Gene/Protein Disease Symptom Drug Enzyme Compound
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Sirolimus (SRL) is a non-nephrotoxic immunosuppressive drug blocking T-cell proliferation through mTOR inhibition. SRL can be used as (1) an early drug in a calcineurin inhibitor-free protocol in the first 3 months after transplantation, (2) in the early and late conversion protocols as suggested by the multicenter randomized CONVERT trial, and (3) in recipients from marginal donors, because calcineurin inhibitors can increase the preexisting renal damage induced by age, hypertension, and diabetes that are frequent in elderly cadaveric donors. In any case, SRL should be used in patients with a cutoff of proteinuria (<or=800 mg/24 hr) or proteinuria-to-creatinine ratio less than 0.11.
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PMID:Review of symposium. Sirolimus in kidney transplantation. 1938 85

Rapamycin is an immunosuppressive drug used to prevent acute allograft rejection in solid organ transplantation. It shows less nephrotoxicity than calcineurin inhibitors. We evaluated the effect of rapamycin in rats undergoing 5/6 nephrectomy, a model of proteinuric and progressive renal failure. Fourteen days after surgery rats were randomized either to receive rapamycin or to remain untreated (control). Rats were humanely killed on day 91; serum creatinine, creatinine clearance, and proteinuria were assessed. Renal sections were stained with periodic acid-Schiff to evaluate glomerular volume (Gv), glomerulosclerosis (GS) and tubulointerstitial damage (TIS); we evaluated GS and TIS by Sirius red staining (SR). Epithelial-to-mesenchymal transition (EMT) was assessed by immunohistochemistry. Rapamycin affected neither serum creatinine nor creatinine clearance; it reduced Gv (controls, 5.9 +/- 3.1 x 10(6); rapamycin, 1.3 +/- 0.7 x 10(6) microm(3)) and proteinuria (control, 349 +/- 146; rapamycin, 56 +/- 27 mg/24 h; P < .05); rapamycin ameliorated GS (control, 78 +/- 7; rapamycin, 36 +/- 7%; P < .05; SR: control, 13.2 +/- 3.5; rapamycin, 3.8 +/- 1.0%; P < .05), and TIS (control, 3.25 +/- 0.5; rapamycin, 1.0 +/- 0.1; P < .05; SR: control, 29 +/- 3; rapamycin, 11 +/- 3%; P < .05). Rapamycin reduced alphaSMA (control, 3.25 +/- 0.5; rapamycin, 1.0 +/- 0.1; P < .05), VIM (control, 3.5 +/- 0.6; rapamycin, 1.0 +/- 1.4; P < .05), and CD68(+) cells infiltration (control, 110 +/- 43; rapamycin, 24 +/- 1 cells; P < .05). Rapamycin slows the progression of renal damage in the rat remnant kidney and may represent a novel approach to the treatment of chronic kidney disease.
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PMID:Rapamycin reduces proteinuria and renal damage in the rat remnant kidney model. 1946 May 62

While conversion of stable renal transplant recipients (RTR) from calcineurin inhibitors (CNI) to sirolimus (SRL) is safe and effective, it is still under investigation for recent, high-risk cases. We studied the long-term effects of conversion of high-risk subjects maintained on a CNI, mycophenolate mofetil, plus steroid regimen to SRL, mycophenolate mofetil, plus steroid on graft and patient outcomes. We retrospectively reviewed the first 100 RTR converted to SRL treatment over approximately 5 years. The main indications for conversion were biopsy-proven acute rejection (BPAR), CNI toxicity, CNI elimination, and acute-tubular necrosis (ATN). Exclusion criteria were limited to bone marrow suppression. The overall mean +/- SD age was 38.5 +/- 15.6 years, including pediatric and geriatric age groups. Mean +/- SD body mass index (BMI) was 28.99 +/- 8.0 and 40% had a BMI > 30. There were 40% RTR from deceased donors and 60% showed 4 to 6 HLA mismatches. Preconversion total BPAR and steroid-resistant rejection incidences were 35% and 14%, respectively. Mean +/- SD time to start of SRL was 11.9 +/- 22.8 months posttransplantation. Proteinuria > 2 g/d, leukopenia, and hyperlipidemia increased significantly after conversion (P = .001, P = .0003, and P = .0001, respectively). Patient and graft survivals were 95% and 90%, respectively. There was significant improvement in graft function postconversion (P < .0001). There was a high incidence of side effects and cases of SRL discontinuation. Multivariate analysis demonstrated the influence of bone marrow suppression, obesity, hyperlipidemia, nutritional status, proteinuria, and graft function on graft and patient outcomes. We concluded that conversion from CNI to SRL was effective among high-risk RTR, but with a high incidence of adverse events during long-term follow-up.
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PMID:Long-term follow-up of 100 high-risk renal transplant recipients converted from calcineurin inhibitors to sirolimus: a single center experience. 1954 4

In participants of the CONVERT trial, which enrolled recipients of kidney transplants, conversion of immunosuppressive therapy from calcineurin inhibitors to sirolimus did not improve renal function. More importantly, the intervention was detrimental among patients with impaired kidney function and/or proteinuria. Sirolimus conversion resulted, however, in lower rates of malignancy.
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PMID:Transplantation: To convert or not to convert: lessons from the CONVERT trial. 1955 93

Although short-term outcomes following kidney transplantation have improved in recent years, allograft viability beyond 1 year has changed little since the introduction of cyclosporine (CsA)-based immunosuppression. Chronic allograft nephropathy (CAN) is a continuing threat to improved long-term outcomes, and regimens that involve calcineurin inhibitors (CNI) are implicated as a result of the progressive fibrosis they promote in renal allografts. Although strategies to reduce the nephrotoxic effects of CNI exposure have shown some success, alternative approaches to reducing nephrotoxicity and graft failure are needed. Sirolimus (SRL) suppresses immune reactions in a mechanism distinct from that of other immunosuppressants and may therefore hold potential for reducing the risk of CAN and improving long-term graft survival. The Rapamune Maintenance Regimen study randomized patients at 3 months either to continue with a regimen of SRL, CsA, and steroids or to have CsA withdrawn and the dose of SRL increased. Patients who were randomized to CsA withdrawal had superior graft and patient survival, demonstrated improved renal function, better blood pressure control, and a lower rate of skin and nonskin posttransplantation malignancy. A key barrier to the wider clinical implementation of SRL in kidney transplantation has, however, been the understanding of its optimal incorporation into standard immunosuppressive protocols. The CONVERT study examined the late conversion (approximately 3 years posttransplantation) from CNI to SRL. Late conversion was associated with inferior outcomes in patients with poor graft function or significant proteinuria following conversion. In addition, a number of short-term adverse events, such as prolongation of delayed graft function and abnormal wound healing, have been more commonly associated with de novo approaches. In designing the optimal approach to achieving long-term CNI-free immunosuppression with SRL, it should therefore be considered how these adverse events may be avoided or minimized. This brings into focus the optimal timing for the introduction of SRL and the potential for a two-stage approach to immunosuppression, minimizing the different short- and long-term risks to both the graft and the patient.
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PMID:Where did we leave off in 2008? Conclusions from the 8th International Symposium. 1965 Dec 92

Since recipients of transplants from elderly donors are exposed to an increased risk of delayed graft function (DGF) and acute rejection episodes, administration of induction treatment represents an alternative to preserve renal mass and improve graft survival. We compared the evolution and histological findings of early graft biopsies among 38 recipients treated with Thymoglobulim (33.6%) versus 75 (66.4%) with basiliximab. No differences were observes in the rate of DGF (P = .39). Forty kidneys were biopsed during the first 2 weeks after transplantation: 9 in the Thymoglobulin group (23.68%) and 31 in the basiliximab group (41.3%). Histological evaluation showed: acute tabular necrosis in 7 (78%) Thymoglobulin patients versus 14 (45%) basiliximab patients, with calcineurin nephrotoxicity in 2 (22%) and 1 (3.2%), respectively. An acute rejection episode was not diagnosed in the Thymoglobulin group, but 13 patients (17.3%) in the basiliximab group experienced this complication (P = .006). Banff classification showed: 6 grade IA (19.4%), 1 grade IB (3.2%), 3 grade IIA (9.7%), 1 grade IIB (3.2%), and 2 grade III (6.5%). Six of these patients required rescue treatment with Thymoglobulin. Serum creatinine and proteinuria levels between the 2 groups were not different (P > .05). There were no differences in cytomegalovirus (CMV) disease (P = .152), admission due to infection (P = .120), or neoplasia (P = .29). Graft and patient survivals at 3 years did not show a difference. The histological findings revealed that low doses of Thymoglobulin were much more effective to prevent renal inflammation and acute rejection episodes than basiliximab among renal transplant recipients, albiet without differences in survival at a mean of 3 years follow-up.
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PMID:Histological findings of early graft biopsies in old donor renal transplant patients receiving induction therapy. 1971 42

Renal transplantation provides the best quality of life for the patients with chronic end-stage renal failure. However, the immunosuppression necessary for graft survival may give rise to infectious complications, an increased risk of cardiovascular and neoplastic diseases, all of which can shorten the patient's survival. The objective of this study was to evaluate the efficacy and safety of the proliferation signal inhibitor immunosuppressant drugs everolimus among patients who develop neoplasms after renal transplantation. This retrospective study included 25 patients (mean age -56.5 +/- 14.1 years) who were diagnosed with posttransplant neoplastic disease and immunosuppressed with calcineurin inhibitors (CNIs). Treatment was initiated with everolimus with or without CNIs. During the follow-up, the renal function (initial serum creatinine 1.4 mg/dL vs final serum creatinine 1.3 mg/dL) and proteinuria levels (initial 0.3 g/d vs final 0.4 g/d) remained stable. There was a low percentage of patients with relapse of their tumor. One patient had a relapse of bladder cancer with tumor progression at 3 years; another patient with melanoma developed lymph node invasion. There were neither acute rejection episodes nor cardiovascular complications. The results suggested that tumor relapse was low. The results suggested that immunosuppression with everolimus combined with low doses of CNIs or in single-drug therapy is safe immunosuppression for patients who develop posttransplant malignant diseases.
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PMID:Everolimus represents an advance in immunosuppression for patients who have developed cancer after renal transplantation. 1971 11

There is evidence that treatment with m-TOR inhibitors can be beneficial in cases of chronic renal allograft dysfunction. However, some authors have reported poor outcomes of renal function if the switch to m-TOR inhibitors is made in the presence proteinuria > 0.8 g/d. The present study sought to provide a retrospective analysis of the clinical outcome of 63 kidney recipients diagnosed with chronic allograft dysfunction whose therapy was converted to rapamycin including 35 subjects with renal biopsy-proven chronic allograft nephropathy. At the time of conversion, patients were divided into three groups: group I (negative proteinuria), group II (proteinuria between 0.3 and 0.8 g/d), and group III (proteinuria > 0.8 g/d). On conversion, 21 recipients had no proteinuria (group I). After a follow-up of 24.6 +/- 12.8 months, they showed a significant improvement in renal function (previous MDRD4 = 39.9 +/- 11.5 mL/m/1.73 m(2), current MDRD4 50.3 +/- 13.3 mL/m/1.73 m(2), P < .05). Fifteen patients (71.4%) developed proteinuria, which was generally mild (0.8 +/- 0.7 g/d) and controlled with angiotensin-converting enzyme inhibitors (42.8%). In group II (n = 18), renal function clearly stabilized after a follow-up of 23.2 +/- 14.4 months (previous MDRD4 = 30 +/- 8.8 mL/m/1.73 m(2), current MDRD4 = 37 +/- 12.2 mL/m/1.73 m(2), NS), although there was a progressive deterioration of previous proteinuria levels (previous proteinuria 0.4 +/- 0.15 g/d, current proteinuria 1.2 +/- 2 g/d, P < .05), which was more frequent and intense in patients whose treatment with calcineurin inhibitors (CNIs) was suspended (with CNI 0.9 +/- 1.7 g/d, without CNI 1.6 +/- 2.2 g/d, P < .05). Group III (n = 24) had a greater degree of renal insufficiency and a worse outcome after 25.9 +/- 18 months of follow-up, with a frank and progressive deterioration in renal function (previous MDRD4 = 38 +/- 17 mL/m/1.73 m(2), current MDRD4 = 32.5 +/- 19.2 mL/m/1.73 m(2), P < .05) and proteinuria (previous proteinuria = 1.5 +/- 0.7 g/d, current proteinuria = 2.5 +/- 2.2 g/d, P < .05) after conversion. Again, the deterioration in proteinuria was more intense in the patients whose previous CNIs were suspended (with CNI = 1.1 +/- 0.9 g/d, without CNI = 4.2 +/- 2.3 g/d, P < .05). In conclusion, for patients with chronic allograft dysfunction who do not present with proteinuria or whose proteinuria is less than 0.8 mg/d, switching to rapamycin is useful, since it clearly improves or stabilizes renal function, although there may be a discrete increase in proteinuria in the second case. However, among patients with proteinuria greater than 0.8 mg/d accompanied by a greater degree of renal insufficiency, conversion to rapamycin leads to deterioration of proteinuria levels and renal function. These data show that conversion to rapamycin in cases of chronic allograft dysfunction must be made early when there is no proteinuria or it is minimal, and that proteinuria is a predictor of the outcome of allograft function.
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PMID:Clinical implications of proteinuria in renal transplant recipients switching to rapamycin for chronic allograft dysfunction. 1971 16

Long-term allograft survival poses a major problem in pediatric renal transplantation, with allograft nephropathy being the principal cause of graft failure after the first post-transplant year. The mechanisms of nephron loss resulting in graft dysfunction are multiple, comprising both immunologic factors such as acute and chronic antibody- or T-cell-mediated rejection and non-immunologic components. The latter include peri-transplant injuries and renovascular lesions (renal artery stenosis, thrombosis) as well as cardiovascular risk factors such as arterial hypertension and hyperlipidemia. Another relevant issue leading to progressive nephron loss and declining kidney transplant function is acute and chronic nephrotoxicity induced by the calcineurin inhibitors (CNIs) ciclosporin (cyclosporine microemulsion) and tacrolimus. Furthermore, the presence of an abnormal lower urinary tract as well as bacterial (recurrent pyelonephritis) and viral (cytomegalovirus [CMV], polyomavirus [BK virus; BKV]) infections are crucial factors involved in the incidence of chronic allograft dysfunction and graft failure. Renovascular lesions and lower urinary tract obstruction are typical indicators for surgical intervention. The aim of treatment in pediatric patients with renal failure secondary to a dysfunctional lower urinary tract is to create a sterile, continent, and nonrefluxive reservoir. Surgical techniques such as bladder augmentation and the introduction of intermittent catheterization and anticholinergic therapy have significantly improved graft outcome. Arterial hypertension, another factor responsible for graft function deterioration in pediatric renal transplant recipients, is controlled preferably by the use of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, which are known to possess nephroprotective properties in addition to their potent antihypertensive effects. Although treatment of subclinical rejection with augmented immunosuppression has been associated with better graft survival, an increase of the immunosuppressive level to avoid subclinical rejection should be weighed against the risk of infection. The majority of viral infections affecting kidney allografts are caused by CMV and BKV. Antiviral CMV prophylaxis or pre-emptive therapy with ganciclovir has been shown to have beneficial effects in the pediatric renal transplant population. Treatment of BKV-induced nephropathy is based on reduction of the immunosuppressant therapy, although specific antiviral agents such as cidofovir and leflunomide are known to inhibit BKV. However, cidofovir itself is nephrotoxic and should therefore be administered cautiously to pediatric renal transplant patients. Since CNIs are likewise known for their nephrotoxic effects, especially with long-term use, alteration of the immunosuppressant regimen is necessary in case of deteriorating graft function due to CNI-induced histopathologic changes. Complete CNI avoidance seems inappropriate because, in this situation in pediatric renal transplant recipients, other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies, which are frequently accompanied by a higher incidence of infections, are needed for rejection prophylaxis. CNI withdrawal and switching of the immunosuppressant regimen from CNI therapy to sirolimus may be an option for some pediatric renal transplant patients with less advanced graft function deterioration. Nevertheless, potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism have to be considered, and controlled studies are lacking. At present, an immunosuppressant maintenance therapy composed of low-dose tacrolimus or ciclosporin (CNI minimization) and mycophenolate mofetil with low-dose corticosteroids appears to be the most promising strategy to adopt in pediatric renal transplant recipients at low or normal immunologic risk.
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PMID:Treatment strategies to minimize or prevent chronic allograft dysfunction in pediatric renal transplant recipients: an overview. 1987 24

Immunosuppressive therapy with calcineurin inhibitors (CNI) must be continued during the weeks following transplant to avoid acute rejection. Over the long-term, however, nephrotoxicity and morbidity induced by CNIs have a negative impact on patient and transplant survival. Therefore, for any organ, it is crucial to free patients from the nephrotoxicity associated with CNIs without risking under-immunosuppression and while maintaining good overall tolerance. For kidney transplants, minimization of CNI use in association with mycophenolate seems to be relatively safe and allows for improved kidney function without an added risk of rejection. The strategy of making a complete switch from CNIs to proliferation signal inhibitors (PSI) also seems to be promising. In patients with chronic allotransplant dysfunction, reduction of CNI doses by 30 to 50% in association with MPA seems to be safe and effective and replacement of CNIs with PSIs is pertinent, though limited by their effect on proteinuria. For liver transplants, late and minimal introduction of CNIs under induction seems to be safe and effective for the preservation of kidney function, especially when precarious. For heart transplants, preliminary studies conducted on a small number of patients suggest that delayed introduction of CNIs at minimal doses and late elimination of the therapy are safe after transplant.
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PMID:[Review of clinical trials on minimization and interruption of calcineurin inhibitors (CNIs) and protocols without CNIs in the transplantation of different organs (kidney, heart, and liver)]. 2012 48


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