Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile

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1 & 2010 International Society of Nephrology Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile Arjang Djamali 1, Carolynn E. Pietrangeli 2, Robert D. Gordon 2 and Christophe Legendre 3 1 Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA; 2 CTI Clinical Trial and Consulting Services, Cincinnati, Ohio, USA and 3 Hôpital Necker Paris, Paris, France Currently used immunosuppressants exacerbate cardiovascular risk. However, attempts to limit the use of these agents increase the risk of allograft rejection. Immunosuppressants targeting signal 2 and signal 3 lymphocyte activation pathways are under clinical development. Clinical data from trials of the Janus family protein tyrosine kinase-3 inhibitor tasocitinib and the costimulation blocker belatacept are presented. Additional pipeline agents are described. Results from two phase III clinical trials of belatacept revealed efficacy that is not inferior to that provided by cyclosporine (CsA). In the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial enrolling recipients of standard criteria living or deceased donor organs, the risk of rejection was higher among patients treated with a more intensive treatment regimen. Increased risk of posttransplant lymphoproliferative disorder, particularly among Epstein Barr virus-patients, was a notable adverse event. Data from a phase II trial of tasocitinib suggested good prophylaxis of rejection. Safety signals included increased risk of infection and potential myelosuppression, leading to anemia, neutropenia, and leukopenia. Both belatacept and tasocitinib were associated with a low cardiovascular risk profile and improved renal function compared with CsA. New immunosuppressive regimens should maintain the effectiveness provided by current agents while preserving renal function and cardiovascular health. Surveillance for new adverse events must be an integral part of the long-term management strategy. ; doi: /ki KEYWORDS: costimulation blockade; JAK-3 inhibitor; kidney transplant; novel immunosuppressants TO CITE THIS ARTICLE: Djamali A, Pietrangeli CE, Gordon RD, Legendre C. Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile. Kidney Int 2010; 78 (Suppl 118): S15 S21. Correspondence: Arjang Djamali, Department of Medicine, University of Wisconsin, H4/564 CSC, 600 Highland Avenue, Madison, Wisconsin 53793, USA. axd@medicine.wisc.edu Despite the success of transplantation to delay the progression of cardiovascular disease in patients with end-stage renal disease, kidney transplant recipients remain at significantly greater risk of cardiovascular death compared with the general population (Figure 1). 1 There is increasing evidence suggesting that commonly used immunosuppressive drugs, including calcineurin inhibitors (CNIs), corticosteroids, and mammalian target of rapamycin inhibitors, contribute to the burden of traditional and nontraditional cardiovascular risk factors. Over the last decade, several treatment strategies have therefore focused on reducing the exposure to immunosuppression-related adverse effects. Cardiovascular mortality was defined as that resulting from arrhythmia, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and/or pulmonary edema (reproduced from Sarnak et al.). 1 Strategies to modify immunosuppression exposure fall into the broad categories of avoidance, withdrawal, and dose minimization. The primary focus has been to reduce exposure to the CNIs, cyclosporine (CsA) and tacrolimus, and corticosteroids. Important examples include recent clinical trials, such as the Spare the Nephron, CONVERT, and Symphony trials (Spare the Nephron; 2 CONVERT; 3 Symphony 4 ). These have tested CNI dose reduction and/or CNI replacement with the mammalian target of rapamycin inhibitor sirolimus, usually in combination with mycophenolate mofetil (MMF). The US Food and Drug Administration (FDA) recently accepted revisions to the Prograf label recommending reduced tacrolimus target trough levels (4 11 ng/ml) when used in combination with anti-interleukin-2 (IL-2) receptor antibody induction therapy and maintenance therapy with MMF. The approval was largely based on the results of the Symphony study. 5 Reduced exposure to CNIs The goal in limiting exposure to CNIs is to reduce the burden of adverse events, including chronic nephrotoxicity reported to be universal by 10 years of maintenance on CsA. 6 However, in one early CNI avoidance trial published in 2001, investigators reported a 53% incidence of acute rejection. 7 This experience fostered further investigation of withdrawal S15

2 A Djamali et al.: Improving immunosuppression-related CV risk Annual mortality (%) >85 Age (years) Figure 1 Cardiovascular mortality among the general population (GP) and among the dialysis and transplant populations. GP male GP female GP black GP white Dialysis male Dialysis female Dialysis black Dialysis white and dose-minimization approaches. In the CAESAR (Cyclosporine Avoidance Eliminates Serious Adverse Renal Toxicity) trial, CNI withdrawal at 6 months was compared with continuation of either low-dose or standard-dose CsA in combination with MMF. The result was an acute rejection rate of 38.0% in the withdrawal arm, compared with 25.4% in the low-dose CsA arm, with no significant difference in glomerular filtration rate (GFR) among treatment groups. 8 Sirolimus (Rapamune, Pfizer, New York, NY, USA) was initially approved by the FDA for use in combination with CsA and corticosteroids to prevent allograft rejection in renal transplant recipients. However, this approach resulted in increased nephrotoxicity and led to further investigation of the potential to withdraw CNI from maintenance regimens. 9,10 The approved indication for sirolimus was revised in 2002 recommending CsA withdrawal 2 4 months after transplantation in patients at low-to-moderate immunological risk. 11 In the CONVERT trial, 830 kidney transplant recipients receiving CsA or tacrolimus who had undergone transplant months earlier were randomized to remain on CNI or convert to sirolimus. 3 Concomitant use of azathioprine or MMF was allowed, but could be discontinued at investigator discretion once stable levels of sirolimus were achieved. There was no difference in calculated GFR 6 in the intent-to-treat analysis at 12 and 24 months of follow-up in patients whose baseline GFR was over 40 ml/min. However, the subgroup of patients who remained on therapy did show a significantly higher GRF at 12 and 24 months. Patients with a baseline GFR between 20 and 40 ml/min had to be withdrawn from the study because of a higher incidence of safety end points among patients converted to sirolimus. A similar effort at conversion from CNI to sirolimus in combination with MMF was made in the Spare the Nephron trial. 2 When considering conversion from CNI-based therapy to sirolimus maintenance therapy, increased risk of rejection and substitution of a novel set of adverse events including hyperlipidemia, hyperglycemia, hematological anomalies, proteinuria, peripheral edema, and impaired wound healing mandate caution and careful risk assessment. 12,13 Furthermore, although patients maintained on combination therapy with sirolimus and MMF alone in the Spare the Nephron study experienced less nephrotoxicity and an improvement in renal function, a significant proportion were unable to tolerate the regimen and had to be returned to CNI-based therapy. 2 Reduced exposure to corticosteroids Because of their significant side-effect burden and metabolic impact, corticosteroids have long been a target of maintenance regimen minimization strategies. Experience with late withdrawal exposed the risk of late acute rejection episodes, prompting investigation of early cessation regimens. 14 However, a meta-analysis of nine corticosteroid withdrawal trials published between 1990 and 1999 revealed a 14% increase in acute rejection incidence (Po0.001) and a 40% increase in the risk of graft failure (P ¼ 0.012). 15 Subsequent studies investigated the impact of timing of withdrawal and induction of immunosuppression on outcomes. A pilot study of corticosteroid-free immunosuppression in a series of 57 patients receiving daclizumab induction, followed by CsA MMF maintenance therapy, resulted in a 25% incidence of acute rejection at 1 year of follow-up. 16 However, the number of patients requiring antihypertensive medications decreased from 17 to 2, and only 4 of 43 nondiabetic patients developed new-onset diabetes (NODAT) over the course of the study, suggesting an improvement in their metabolic profile. In a 4-year follow-up of a series of 477 kidney transplant recipients in whom prednisone was discontinued on postoperative day 6, Matas et al. 17 reported a significantly lower incidence of NODAT after transplantation, cataracts and avascular necrosis, compared with a historical control group of patients maintained on prednisone. It is important to note that 85% of patients with functioning grafts remained prednisone free at the end of the follow-up period, and the rates of acute and chronic rejection were not increased. A subsequent analysis revealed equivalent graft half-life among both groups of patients, regardless of living or deceased donor organ source (living donor: 25.0 and 33.4 years in historical controls vs rapid prednisone discontinuation; deceased donor: 17.2 and 22.5 years, respectively). 18 In a report for the Astellas Corticosteroid Withdrawal Study Group, Woodle et al. 19 summarized the experience of a separate study of 386 patients receiving antibody induction and tacrolimus-mmf maintenance therapy. Outcomes at 5 years were compared between a group of patients who discontinued corticosteroids on postoperative day 7 and a group who continued on low-dose corticosteroids. Although the primary composite end point of death, graft loss, or moderate-to-severe acute rejection was equivalent between treatment groups, the incidence of biopsy-confirmed acute S16

3 A Djamali et al.: Improving immunosuppression-related CV risk rejection was higher in the corticosteroid withdrawal group (17.8 vs 10.8%; P ¼ 0.058). The incidence of biopsy-proven chronic allograft nephropathy was significantly higher in the corticosteroid withdrawal group (9.9 vs 4.1%; P ¼ 0.028). Long-term renal allograft survival and calculated creatinine clearance were similar, with no difference in the proportion of patients developing NODAT overall (withdrawal 21.5 vs 20.9%). However, fewer patients in the withdrawal group required insulin (3.7 vs 11.6%; P ¼ 0.049). With the exception of 5-year follow-up values, serum triglyceride levels also improved significantly among patients not maintained on corticosteroids for a long term. In a recent meta-analysis of 30 randomized corticosteroidsparing clinical trials enrolling 5949 adult kidney recipients, Pascual et al. 20 found that, despite an increase in the risk of acute rejection episodes, corticosteroid avoidance is not associated with increased graft loss. Including MMF and tacrolimus in these regimens decreased the risk of acute graft rejection. The use of everolimus, an alternative mammalian target of rapamycin inhibitor, also reduced the risk. Corticosteroid-sparing withdrawal strategies were associated with reduced requirement for antihypertensive and antihyperlipidemics drugs; reduced serum cholesterol; a lower incidence of NODAT requiring treatment; and fewer cataracts. Corticosteroid avoidance was not associated with a change in serum cholesterol, but was associated with fewer cardiovascular events. LIMITATIONS OF DOSE-MINIMIZATION STUDIES Efforts to reduce exposure to CNIs may indeed reduce posttransplant cardiovascular risk. However, definitive longterm data are lacking to conclude that CNI minimization, avoidance, or withdrawal leads to graft and patient survival as well as that shown in long-term results obtained with conventional CNI-based maintenance therapy, especially in patients with increased immunological risk factors. Therefore, minimizing nephrotoxicity or other cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia through CNI reduction or avoidance must be considered in the context of the immunological risk profile of the renal allograft. CNI minimization or avoidance in patients with a history of previous graft loss, previous acute rejection episodes (especially high-grade acute rejection or rejection associated with residual loss of graft function), and high grades of human leukocyte antigen mismatch or antibody presensitization may increase the risk of immunological graft loss. Evidence for the importance of CNIs was provided by results of the Efficacy Limiting Toxicity Elimination Symphony study, which compared standard-dose CsA with reduceddose CsA, reduced-dose tacrolimus (targeted tacrolimus whole-blood trough level 3 7 ng/ml), and sirolimus-based CNI-free maintenance therapies. All patients were treated with MMF and a corticosteroid-tapering regimen. With the exception of patients enrolled in the standard-dose CSA arm of the study, all received induction antibody treatment with daclizumab. 4 At 1 year of follow-up, optimal control of acute rejection and renal function was achieved in the low-dose tacrolimus MMF treatment arm (acute rejection: tacrolimus 12.3 vs 37.2% (sirolimus); 25.8% (standard dose CsA); 24.0% (low-dose CsA); Po in all four groups; GFR: 65.4±27.0 ml/ min per 1.73 m 2 vs 56.7±26.9; 57.1±25.1; 59.4±25.1, respectively; Po0.001 in all four groups). However, the differences in renal function disappeared at the 2- and 3-year evaluation points. Questions remain on the relatively low protocol trough level targets for sirolimus (4 8 ng/ml). Indeed, the Cochrane database analysis reported that sirolimus trough levels of less than ng/ml are associated with increased risk of acute rejection. 21 However, the Symphony study was specifically designed to compare the efficacy and safety of low-dose CsA, tacrolimus, and sirolimus, and the higher complication rate associated with increased sirolimus exposure must be taken into account. 22 Similarly, there still remains a concern that corticosteroid avoidance or withdrawal may increase the risk of late graft loss. 23 As with CNI drugs, corticosteroid avoidance or withdrawal should be considered with caution in patients at increased immunological risk. EMERGING IMMUNOSUPPRESSIVE AGENTS The results of studies attempting to modify regimens using existing immunosuppressive agents have exposed the need for agents that maintain or improve the efficacy of calcineurinbased immunosuppression, but avoid nephrotoxicity and cardiovascular and metabolic adverse events. Improved understanding of the intra- and intercellular mechanisms of T-cell activation, resulting largely from the study of existing immunosuppressive agents, has led to rational strategies to develop medications that bypass the calcineurin pathway. A summary of selected classes of agents in development and their mechanisms of action is presented in Table 1. The CD28 costimulation blocker belatacept and the JAK- STAT inhibitor tasocitinib (CP-690,550) are in the later stages of clinical development. Belatacept is a fusion protein engineered through a single amino-acid substitution to increase the avidity of CTLA-4 Ig (abatacept, approved for treatment of rheumatoid arthritis and juvenile idiopathic arthritis) for CD80 and CD86. 24,25 The JAK-STAT inhibitor tasocitinib is a protein tyrosine kinase inhibitor that blocks the common gamma chain cytokine receptor (g c ), downregulating responses to IL-2, IL-4, IL-7, IL-9, IL-15, and IL Additional targets include protein kinase-c (sotrastaurin), various complement components and split products (eculizumab, rhc1inh, TP-10, nafomostat), adhesion molecules (efalizumab), and selectins (YSPSL, bimosiamose, glycyrrhizic acid), as well as chemokines (reparixin/repertaxin) and proteasomes (bortezomib). Currently under investigation in transplantation, the role of these drugs as induction or adjunct therapy to maintenance regimens has yet to be determined. Bortezomib, the first proteasome inhibitor studied in humans, is indicated for the treatment of mantle cell S17

4 A Djamali et al.: Improving immunosuppression-related CV risk Table 1 Immunosuppressive agents in development Class Candidate agent(s) (manufacturer) Development status, March 2010 Costimulation blocker Belatacept (Bristol-Myers Squibb, Princeton, NJ, USA) Phase III kidney tx; FDA Advisory Committee Review 3/2010 Phase II liver tx JAK-STAT inhibitor Tasocitinib CP-690,550 (Pfizer, New York, NY, USA) Phase II kidney tx Protein kinase-c inhibitor Sotrastaurin AEB071 (Novartis, Basel, Switzerland) Ex-US phase II kidney tx Complement inhibitor Adhesion molecule inhibitor Selectin inhibitor Eculizumab (Alexion, Cheshire, CT, USA) rhc1inh (Pharming, Leiden, The Netherlands) TP-10 (T Cell Sciences, Needham, MA, USA) Nafamostat (SK Chemical Life Science, Swuan-si, South Korea) Efalizumab anti-cd11a (Genentech, San Francisco, CA, USA) YSPSL (Y s Therapeutics, San Bruno, CA, USA) Bimosiamose (BIMO; Revotar/ Encsysive Pharma, Houston, TX, USA) Glycyrrhizic acid (multiple manufacturers) Phase II kidney tx AMR prophylaxis Phase I AMR treatment kidney tx Lung transplant IRI Phase IV liver tx (Korea) Withdrawn 3/2009 PML Phase II kidney tx; liver tx underway Preclinical Approve for liver disease treatment (Japan, China); not approved in the United States Phase II kidney tx (DGF), lung tx CXCR1/CXCR2 chemokine Reparixin/Repertaxin (Dompé Pharma, Milano, Italy) inhibitor Proteasome inhibitor Bortezomib (Millennium Pharmaceuticals, Mayo Clinic AMR treatment protocol Cambridge, MA, USA) sirna I5NP (Quark Pharma, Fremont, CA, USA) Phase I/II kidney tx DGF Abbreviations: AMR, antibody-mediated rejection; DGF, delayed graft function; FDA, Food and Drug Administration; INH, inhibitor; IRI, ischemia reperfusion injury; PML, progressive multifocal leukoencephalopathy; rh, recombinant human; si, small interfering; tx, transplantation. lymphoma and relapsed multiple myeloma. 27 More recently, it has been studied for its potential as treatment for antibodymediated rejection. 28,29 Efalizumab is directed at the CD11a portion of the integrin leukocyte function-associated antigen The drug was originally approved for the treatment of moderate-tosevere psoriasis, but was voluntarily withdrawn by the manufacturer after reports of four cases of progressive multifocal leukoencephalopathy attributed to reactivation of JC or BK viral infection in the brain. 31 The results of one phase II trial in a small series of living or deceased donor kidney recipients suggest that combining lower-dose efalizumab with half-dose CNI-based therapy may warrant further investigation in transplantation. 32 The ability of a small interfering RNA (sirna) to prevent the development of delayed graft function is also under investigation. Although the clinical trial is still active, it is not currently recruiting patients ( The anti-cd20 monoclonal antibody rituximab, approved for the treatment of non-hodgkin s lymphoma, B-cell chronic lymphocytic leukemia, and rheumatoid arthritis is also under study in kidney transplant recipients for its potential in rejection prophylaxis and for the desensitization of patients at risk for antibody-mediated rejection and treatment. 33,34 Among the agents listed in Table 1, the costimulation blocker belatacept is in the latest stage of clinical development. Results of two phase III clinical trials of belatacept conducted in 666 recipients of standard criteria living or deceased donor organs (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial BENEFIT) and in 543 patients receiving extended criteria donor kidneys (BENEFIT-EXT) have recently been published. 35,36 The three-arm design of the belatacept phase III trials called for administration of the fusion protein according to a moreintensive (MI) or less-intensive (LI) schedule, comparing outcomes to CsA-based therapy. The iothalamate-measured GFR at 1 year was superior in patients maintained in either belatacept treatment group (BENEFIT: 65, 63, and 50 ml/min for belatacept MI, LI, and CsA treatment groups, respectively; Pp0.001 MI or LI vs CsA). In BENEFIT-EXT, the mean measured GFR was 4 7 ml/min higher on belatacept compared with CsA (P ¼ MI vs CsA; P ¼ LI vs CsA). The incidence of chronic allograft nephropathy, described histologically as interstitial fibrosis and tubular atrophy, was lower in patients who received belatacept (BENEFIT: 40 and 54% vs 71% in MI, LI, and CsA groups, respectively; BENEFIT-EXT: 82 and 80% vs 95%, respectively). 35,36 The results suggest improved renal function on maintenance immunosuppression that bypasses the calcineurin pathway. However, the incidence of acute rejection in the BENEFIT trial was significantly higher in patients receiving belatacept MI compared with CsA (22, 17, and 7% for belatacept MI, LI, and CsA treatment groups, respectively; deemed significant). 35 At the same time, renal function was superior even among patients who experienced acute rejection on belatacept, perhaps underscoring the notion of qualitative differences in acute rejection episodes. At the recent FDA Advisory Committee hearing to the NDA for belatacept (1 March 2010), an independent FDA analysis of the phase III data again revealed a higher rate of acute rejection but better renal function and graft survival for patients treated with the low-intensity belatacept regimen compared with patients receiving CsA. Longer follow-up is required to determine whether the difference in renal function and associated graft survival will persist despite S18

5 A Djamali et al.: Improving immunosuppression-related CV risk the difference in acute rejection. Interestingly, the incidence of acute rejection was equivalent among treatment groups in the higher-risk BENEFIT-EXT trial (18% MI and 18% LI vs 14% CsA). 36 Four Janus family protein tyrosine kinases (JAKs) have been identified in humans. JAK3 has a unique role in the development and function of hematopoietic cells, as JAK3 mutations and deletions in both rodent models and in humans have been associated with severe immunodeficiencies JAK3 associates with the common g c shared by receptors for cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Therefore, inhibiting JAK3 should limit T-cell proliferation and activation, normally triggered by a battery of cytokines. Indeed, early research revealed that targeting the JAK/ STAT pathway could prevent organ allograft rejection and vasculopathy, opening a new avenue of drug development in immunosuppression. 40,41 More recently, investigators involved in the phase II multicenter randomized trial of the JAK inhibitor tasocitinib (CP-690,550) tested two doses of the drug (15 mg b.i.d. or 30 mg b.i.d.) in patients receiving anti-il2 receptor induction immunosuppression. The study drug was compared with tacrolimus MMF corticosteroid maintenance therapy. 42 Biopsy-proven acute rejection developed in 5.3 and 21.1% of patients treated with lower-dose and higher-dose CP-690,550, respectively, compared with 9.8% of patients in the tacrolimus treatment arm. The data suggest that blocking the function of multiple cytokines through a noncalcineurin pathway may be effective in preventing allograft rejection. Cardiovascular risk profile with new immunosuppressive agents The belatacept clinical trials collected data on cardiovascular risk factors, including blood pressure, lipid profiles, and blood glucose levels. By 1 year of follow-up, mean systolic blood pressure was significantly lower among patients maintained on either dose schedule of belatacept, compared with CsA. In addition, total cholesterol and triglyceride levels were significantly lower among belatacept-treated patients. Among recipients of extended donor criteria organs, the incidence of NODAT was significantly lower in patients receiving MI belatacept therapy compared with CsA; the incidence was numerically lower compared with CsA treatment in both belatacept treatment arms, in both studies. Taken together, the data suggest an improved short-term cardiovascular risk profile among patients maintained on belatacept. The impact on cardiovascular events and cardiovascular mortality awaits longer follow-up. Although relatively few patients were treated with tasocitinib in the phase II trial, early results suggest that surveillance of lipid levels may be warranted. 42 A total of 13 of 40 (32.5%) tasocitinib-treated patients developed hyperlipidemia or hypercholesterolemia, compared with 2 of 21 (9.5%) patients who received tacrolimus. Investigators noted that the mean decrease in systolic blood pressure was higher in the tacrolimus treatment arm ( 17.1±30.5 mm Hg vs 11.6±30.6 and 11.2±20.0 mm Hg in the tasocitinib 15 or 30 mg groups, respectively). Perhaps a broader lesson may be learned from long-term clinical trials of cardiovascular risk management in the general population. At least four large population-based clinical trials have demonstrated reduced risk of cardiovascular events and cardiovascular death by controlling blood glucose (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications DCCT/EDIC (type 1 diabetes); Action to Control Cardiovascular Risk in Diabetes ACCORD (type 2 diabetes)), lipid levels (Treat to New Targets Study), and blood pressure (Blood Pressure Lowering Treatment Trialists Collaboration) The results of these studies underscore the importance of lifestyle management in maintaining cardiovascular health. It is compelling to extrapolate the findings to transplant recipients. The cardiovascular risk profile emerging from clinical trials with newer immunosuppressive agents is encouraging. However, there is currently no evidence of benefit with respect to the occurrence of cardiovascular events or cardiovascular mortality. Transplant patients combine the unique pressures of underlying disease with alloimmune response and the medications used to control it, further complicating their cardiovascular status. Taken together, our experience suggests that long-term study or surrogates for long-term outcomes are required to objectively judge the effect of new immunosuppressive strategies on cardiovascular outcomes. Additional safety signals Reactivation of latent viral infection is emerging as a surveillance issue in patients receiving either belatacept or tasocitinib. Increased risk of posttransplant lymphoproliferative disorder has been noted in patients receiving belatacept. FDA analysis of the belatacept BENEFIT and BENEFIT-EXT data revealed 14 of 949 cases of posttransplant lymphoproliferative disorder (1.5% incidence overall) among belatacepttreated patients compared with 1 of 478 (0.2% overall) CsA-treated recipients. 47 Epstein Barr virus-negative serostatus and the use of T-cell-depleting antibodies have been identified as risk factors for the development of posttransplant lymphoproliferative disorder, which seems to have a unique central nervous system presentation. The use of belatacept may be limited to Epstein Barr virus þ patients. The incidence of infection in the brain, and the development of progressive multifocal leukoencephalopathy in one recipient in the kidney trials warrant vigilance as increased numbers of patients are treated. In the phase II tasocitinib trial, there was a significantly higher incidence of infection, including cytomegalovirus, and nephropathy because reactivation of the BK virus occurred in 4 of 20 patients (20.0%) treated with tasocitinib 30 mg b.i.d. 42 Estimated GFR was similar among all treatment arms at 12 months (83.6 ml/min, 77.6 and 73.3 in groups treated with CP15, CP30, or tacrolimus, respectively). A number of S19

6 A Djamali et al.: Improving immunosuppression-related CV risk manufacturers, including Rigel Pharmaceuticals, Wyeth/ Pharmacopeia, and Cytopia/Novartis, are developing additional JAK inhibitors for treatment of rheumatoid arthritis and for transplant immunosuppression. 48 FINAL THOUGHTS The current immunosuppressive regimens are effective in reducing the risk of T-cell-mediated rejection. However, additional approaches are needed to address the longneglected impact of antibody-mediated rejection on chronic graft loss. As preservation of renal function is one of the most important factors in reducing cardiovascular risk in kidney transplant recipients, balancing immunosuppression with cardiovascular risk will be a new frontier in transplant medicine and immunology. Whether some of the novel agents will offer valid alternatives to currently established therapy remains to be seen. Meanwhile, individualized tailoring of currently available therapy to best fit the individual patient requires great attention to detail and careful monitoring of the kidney transplant recipient. We still lack proteomic- and genomic-based strategies with which to achieve more sophisticated individualization of immunosuppressive therapy and risk reduction. DISCLOSURE AD has received consulting fees from BMS and Millennium, and CL has received consulting and lecture fees from BMS. CEP and RDG have declared no competing interests. REFERENCES 1. Sarnak MJ, Levey AS, Schoolwerth AC et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension 2003; 42: Pearson T, Mulgaonkar S, Patel A et al. 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