Calcineurin inhibitors have been the choice for maintenance immunosuppression (IS) in kidney transplant recipients (KTR), but they are associated with nephrotoxicity and metabolic side effects. We aim to compare the long-term outcomes of KTR on belatacept (bela) versus tacrolimus (tac) IS, in all KTRs and various subgroups. Using the UNOS-STAR files, we identified adult first-KTR from 2010 to 2022. Patients were categorized based on maintenance-IS at index transplant admission by creating a propensity score matched cohort at 1:5 rate using several clinical characteristics. Primary outcomes included patient death, graft failure (GF), and death-censored graft failure (DCGF). Secondary outcomes included delayed graft function (DGF), acute-rejections (AR) within a year, and serum creatinine (Cr) at 1-year. The propensity-matched cohort included KTRs on bela (N = 2612) and tac (N = 12760). There was no significant difference in the hazard ratio of death (1.03 [0.92, 1.14]), GF (1.07 [0.97, 1.17]), or DCGF (1.11 [0.98, 1.25]). A sensitivity analysis comparing a propensity-matched cohort of bela + tac (n = 2033) versus tac (n = 9004); demonstrated significantly reduced risks of death (0.87 [0.76-1.00], p = 0.043) and GF (0.73 [0.64-0.83] p < 0.001) compared to those on Tac alone. In conclusion, bela + tac seems to be a nephron-sparing and rejection-lowering IS regimen with overall improved graft and patient outcomes when compared to the current standard of tacrolimus. Larger Randomized Controlled studies are needed.

To investigate the effect of calcium channel blockers (CCBs) on tacrolimus blood concentrations in renal transplant recipients with different CYP3A5 genotypes.

This retrospective cohort study included renal transplant recipients receiving tacrolimus-based immunosuppressive therapy with or without CCBs in combination. Patients were divided into combination and control groups based on whether or not they were combined with CCBs, and then further analyzed according to the type of CCBs (nifedipine/amlodipine/felodipine). Propensity score matching was conducted for the combination and the control groups using SPSS 22.0 software to reduce the impact of confounding factors. The effect of different CCBs on tacrolimus blood concentrations was evaluated, and subgroup analysis was performed according to the patients' CYP3A5 genotypes to explore the role of CYP3A5 genotypes in drug-drug interactions between tacrolimus and CCBs.

A total of 164 patients combined with CCBs were included in the combination groups. After propensity score matching, 83 patients with nifedipine were matched 1:1 with the control group, 63 patients with felodipine were matched 1:2 with 126 controls, and 18 patients with amlodipine were matched 1:3 with 54 controls. Compared with the controls, the three CCBs increased the dose-adjusted trough concentration (C0/D) levels of tacrolimus by 41.61%-45.57% (P < 0.001). For both CYP3A5 expressers (CYP3A5*1*1 or CYP3A5*1*3) and non-expressers (CYP3A5*3*3), there were significant differences in tacrolimus C0/D between patients using felodipine/nifedipine and those without CCBs (P < 0.001). However, among CYP3A5 non-expressers, C0/D values of tacrolimus were significantly higher in patients combined with amlodipine compared to the controls (P = 0.001), while for CYP3A5 expressers, the difference in tacrolimus C0/D values between patients with amlodipine and without was not statistically significant (P = 0.065).

CCBs (felodipine/nifedipine/amlodipine) can affect tacrolimus blood concentration levels by inhibiting its metabolism. The CYP3A5 genotype may play a role in the drug interaction between tacrolimus and amlodipine. Therefore, genetic testing for tacrolimus and therapeutic drug monitoring are needed when renal transplant recipients are concurrently using CCBs.

Kidney transplantation (KTx) from small donors is associated with inferior graft survival in registry studies, whereas single-center studies show favorable results.

We compared 175 pediatric KTx from small donors ≤20 kg (SDKTx) with 170 age-matched recipients from adult donors (ADKTx) from 20 centers within the Cooperative European Paediatric Renal Transplant Initiative registry. Graft survival and estimated glomerular filtration rate (eGFR) were analyzed by Cox regression and mixed models. Detailed data on surgical and medical management were tested for association with graft survival.

One-year graft survival was lower after SDKTx compared with ADKTx (90.9% versus 96.5%; odds ratio of graft loss, 2.92; 95% confidence interval [CI], 1.10-7.80; P  = 0.032), but 5-y graft survival was comparable (90.9% versus 92.7%; adjusted hazard ratio of graft loss 1.9; 95% CI, 0.85-4.25; P  = 0.119). SDKTx recipients had an annual eGFR increase of 8.7 ± 6.2 mL/min/1.73 m² compared with a decrease of 6.9 ± 5.7 mL/min/1.73 m² in ADKTx recipients resulting in a superior 5-y eGFR (80.5 ± 25.5 in SDKTx versus 65.7 ± 23.1 mL/min/1.73 m² in ADKTx; P  = 0.008). At 3 y posttransplant, eGFR after single SDKTx was lower than after en bloc SDKTx (86.6 ± 20.4 versus 104.6 ± 35.9; P  = 0.043) but superior to ADKTx (68.1 ± 23.9 mL/min/1.73 m²). Single-kidney SDKTx recipients had a lower rate of hypertension at 3 y than ADKTx recipients (40.0% versus 64.7%; P  = 0.008).

Compared with ADKTx, 5-y graft function is superior in SDKTx and graft survival is similar, even when performed as single KTx. Utilizing small donor organs, preferably as single kidneys in experienced centers, is a viable option to increase the donor pool for pediatric recipients.

Background: Chronic kidney disease (CKD) elevates the risk of cardiovascular disease (CVD) and mortality. Uremic cardiomyopathy, frequently observed in CKD and end-stage renal disease (ESRD), involves alterations in cardiac structure and function, which may reverse post-kidney transplantation, although data remain controversial. This study examines the relationship between graft function and changes in cardiac parameters pre- and post-transplantation in kidney transplant recipients. Methods: A total of 145 pediatric and adult recipients of living or deceased donor kidney transplants were enrolled at Gazi Yaşargil Training and Research Hospital. This cohort study utilized transthoracic echocardiographic (TTE) imaging pre-transplant and at least two years post-transplant. Echocardiographic parameters were analyzed using standard techniques. Results: The mean age of the participants was 35 years, with 60% male. The average dialysis duration prior to transplantation was 27 months. Most recipients (83.4%) received kidneys from living donors. Left ventricular diastolic dysfunction increased significantly post-transplant (p < 0.05), while other cardiac dimensions and functions, such as ejection fraction and pulmonary artery pressure, showed no significant change (p > 0.05). Notably, diastolic dysfunction worsened in patients with dysfunctional grafts (GFR < 45), correlating with increased pulmonary artery pressure post-transplant. The rate of antihypertensive drug use and the prevalence of diabetes mellitus increased significantly post-transplant (p < 0.05). Conclusions: This study demonstrates that left ventricular diastolic dysfunction present before kidney transplantation continues to persist post-transplantation in patients with end-stage renal disease undergoing chronic kidney disease treatment. Furthermore, it shows an increased rate of pulmonary artery pressure and pericardial effusion in patients with dysfunctional grafts after transplantation. Further research is required to explore strategies to reverse uremic cardiomyopathy and reduce cardiovascular risk in these patients.

Left ventricular hypertrophy (LVH) in patients with end stage renal disease undergoing renal replacement is linked to an increased risk for cardiovascular diseases. Dialysis does not completely prevent or correct this abnormality, and the evidence for kidney transplantation (KT) varies. This analysis aims to explore the relationship between KT and LVH.

MEDLINE and Scopus were systematically searched in October 2023. All cross-sectional and longitudinal studies that fulfilled our inclusion criteria were included. Outcome was left ventricular mass index (LVMI) changes. We conducted a meta-analysis using a random effects model. Meta-regression was applied to examine the LVMI changes dependent on various covariates. Sensitivity analysis was used to handle outlying or influential studies and address publication bias.

From 7416 records, 46 studies met the inclusion criteria with 4122 included participants in total. Longitudinal studies demonstrated an improvement of LVMI after KT -0.44 g/m2 (-0.60 to -0.28). Blood pressure was identified as a predictor of LVMI change. A younger age at the time of KT and well-controlled anemia were also associated with regression of LVH. In studies longitudinally comparing patients on dialysis and renal transplant recipients, no difference was detected -0.09 g/m2 (-0.33 to 0.16). Meta-regression using changes of systolic blood pressure as a covariate showed an association between higher blood pressure and an increase in LVMI, regardless of the modality of renal replacement treatment.

In conclusion, our results indicated a potential cardiovascular benefit, defined as the regression of LVH, after KT. This benefit was primarily attributed to improved blood pressure control rather than the transplantation itself.

Donor-derived cell-free DNA (dd-cfDNA) is used as a biomarker for detection of antibody-mediated rejection (ABMR) and other forms of graft injury. Another potential indication is guidance of immunosuppressive therapy when no therapeutic drug monitoring is available. In such situations, detection of patients with overt or subclinical graft injury is important to personalize immunosuppression. We prospectively measured dd-cfDNA in 22 kidney transplant recipients (KTR) over a period of 6 months after conversion to belatacept for clinical indication and assessed routine clinical parameters. Patient and graft survival was 100% after 6 months, and eGFR remained stable (28.7 vs. 31.1 mL/min/1.73 m², p = 0.60). Out of 22 patients, 2 (9%) developed biopsy-proven rejection-one episode of low-grade TCMR IA and one episode of caABMR. While both episodes were detected by increase in creatinine, the caABMR episode led to increase in absolute dd-cfDNA (168 copies/mL) above the cut-off of 50 copies/mL, while the TCMR episode did show slightly increased relative dd-cfDNA (0.85%) despite normal absolute dd-cfDNA (22 copies/mL). Dd-cfDNA did not differ before and after conversion in a subgroup of 12 KTR with previous calcineurin inhibitor therapy and no rejection (12.5 vs. 25.3 copies/mL, p = 0.34). In this subgroup, 3/12 (25%) patients showed increase of absolute dd-cfDNA above the prespecified cut-off (50 copies/mL) despite improving eGFR. Increase in dd-cfDNA after conversion to belatacept is common and could point towards subclinical allograft injury. To detect subclinical TCMR changes without vascular lesions, additional biomarkers or urinary dd-cfDNA should complement plasma dd-cfDNA. Resolving CNI toxicity is unlikely to be detected by decreased dd-cfDNA levels. In summary, the sole determination of dd-cfDNA has limited utility in the guidance of patients after late conversion to belatacept. Further studies should focus on patients undergoing early conversion and include protocol biopsies at least for patients with increased dd-cfDNA.

Kidney transplantation is considered the treatment of choice for end-stage kidney disease patients. However, the residual cardiovascular risk remains significantly higher in kidney transplant recipients (KTRs) than in the general population. Hypertension is highly prevalent in KTRs and represents a major modifiable risk factor associated with adverse cardiovascular outcomes and reduced patient and graft survival. Proper definition of hypertension and recognition of special phenotypes and abnormal diurnal blood pressure (BP) patterns is crucial for adequate BP control. Misclassification by office BP is commonly encountered in these patients, and a high proportion of masked and uncontrolled hypertension, as well as of white-coat hypertension, has been revealed in these patients with the use of ambulatory BP monitoring. The pathophysiology of hypertension in KTRs is multifactorial, involving traditional risk factors, factors related to chronic kidney disease and factors related to the transplantation procedure. In the absence of evidence from large-scale randomized controlled trials in this population, BP targets for hypertension management in KTR have been extrapolated from chronic kidney disease populations. The most recent Kidney Disease Improving Global Outcomes 2021 guidelines recommend lowering BP to less than 130/80 mmHg using standardized BP office measurements. Dihydropyridine calcium channel blockers and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers have been established as the preferred first-line agents, on the basis of emphasis placed on their favorable outcomes on graft survival. The aim of this review is to provide previous and recent evidence on prevalence, accurate diagnosis, pathophysiology and treatment of hypertension in KTRs.

It has been reported that up to 90% of organ transplant recipients have suboptimal blood pressure control. Uncontrolled hypertension is a well-known culprit of cardiovascular and overall morbidity and mortality. In addition, rigorous control of hypertension after organ transplantation is a crucial factor in prolonging graft survival. Nevertheless, hypertension after organ transplantation encompasses a broader range of causes than those identified in non-organ transplant patients. Hence, specific management awareness of those factors is mandated. An in-depth understanding of hypertension after organ transplantation remains a debatable issue that necessitates further clarification. This article provides a comprehensive review of the prevalence, risk factors, etiology, complications, prevention, and management of hypertension after organ transplantation.

Hypertension is common in kidney transplantation recipients and may be difficult to treat. Factors present before kidney transplantation, related to the transplantation procedure itself and factors developing after transplantation may contribute to blood pressure (BP) elevation in kidney transplant recipients. The present consensus is based on the results of three recent systematic reviews, the latest guidelines and the current literature. The current transplant guidelines, which recommend only office BP assessments for risk stratification in kidney transplant patients should be reconsidered, given the presence of white-coat hypertension and masked hypertension in this population and the better prediction of adverse outcomes by 24-h ambulatory BP monitoring as indicated in recent systematic reviews. Hypertension is associated with adverse kidney and cardiovascular outcomes and decreased survival in kidney transplant recipients. Current evidence suggests calcium channel blockers could be the preferred first-step antihypertensive agents in kidney transplant patients, as they improve graft function and reduce graft loss, whereas no clear benefit is documented for renin-angiotensin system inhibitor use over conventional treatment in the current literature. Randomized control trials demonstrating the clinical benefits of BP lowering on kidney and major cardiovascular events and recording patient-related outcomes are still needed. These trials should define optimal BP targets for kidney transplant recipients. In the absence of kidney transplant-specific evidence, BP targets in kidney transplant recipients should be similar to those in the wider chronic kidney disease population.

Background: Shortened allograft survival, and cardiovascular morbidity and mortality are consequences of inadequate control of hypertension for kidney transplant recipients (KTRs). Literature suggests the risk is multifactorial, although few studies have evaluated risk factors in relation to guideline recommended blood pressure (BP) goals in the early post-kidney transplant period. This study will elucidate factors associated with controlled BP in KTRs. Methods: Adult KTRs who were transplanted between January 1, 2013, and October 31, 2018, were evaluated. Coprimary outcomes included the proportion of patients who had controlled BP at postoperative day (POD) 30 and identification of the covariates associated with controlled BP at POD 30. Additional outcomes included the proportion of patients who had controlled BP at POD 60 and 90; the difference in the average number of antihypertensive medications taken pretransplant vs POD 30, 60, and 90 for patients with controlled BP at POD 30; antihypertensive use rates pretransplant vs POD 30 and 90; and class of antihypertensive used pretransplant vs POD 30 and 90. Results: At POD 30, 44% (100/226) of patients had controlled BP. The proportion of patients with controlled BP at POD 60 and 90 were 37% (82/220) and 40% (79/196), respectively. In bivariate analyses, lack of recipient hypertension (75% vs 42.5%, P = .04); fewer days on dialysis (1684 vs 2189 days, P = .005); absence of delayed graft function (51.2% vs 35.6%, P = .02); younger donor age (30 vs 40 years, P < .001); absence of donor hypertension (46.9% vs 29.3%, P = .004); and a lower median kidney donor profile index (29% vs 40%, P = .03) were associated with controlled BP at POD 30. In a multivariate analysis, donor age was independently associated with controlled BP at POD 30 (P = .03). Conclusions: This study suggests that younger donor age is associated with controlled BP, and conversely, older donor age is associated with uncontrolled BP in KTRs in the early post-kidney transplant period. Patients receiving a graft from older donors should have their BP closely monitored.

Calcineurin inhibitors (CNIs) have been the backbone immunosuppressant for solid organ transplant recipients for decades. Long-term use of CNIs unfortunately is associated with multiple toxicities, with the biggest concern being CNI-induced nephrotoxicity. Belatacept is a novel agent approved for maintenance immunosuppression in renal transplant recipients. In the kidney transplant literature, it has shown promise as being an alternative agent by preserving renal function and having a minimal adverse effect profile. There are emerging studies of its use in other organ groups, particularly liver transplantation, as well as using with other alternative immunosuppressive strategies. The purpose of this review is to analyze the current literature of belatacept use in solid organ transplantation and discuss its use in current practice.

Although tacrolimus is the basis of most maintenance immunosuppression regimens for kidney transplantation, concerns about toxicity have made alternative agents, such as belatacept, attractive to clinicians. However, limited data exist to directly compare outcomes with belatacept-based regimens to tacrolimus.

We performed a propensity score matched cohort study of adult kidney transplant recipients transplanted between May 1, 2001, and December 31, 2015, using national transplant registry data to compare patient and allograft survival in patients discharged from their index hospitalization on belatacept-based versus tacrolimus-based regimens.

In the primary analysis, we found that belatacept was not associated with a statistically significant difference in risk of patient death (hazard ratio, 0.84; 95% confidence interval [CI], 0.61-1.15, P = 0.28) or allograft loss (hazard ratio, 0.83; 95% CI, 0.62-1.11; P = 0.20) despite an increased risk of acute rejection in the first year posttransplant (odds ratio, 3.12; 95% CI, 2.13-4.57; P < 0.001). These findings were confirmed in additional sensitivity analyses that accounted for use of belatacept in combination with tacrolimus, transplant center effects, and differing approaches to matching.

Belatacept appears to have similar longitudinal risk of mortality and allograft failure compared with tacrolimus-based regimens. These data are encouraging but require confirmation in prospective randomized controlled trials.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m² for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m² for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

Calcineurin inhibitor (CNI)-induced nephrotoxicity and chronic graft dysfunction with deteriorating glomerular filtration rate (GFR) are common problems of kidney transplant recipients. The aim of this study was to analyze the role of belatacept as a rescue therapy in these patients.

In this retrospective, observational study we investigated 20 patients (10 females, 10 males) who were switched from a CNI (tacrolimus) to a belatacept-based immunosuppression because of CNI intolerance or marginal transplant function. Patient follow-up was 12 months.

Patients were converted to belatacept in mean 28.8 months after transplantation. Reasons for conversion were CNI intolerance (14 patients) or marginal transplant function (6 patients). Mean estimated GFR (eGFR) before conversion was 22.2 ± 9.4 ml/min at baseline and improved significantly to 28.3 ± 10.1 ml/min at 4 weeks and to 32.1 ± 12.6 ml/min at 12 months after conversion. Serum bicarbonate significantly increased from 24.4 ± 3.2 mmol/l at baseline to 28.7 ± 2.6 mmol/l after 12 months. Conversion to belatacept decreased parathyroid hormone and phosphate concentrations significantly, whereas albumin levels significantly increased. In 6 cases an acute rejection preceded clinically relevant CNI toxicity; only two patients suffered from an acute rejection after conversion. Belatacept was well tolerated and there was no increase in infectious or malignant side effects.

A late conversion from a tacrolimus-based immunosuppression to belatacept is safe, effective and significantly improves renal function in kidney transplant recipients. Additionally, the conversion to belatacept has a beneficial impact on acid-base balance, mineral-bone and protein metabolism, independently of eGFR.

For the select fortunate recipients of organ transplants, transplantation affords the rare opportunity for a new life. Given the scarcity of organs for transplantation, it is imperative that the health of transplant recipients be optimized in order to fully benefit from this gift of life. Unfortunately, hypertension is highly prevalent in the transplant population and it is considered a major cardiovascular risk factor contributing to mortality and morbidity in this population. In this chapter, we expound on the epidemiology, unique pathophysiology, evaluation, and management of hypertension as it pertains to the solid organ transplant recipient. In addition, a brief commentary is made on the subject of hypertension following living kidney donation, and practical aspects of management of hypertension in the solid organ recipient are summarized at the end of the chapter.

Hypertension is a prevalent problem in kidney transplant recipients that is known to be a "traditional" risk factor for atherosclerotic cardiovascular disease leading to premature allograft failure and death. Donor, peritransplant, and recipient factors affect hypertension risk. Blood pressure control after transplantation is inversely associated with glomerular filtration rate (GFR). Calcineurin inhibitors, the most commonly used class of immunosuppressives, cause endothelial dysfunction, increase vascular tone, and sodium retention via the renin-angiotensin-aldosterone system resulting in systemic hypertension. Steroid withdrawal seems to have little impact on blood pressure control. Newer agents like belatacept appear to be associated with less hypertension. Transplant renal artery stenosis is an important, potentially treatable cause of hypertension. Dihydropyridine calcium channel blockers mitigate calcineurin inhibitor nephrotoxicity and may be associated with improved estimated GFR. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are not recommended in the first 3 to 6 months given their effects on reduced estimated GFR, anemia, and hyperkalemia. The use of ß-blockers may be associated with improved patient survival, even for patients without cardiovascular disease. Living donation may increase blood pressure by 5 mm Hg or more. Some transplant centers accept Caucasian living donors with well-controlled hypertension on a single agent if they agree to close follow-up.

This review will discuss the mechanism of action and important kidney transplant clinical trial data for the small molecule Janus kinase (JAK) 3 inhibitor tofacitinib , formerly known as CP-690,550 and tasocitinib.

Successful kidney transplantation requires adequate immunosuppression. Current maintenance immunosuppressive protocols which rely on calcineurin inhibitors have long-term nephrotoxicity and negative impact on cardiometabolic risk factors. JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors, particularly members of the cytokine receptor common gamma (cγ) chain family. JAK3 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis. Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared to control. Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival. There was also a lower rate of new onset diabetes after transplant. However, there was a trend toward more infections, including cytomegalovirus and BK virus nephritis.

Tofacitinib may be a promising alternative to calcineurin inhibitors. The optimal therapeutic window is still being determined.

Arterial hypertension is prevalent among kidney transplant recipients. The multifactorial pathogenesis involves the interaction of the donor and the recipient's genetic backgrounds with several environmental parameters that may precede or follow the transplant procedure (eg, the nature of the renal disease, the duration of the chronic kidney disease phase and maintenance dialytic therapy, the commonly associated cardiovascular disease with atherosclerosis and arteriosclerosis, the renal mass at implantation, the immunosuppressive regimen used, life of the graft, and de novo medical and surgical complications that may occur after a transplant). Among calcineurin inhibitors, tacrolimus seems to have a better cardiovascular profile. Steroid-free protocols and calcineurin inhibitor-free regimens seem to be associated with better blood pressure control. Posttransplant hypertension is a major amplifier of the chronic kidney disease-cardiovascular disease continuum. Despite the adverse effects of hypertension on graft and patient survival, blood pressure control remains poor because of the high cardiovascular risk profile of the donor-recipient pair. Although the optimal blood pressure level remains unknown, it is recommended to maintain the blood pressure at < 130/80 mm Hg and < 125/75 mm Hg in the absence or presence of proteinuria.

To date, no study has described the pre-transplant and transplant risk factors for end-organ damage based on arterial hypertension in children after kidney transplantation (KTX).

A retrospective chart review was performed of 206 children with KTX between 1991 and 2007. Patients<120 cm were excluded as no validated percentiles for 24-h ambulant blood pressure monitoring (ABPM) exist. Complete data sets were available for 116 patients. Data were recorded at 12, 24 and 36 months post- KTX. We analysed the influence of donor age, age at transplantation, pre-emptive transplantation, living or deceased transplantation and glomerular filtration rate (GFR) on the presence of end-organ damage, ABPM, ABPM standard deviation score and the numbers of anti-hypertensives used.

Lower donor age and the decade of transplantation were associated with less detection of end-organ damage (P=0.001). A lower need for anti-hypertensive medication (P=0.001) was detected in children who received organs from living donors and from deceased donors with a donor age<35 years and who were transplanted pre-emptively. Low recipient age was the only factor associated with lower ABPM (P=0.001). In our study, the type of immunosuppressive regimen and the GFR had no influence on the blood pressure.

It may be speculated that the risk of arterial hypertension and associated end-organ damage in children after KTX could be reduced by using organs from young donors with an advantage for living related and pre-emptive donation.

Signaling through the costimulatory pathway is critical in the regulation of T cell activation. Abatacept, a selective costimulatory antagonist FDA approved for the treatment of moderate to severe rheumatoid arthritis, binds to CD80 and CD86 on antigen presenting cells, blocking the interaction with CD28 on T cells. Belatacept, a second generation CTLA4-Ig with 2 amino acid substitutions, has shown considerable promise in clinical transplantation as part of a maintenance immunosuppression regimen. This review will summarize the role of costimulation in T cell activation, detail the development of costimulation antagonists and highlight the pertinent clinical trials completed and ongoing utilizing belatacept as part of an immunosuppressive regimen in organ transplantation.

Cardiovascular disease, the most common cause of death with a functioning graft among kidney transplant recipients, can be exacerbated by immunosuppressive drugs, particularly the calcineurin inhibitors. Belatacept, a selective co-stimulation blocker, may provide a better cardiovascular/metabolic risk profile than current immunosuppressants.

Cardiovascular and metabolic endpoints from two Phase III studies (BENEFIT and BENEFIT-EXT) of belatacept-based regimens in kidney transplant recipients were assessed at month 12. Each study assessed belatacept in more intensive (MI) and less intensive (LI) regimens versus cyclosporine A (CsA). These secondary endpoints included changes in blood pressure, changes in serum lipids, and the incidence of new-onset diabetes after transplant (NODAT).

A total of 1209 patients were randomized and transplanted across the two studies. Mean systolic blood pressure was 6 to 9 mm Hg lower and mean diastolic blood pressure was 3 to 4 mm Hg lower in the MI and LI groups versus CsA (P ≤ 0.002) across both studies at month 12. Non-HDL cholesterol was lower in the belatacept groups versus CsA (P<0.01 MI or LI vs. CsA in each study). Serum triglycerides were lower in the belatacept groups versus CsA (P<0.02 MI or LI vs. CsA in each study). NODAT occurred less often in the belatacept groups versus CsA in a prespecified pooled analysis (P<0.05 MI or LI vs. CsA).

At month 12, belatacept regimens were associated with better cardiovascular and metabolic risk profiles, with lower blood pressure and serum lipids and less NODAT versus CsA. The overall profile of belatacept will continue to be assessed over the 3-year trials.

Arterial hypertension is frequently observed in renal transplant recipients. Its pathogenesis is multifactorial in most cases. Calcineurin inhibitors (CNI) can increase peripheral vascular resistance by inducing arteriolar vasoconstriction and can cause extracellular fluid expansion by reducing the glomerular filtration rate (GFR), activating the renin-angiotensin system (RAS), and by inactivating the atrial natriuretic peptide. Glucocorticoids can impair urinary water and salt excretion. Poor graft function can lead to increased extracellular volume and inappropriate production of renin. Native kidneys, older age of the donor and transplant renal artery stenosis (TRAS) may also contribute to the development of hypertension. Arterial hypertension not only can increases the risk for cardiovascular events but can also deteriorate renal allograft function. A number of studies have shown that the higher the levels of blood pressure are, the higher is the risk of graft failure. On the other hand, a good control of blood pressure may prevent many cardiovascular and renal complications. Appropriate lifestyle modification is the first step for treating hypertension. Calcium channel blockers (CCB) and renin-angiotensin system (RAS) inhibitors are the most frequently used antihypertensive agents, but in many cases, a combination of these and other drugs is required to obtain good control of hypertension.

Prolonged use of calcineurin inhibitors (CNIs) in kidney transplant recipients is associated with renal and nonrenal toxicity and an increase in cardiovascular risk factors. Belatacept-based regimens may provide a treatment option for patients who switch from CNI-based maintenance immunosuppression.

This is a randomized, open-label Phase II trial in renal transplant patients with stable graft function and receiving a CNI-based regimen. Patients who were ≥6 months but ≤36 months after transplantation were randomized to either switch to belatacept or continue CNI treatment. All patients received background maintenance immunosuppression. The primary end point was the change in calculated GFR (cGFR) from baseline to month 12.

Patients were randomized either to switch to belatacept (n=84) or to remain on a CNI-based regimen (n=89). At month 12, the mean (SD) change from baseline in cGFR was higher in the belatacept group versus the CNI group. Six patients in the belatacept group had acute rejection episodes, all within the first 6 months; all resolved with no allograft loss. By month 12, one patient in the CNI group died with a functioning graft, whereas no patients in the belatacept group had graft loss. The overall safety profile was similar between groups.

The study identifies a potentially safe and feasible method for switching stable renal transplant patients from a cyclosporine- or tacrolimus-based regimen to a belatacept-based regimen, which may allow improved renal function in patients currently treated with CNIs.

At 1 year, belatacept was associated with similar patient/graft survival, better renal function, and an improved cardiovascular/metabolic risk profile versus cyclosporine A (CsA) in the Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT) studies. Acute rejection was more frequent with belatacept in BENEFIT. Posttransplant lymphoproliferative disorder (PTLD)--specifically central nervous system PTLD--was observed more frequently in belatacept-treated patients. This analysis assesses outcomes from BENEFIT and BENEFIT-EXT after 2 years of treatment.

Patients received a more intensive (MI) or a less intensive (LI) regimen of belatacept or a CsA-based regimen.

Four hundred ninety-three of 666 patients (74%) in BENEFIT and 347 of 543 (64%) in BENEFIT-EXT completed 2 years of treatment. The proportion of patients who survived with a functioning graft was similar across groups (BENEFIT: 94% MI, 95% LI, and 91% CsA; BENEFIT-EXT: 83% MI, 84% LI, and 83% CsA). Belatacept's renal benefits were sustained, as evidenced by a 16 to 17 mL/min (BENEFIT) and an 8 to 10 mL/min (BENEFIT-EXT) higher calculated glomerular filtration rate in the belatacept groups versus CsA. There were few new acute rejection episodes in either study between years 1 and 2. Because PTLD risk was highest in Epstein-Barr virus (EBV) (-) patients, an efficacy analysis of EBV (+) patients was performed and was consistent with the overall population results. There were two previously reported cases of PTLD in each study between years 1 and 2 in the belatacept groups. The overall balance of safety and efficacy favored the LI over the MI regimen.

At 2 years, belatacept-based regimens sustained better renal function, similar patient/graft survival, and an improved cardiovascular/metabolic risk profile versus CsA; outcomes that were maintained in EBV (+) patients. No new safety signals emerged.

The majority of patients become hypertensive following kidney transplantation. Its occurrence is associated not only with increased fatal and nonfatal cardiovascular events but also with decreased allograft survival. This review summarizes the current knowledge of the epidemiology, etiology, pathophysiology, and management of post-transplant hypertension.

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1-year, randomized, controlled, open-label, exploratory study assessed two belatacept-based regimens compared to a tacrolimus (TAC)-based, steroid-avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept-mycophenolate mofetil (MMF), belatacept-sirolimus (SRL), or TAC-MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty-nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept-MMF, belatacept-SRL and TAC-MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two-thirds of patients in the belatacept groups remained on CNI- and steroid-free regimens at 12 months and the calculated glomerular filtration rate was 8-10 mL/min higher with either belatacept regimen than with TAC-MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC-based regimen.

Belatacept, a costimulation blocker, may preserve renal function and improve long-term outcomes versus calcineurin inhibitors in kidney transplantation. This Phase III study (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) assessed a more intensive (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adults receiving a kidney transplant from living or standard criteria deceased donors. The co-primary endpoints at 12 months were patient/graft survival, a composite renal impairment endpoint (percent with a measured glomerular filtration rate (mGFR) <60 mL/min/1.73 m(2) at Month 12 or a decrease in mGFR > or =10 mL/min/1.73 m(2) Month 3-Month 12) and the incidence of acute rejection. At Month 12, both belatacept regimens had similar patient/graft survival versus cyclosporine (MI: 95%, LI: 97% and cyclosporine: 93%), and were associated with superior renal function as measured by the composite renal impairment endpoint (MI: 55%; LI: 54% and cyclosporine: 78%; p < or = 0.001 MI or LI versus cyclosporine) and by the mGFR (65, 63 and 50 mL/min for MI, LI and cyclosporine; p < or = 0.001 MI or LI versus cyclosporine). Belatacept patients experienced a higher incidence (MI: 22%, LI: 17% and cyclosporine: 7%) and grade of acute rejection episodes. Safety was generally similar between groups, but posttransplant lymphoproliferative disorder was more common in the belatacept groups. Belatacept was associated with superior renal function and similar patient/graft survival versus cyclosporine at 1 year posttransplant, despite a higher rate of early acute rejection.

We performed a case-control study in renal transplant patients between 1998 and 2003 to identify risk factors for arterial hypertension over the medium term in pediatric patients undergoing renal transplantation. Three years after transplant, patients were classified into hypertensive or control groups. The following risk factors were analyzed: hypertension before transplant, glomerular filtration rate at sixth posttransplant month, acute rejection episodes, renal artery stenosis, accumulated prednisone and calcineurin inhibitor doses, presence of native kidneys, donor type (living or cadaver), body mass index at 1 year posttransplant, and glomerular disease as renal insufficiency etiology. Of 161 transplants, 124 fulfilled the inclusion criteria; 63 were hypertensive, and 61 were controls. Univariate analysis showed hypertension before transplant (52/63 vs. 27/61, p < 0.001), glomerulopathies (23/63 vs. 12/61, p = 0.001), glomerular filtration rate at 6 months (71 +/- 18 vs, 80 +/- 18 ml/min per 1.73 m(2), p = 0.003) as risk factors. A tendency to statistical significance was observed with regard to body mass index (SDS) in the first year (0.40 +/- 1.10 vs, 0.04 +/- 1.10, p = 0.072). Multivariate analysis showed statistical significance concerning previous hypertension and glomerular filtration rate at 6 months. Hypertension before transplant and early graft function are the major risk factors for hypertension in the medium term following renal transplant.

Arterial hypertension in renal transplant patients plays a major role in the progression to chronic allograft failure, and in morbidity and mortality associated with cardiovascular disease. Its cause is diverse, with contributions not only from donor and/or recipient factors, but it also is influenced strongly by the type of immunosuppressive regimen. Despite increased awareness of the adverse effects of hypertension in both graft and patient survival, long-term studies have shown that arterial hypertension in the transplant population has not been controlled adequately. Ambulatory blood pressure measurements provide the advantage of a better assessment of the diurnal blood pressure variation, a predictor of target organ damage and cardiovascular morbidity and mortality events. Although the available data do not support the recommendation of any class of antihypertensive medication as preferred agents for blood pressure management in the transplant population, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have shown beneficial effects beyond their antihypertensive effects. Clinical data in transplant recipients are emerging that suggest that applying interventions proven to be effective in reducing cardiovascular morbidity and mortality in the general population may be effective for the transplant population.