with less immunosuppression than is currently standard.     

Influence of pharmacogenetic polymorphisms in routine immunosuppression therapy after renal transplantation

Pharmacogenetics is the study of the cause of various individual responses to the same pharmacologic therapy. Genetic alterations in a single nucleotide in the genes responsible for transport and metabolism of an immunosuppression drug may modify patient response. Although pharmacogenetics is of interest, its clinical relevance remains to be demonstrated. The objective of the present study was to evaluate the effect of single-nucleotide polymorphisms (SNPs) in renal transplant recipients and their donors relative to blood concentrations of tacrolimus in the first 2 weeks posttransplantation. Seventy-one blood samples each from renal transplant recipients and their donors were analyzed using a genetic analysis system (MassARRAY; Sequenom, Inc, San Diego, California) in an attempt to characterize the more relevant SNPs of the ABCB1 and CYP3A5 genes for correlation with recipient trough concentrations of drug. Two-way analysis of variance and Bonferroni post hoc tests were used. In agreement with theoretical predictions, the wild-type genotype in ABCB1 SNPs (CC) tended to stabilize drug concentrations within the therapeutic range, whereas the T variant induced a mean increase in blood concentrations of more than 60%. These findings are in agreement with statistical tests that compared mean concentrations in various recipient-donor populations and found significant differences between them (P < .001) in CC vs TT, and P < .01 in CT vs TT). Donor genotype did not seem to be relevant. However, further studies are required to achieve more robust conclusions.