Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts.

BACKGROUND: KRP203, a structural FTY720 analogue, has 5-fold greater selectivity for binding to sphingosine-1-phosphate receptor (S1PR) 1 (S1PR(1)) versus S1PR3 and 100-fold greater selectivity over S1PR(2) and S1PR(5). Although the immunoregulatory effects of FTY720 have been tested in clinical and experimental research, the therapeutic efficacy of KRP203 in allograft models remains elusive. In this study, we investigated the potential of KRP203 alone and in combination with intragraft injection of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) to induce islet allograft tolerance. METHODS: BALB/c (H-2(d)) mice received transplants of fresh C57BL/10 (H-2(b)) islet allografts under the kidney capsule and were treated for 7 days with 0.3, 1.0, or 3.0 mg/kg KRP203 alone or in combination with intragraft-infused Tregs. RESULTS: Untreated BALB/c mice acutely rejected C57BL/10 islet allografts at a mean survival time of 13.8 ± 2.7 days (n=5). A 7-day dosing of 0.3 or 1.0 mg/kg KRP203 produced long-term islet allograft survival (9200 days) in one of five and two of seven recipients, respectively. A 3 mg/kg KRP203 dose resulted in islet graft survival for more than 200 days in 5 of 12 recipients. Whereas recipients that received 500 allogeneic islets admixed with 5 x 10(5) - 7 x 10(5) Tregssurvived 83.6 ± 67.2 days, addition of transient 3 mg/kg KRP203 therapy induced prolonged drug-free graft survival (9200 days) in all recipients. CONCLUSIONS: A brief treatment with KRP203 significantly prolonged islet allograft survival, whereas additional intragraft delivery of Tregs induced tolerogenic effects selective to islet alloantigens.

YSPSL (rPSGL-Ig) for improvement of early renal allograft function: a double-blind, placebo-controlled, multi-center Phase IIa study.

INTRODUCTION: Recombinant P-selectin glycoprotein ligand IgG fusion protein, rPSGL-Ig (YSPSL), a fusion protein of human P-selectin ligand and IgG1-Fc, blocks leukocyte adhesion and protects against ischemia reperfusion injury (IRI) in animal models. PATIENTS AND METHODS: This randomized 15-center, double-blind, 59-patient Ph2a study assessed YSPSL's safety in recipients of deceased-donor kidney allografts and its potential efficacy in improving early graft function. Two doses and two dosing modalities were evaluated. RESULTS: No drug-specific toxicities or increased adverse event rates were noted. Two YSPSL-treated patients died of causes determined as unrelated to study drug. YSPSL did not reduce the incidence of dialysis within the first week post-transplant (41% in treated vs. 20% in placebo patients). Renal function endpoints scored at post-operative days 1 & 2 were also not impacted by YSPSL. However, at day 5, the fraction of patients with serum creatinine above 6 mg/dL was lower in the YSPSL vs. placebo group (26% vs. 55%, p = 0.043). Large variations in the dialysis-delayed graft function (DGF) rates were observed between centers, independently of treatment assignment, indicating subjectivity of this endpoint. CONCLUSION: In this first Ph2a study in kidney transplantation, YSPSL was safe but did not impact the dialysis-DGF rate. Further studies with more objective efficacy endpoints are required to define the impact of YSPSL on early renal allograft function.

Comparing an early corticosteroid/late calcineurin-free immunosuppression protocol to a sirolimus-, cyclosporine A-, and prednisone-based regimen for pancreas-kidney transplantation.

AIM: A prednisone and calcineurin inhibitor (CNI)-free protocol was compared with a sirolimus, cyclosporine A (CsA), and prednisone-based immunosuppressive regimen for simultaneous pancreas-kidney transplantation (SPK). METHODS: A nonrandomized, single-center, sequential study enrolled low-immune responder SPK transplant recipients. The prednisone/CNI-free (minimization) group of 22 patients received thymoglobulin followed by sirolimus and reduced-dose CsA. Prednisone was withdrawn on day 5, and recipients were converted from CsA to mycophenolic acid at 6 months posttransplantation. The sirolimus/CsA group of 20 consecutive recipients transplanted immediately before this series received thymoglobulin followed by sirolimus, reduced-dose CsA, and prednisone. RESULTS: Donor and recipient demographic variables were equivalent between groups. The 24-month actual patient, kidney, and pancreas survivals for the minimization group were 100%, 100%, and 91% vs. 100%, 95%, and 95% for the sirolimus/CsA group (P=not significant [NS] for patient, kidney, and pancreas survivals). One acute rejection occurred in the minimization group and none in the sirolimus/CsA group. After withdrawal of CsA at 6 months, the minimization group showed an increase in mean estimated glomerular filtration rate, resulting in a significant improvement in renal function compared with the sirolimus/CsA group. At 24 months, the mean glomerular filtration rate of the minimization and sirolimus/CsA groups was 71.6+/-11.2 mL/min/1.73 m and 60.1+/-13.4 mL/min/1.73 m, respectively (P<0.05). Mean fasting blood glucose levels were equivalent between groups at all time points studied. CONCLUSION: Low-immune responder SPK recipients receiving a prednisone/CNI-free protocol achieved similar 2-year graft survivals and improved renal function compared with those treated with a sirolimus, CsA, and prednisone regimen.

mTOR inhibition: the learning curve in kidney transplantation.

All immunosuppressive medications require a learning curve that enables clinicians to improve the therapeutic index of agents. Mammalian target of rapamycin (mTOR) inhibitors are potentially a less nephrotoxic form of immunosuppression than calcineurin inhibitors (CNIs) that has been used in kidney transplant recipients for more than two decades. This drug class has a novel immunosuppressive action, probably mediated in part through inhibition of growth receptor signaling mechanisms. In addition, it has a unique drug toxicity, which is partially dose-related. This medication class also possesses antiproliferative activity, which may be useful in-post-transplant patients with increased atherosclerotic and malignancy risks. mTOR inhibitors have been utilized for de novo immunosuppression with CNIs, corticosteroids, and antimetabolites. mTOR inhibitors also have been used as CNI-sparing agents both early and late post-transplant. Much debate remains over how to best utilize mTOR inhibition in kidney transplantation.

Repeat renal allografts treated with sirolimus, cyclosporine, anti-thymocyte globulin induction and continuous steroids achieve similar immunosuppressive efficacy as primary transplants.

OBJECTIVE: We sought to examine repeat versus primary renal transplantations using sirolimus-based regimens. METHODS: We compared 98 repeat versus 200 matched primary recipients treated de novo with sirolimus plus cyclosporine. Every repeat case received polyclonal antibody induction and continuous steroids. Outcomes were evaluated over a mean five-year follow-up by univariate and multivariate techniques. Kaplan-Meier plots were analyzed with using log-rank statistics with significance at P < or = 0.05. RESULTS: Significant differences in demographic features included greater panel reactive antibody (PRA), younger age, fewer HLA-mismatches and more pre-emptive repeat versus primary grafts. Neither graft and patient survivals, nor incidences of biopsy-proven acute rejection (BPAR), chronic vasculopathy or tubular atrophy/interstitial fibrosis among biopsies performed for cause were significantly different at 1 and 5 years. Younger recipients, better HLA matches and absence of diabetes promoted repeat graft survival; whereas older age, longer cold ischemia time and BPAR reduced primary transplant outcomes. Renal function was similar at 1, 3, 12, 24, 48 and 60 months. CONCLUSION: At 5 years this sirolimus regimen achieved similar efficacy for repeat versus primary transplantations.

Impact of reduced nephron mass on cyclosporine- and/or sirolimus-induced nephrotoxicity.

BACKGROUND: We evaluated the impact of reduced nephron mass on nephrotoxicity by cyclosporine A (CsA) and/or sirolimus (SRL). METHODS: Renal function was tested in salt-depleted rats bearing two kidneys (2K), one kidney, or half a kidney (1/2K) and treated for 7 or 28 days with CsA (5 mg/kg) and/or SRL (0.8 mg/kg). We also measured the expression of aquaporin-2, sodium/phosphate cotransporter (NaPi)-2, paracellin-1, and kidney injury molecule (KIM)-1 by real-time polymerase chain reaction. RESULTS: At 7 days in 2K, serum creatinine clearance (CrCl) was decreased only in CsA/SRL-treated group (P<0.05) compared with controls; in 1/2K, CrCl was decreased in all groups, but most dramatically in CsA/SRL group (P<0.05). Extended 28-day therapy worsened CrCl in all 1/2K groups (P<0.01). Although the expression of aquaporin-2, NaPi-2, and paracellin-1 mRNAs tended to increase in kidneys with a reduced nephron mass, NaPi-2 mRNA levels decreased in 1/2K rats exposed to CsA/SRL for 28 days (P<0.05). In contrast, low KIM-1 mRNA expression in control 2K rats increased fourfold in untreated 1/2K (P<0.05), and 50- to 200-fold in CsA/SRL-treated 1/2K (P=0.01). CONCLUSIONS: Nephrotoxicity is significantly worsened by reduced nephron mass, which correlates with increased expression of KIM-1 and inhibited expression of NaPi-2.

Forty years of publication of transplantation proceedings--the second decade: the cyclosporine revolution.

With surgical tools in place, increased knowledge concerning immunogenetics and alloimmunity as well as improved management of immunocompromised patients, the foundations were lain for the rapid development of the transplantation enterprise. In contrast to pre-transplant conditioning by thoracic duct drainage or total lymphoid irradiation, which were too cumbersome for routine execution among the burgeoning recipient pool, cyclosporine was a facile method to produce immunosuppression de novo after transplantation. On the one hand, clinical data confirmed the potency of cyclosporine in a variety of clinical settings. On the other hand, a pleiotropic array of side effects, particularly nephrotoxicity, beclouded the regimens, even when used in reduced doses in combination with azathioprine or together with rigorous individualization of therapy by concentration control. The advent of cyclosporine condemned conditioning by pretransplant blood transfusions and donor-recipient HLA matching to therapeutic obsolescence. However, cross-matching achieved greater significance particularly due to the development of flow cytometry methods to detect modest amounts of anti-donor antibody. Adjunctive treatments with polyclonal preparations or monoclonal antibodies were developed to provide an additional layer of security during the critical induction phase of immunosuppression and for treatment of rejection episodes refractory to high dose steroid therapy. Active immunologic investigation was stimulated by antibodies that discriminated CD4+ versus CD8+ T cells, leading to dissection of their numbers of precursors or mature elements as well as their distinct activities. The search for methods to induce, maintain and detect the state of transplantation tolerance continued. The encouraging results in clinical transplantation raised a variety of ethical concerns related to public attitudes; to retrieval, distribution, and allocation of the limited supply of deceased donor organs; the increased utilization of living persons; the opportunities for commerce; the quasi-righteous requests for organ gifts by unrelated individuals and the scant financial resources for long-term treatment with costly immunosuppression. Transplantation had now achieved its rightful place in the clinical armamentarium.

Sirolimus-based therapy for kidney transplantation from expanded criteria donors.

The new class of immunosuppressants--inhibitors of the mammalian target of rapamycin--has no nephrotoxicity and the capacity to inhibit vascular smooth cell proliferation. These characteristics may afford considerable clinical advantages in the transplantation of kidneys from expanded criteria donors (ECD). Six clinical experiences of the use of sirolimus (SRL) in ECD kidneys recipients have been reported in the literature. Although the results varied somewhat, probably due to differences in the types of deceased donor and in the immunosuppressive regimens used, it seems that a calcineurin inhibitor free, SRL-based protocol can assure a good immunosuppressive effect with less nephrotoxicity and a low incidence of cytomegalovirus infection. For recipients of ECD kidneys at low immunological risk, we would recommend a regimen based on antithymocyte globulin induction and SRL, mycophenolate mofetil, and steroids for maintenance. For strongly responding recipients, we recommend SRL combined with a reduced, 76% to 87% dose of calcineurin inhibitor.

Comparison of sirolimus plus tacrolimus versus sirolimus plus cyclosporine in high-risk renal allograft recipients: results from an open-label, randomized trial.

BACKGROUND: The efficacy and safety of sirolimus (SRL) plus tacrolimus (TAC) versus SRL plus cyclosporine (CsA) were compared in high-risk renal allograft recipients. METHODS: Evaluable patients (448) were randomly assigned (1:1) before transplant to receive SRL+TAC or SRL+CsA with corticosteroids. Eligible patients were black and/or repeat transplant recipients, and/or those with high titer of panel-reactive antibodies. RESULTS: Demographics were similar between groups. Both treatments demonstrated equivalent efficacy of the composite endpoint at 12 months with efficacy failure rates of 21.9% vs. 23.2% (SRL+TAC vs. SRL+CsA, respectively, 95% CI -10.0 to 7.1, P=0.737). Biopsy-confirmed acute rejection rate (13.8% vs. 17.4%) and graft survival rate (89.7% vs. 90.2%) were similar (SRL+TAC vs. SRL+CsA, respectively). In evaluable patients (received at least 1 dose of study drug), renal function (calculated Nankivell glomerular filtration rate) was not superior in SRL+TAC versus SRL+CsA (54.5 vs. 52.6 mL/min, P=0.466); however, in on-therapy patients, glomerular filtration rate was significantly higher in SRL+TAC at most time points. At 12 months, there were no significant differences in rates of death, discontinuation because of adverse events, hypercholesterolemia, hyperlipemia, or proteinuria. Diarrhea and herpes simplex infections occurred significantly more often in SRL+TAC patients. Hypertension, cardiomegaly, increased creatinine, overdose (primarily calcineurin inhibitor toxicity), acne, urinary tract disorders, lymphocele, and ovarian cysts occurred significantly more often in SRL+CsA patients. CONCLUSIONS: This study demonstrated that SRL-based therapy was efficacious in high-risk renal allograft recipients in the first year after transplant, providing equivalent efficacy with CsA or TAC, similar graft survival, low biopsy-confirmed acute rejection rates, excellent renal function, and an acceptable safety profile.

Accuracy and variability of equations to estimate glomerular filtration rates in renal transplant patients receiving sirolimus and/or calcineurin inhibitor immunosuppression.

Measured glomerular filtration rates (mGFRs) were obtained by (99)mTc-DPTA, (125)I-iothalamate, iohexol, (51)Cr-EDTA, non-radiolabeled iothalamate, or inulin clearance from centers agreeing to perform mGFR in six completed and one ongoing Wyeth Research multicenter trials evaluating sirolimus (SRL) in regimens with or without a calcineurin inhibitor (CNI). Estimated GFRs (eGFRs) were calculated by the Cockcroft-Gault (eGFR(CG)), Nankivell (eGFR(NK)), and simplified Modification of Diet in Renal Disease (eGFR(MDRD)) equations. Bias, precision, and accuracy for each of these equations were estimated by tertiles and by regimen. For the Rapamune Maintenance Regimen (RMR) trial, eGFR outcomes were also compared between treatments {[SRL-cyclosporine (CsA) versus SRL]} using the three eGFR formulas. In the lowest mGFR tertile (6-40 ml/min), eGFR(MDRD) gave the best accuracy with the least bias whereas eGFR(NK) and eGFR(CG) performed better in the highest mGFR tertile (58-139 ml/min). At 24 months in the RMR study, mean differences in eGFR between treatments were 13.6, 14.2, and 13.5 ml/min/1.73 m(2) for eGFR(CG), eGFR(NK), and eGFR(MDRD), respectively, favoring CsA withdrawal (P-values for all <0.001). The accuracy of the three eGFR equations was affected by mGFR range but not by immunosuppressive regimens utilizing SRL, SRL-CNI or CNI-based therapy.

Interventional radiologic management of renal transplant dysfunction: indications, limitations, and technical considerations.

Renal transplantation is the treatment of choice for most patients with end-stage renal disease. However, in spite of continuous progress in surgical techniques and immunosuppressive therapy, a wide variety of vascular and nonvascular complications can arise postoperatively. Vascular complications include transplant renal artery stenosis, arteriovenous fistulas or intrarenal pseudoaneurysms following renal transplant biopsy, extrarenal pseudoaneurysms, and graft thrombosis. Nonvascular complications include urologic complications (eg, ureteral obstruction, urine leak) and perigraft fluid collections (eg, lymphocele, abscess, hematoma, urinoma). These postoperative complications can be diagnosed and managed with minimally invasive techniques; however, an understanding of renal transplant anatomy and the risks of posttransplantation immunosuppressive therapy unique to this patient population is essential to their successful application. In addition, familiarity with the indications for and limitations of these techniques as well as collaboration between the radiologist and the transplantation surgeon are vital for maximizing the chances of renal allograft survival.

BK virus-associated nephropathy in sirolimus-treated renal transplant patients: incidence, course, and clinical outcomes.

BACKGROUND: Because the course of polyoma virus-associated nephropathy (PVAN) has not been evaluated in a large cohort of patients receiving sirolimus (SRL)-based regimens, we have herein presented the incidence, clinical characteristics, and outcomes of 378 renal transplant recipients treated with SRL-based immunosuppression. METHODS: This retrospective single center study evaluated 344 kidney alone (KTX) and 34 simultaneous pancreas-kidney (SPK) transplantations performed between June 2000 and December 2004. RESULTS: At a mean follow-up of 43.3 months, six kidney (1.7%) and three kidney-pancreas (9.0%) transplanted patients displayed biopsy-proven PVAN. The mean time to diagnosis after transplantation was 18.2 months (range: 3.5-31.1 months), with a higher incidence among patients exposed (4.23%) versus not exposed to rabbit antithymocyte globulin (rATG; 0.53%; P=0.019) or SPK (9.0%) versus KTX (1.7%) recipients (odds ratio: 5.43; confidence interval: 1.29-22.8; P=0.038). Despite treatment with cidofovir, reduced immunosuppression and maintenance therapy with no agents other than SRL (C0=10.2+/-2.7 ng/dL) plus modest doses of prednisone (< or =5 mg), five patients (55.5%) experienced renal allograft failure. No rejection episodes were documented during the PVAN treatment and pancreatic function continued to be excellent among the SPK patients. CONCLUSIONS: Patients treated with SRL-based immunosuppression showed an incidence at the lower end of the range described with various other contemporaneous immunosuppressive regimens and with other cohorts not undergoing BK virus polymerase chain reaction surveillance. Exposure to rATG and SPK transplantation represented risk factors for the occurrence of PVAN, which showed a pernicious course despite withdrawal of calcineurin antagonists and/or mycophenolate mofetil.

[Lymphocele and kidney transplantation]. / Lymphokele és vesetranszplantáció

INTRODUCTION: Lymphocele is a special complication following kidney transplantation. The authors examined the factors associated with an increased occurrence of clinically significant perinephric fluid collections and/or lymphoceles among sirolimus-treated renal transplant recipients. AIM: From the point of view of the lymphocele a comparison was made for the risks and benefits of the conventional and a newer immunosuppressive combination. METHODS: At the University of Texas in Houston in a retrospective study the incidence, predisposing factors, and consequences of these fluid collections among patients treated with sirolimus-cyclosporine-prednisone ( n = 354, Group I) versus cyclosporine-prednisone-azathioprine ( n = 136, Group II) were compared. RESULTS: More Group I patients (135/354; 38.1%) displayed perinephric fluid collections than Group II patients (24/136; 17.6%; p < 0.001). In both subgroups the serum creatinine levels were elevated at the time of diagnosis from a nadir of 179.5 +/- 141.7 to 359.9 +/- 259.6 mmol/l (Group III, sirolimus treated) and from 222.6 +/- 205.9 to 383.7 +/- 255.2 mmol/l (Group IV, sirolimus free). A significantly greater number of patients required treatment for lymphoceles among Group I (15.8%; 56/354) versus Group II recipients (4.4%; 6/136; p < 0.001). Single or repeated percutaneous drainage procedures successfully treated 35 Group I patients versus all 6 Group IV patients ( p = 0.033). No patients in Group II versus 21 patients in Group I underwent surgical procedures ( p < 0.001). A significantly higher rate and higher histologic grade of acute rejection episodes, particularly proximate to the onset of the lymphocele, occurred among Group IV patients, namely 54.2% (13/24) versus 21.4% (29/135) Group III patients ( p < 0.001). Additionally we report the case of a 29-year-old patient who underwent a lymphocele fenestration with omentoplasty 8 years after his transplantation. Despite an Influenza A + Chlamydia pneumonia and acute rejection which was followed by a GI bleeding and stomach resection he fully recovered and is doing well with an excellent kidney function a year after. CONCLUSIONS: Addition of sirolimus to a cyclosporine-prednisone regimen resulted in both a higher incidence and a requirement for more aggressive treatment of perinephric fluid collections and/or lymphoceles with a much lower acute rejection frequency.