High frequency of valganciclovir underdosing for cytomegalovirus prophylaxis after renal transplantation.

BACKGROUND: The correct valganciclovir dose for cytomegalovirus (CMV) prophylaxis depends on renal function estimated by the Cockcroft-Gault (CG) estimated creatinine clearance (CG-CrCl) formula. Patients with delayed or rapidly changing graft function after transplantation (tx) will need dose adjustments. METHODS: We performed a retrospective investigation of valganciclovir dosing in renal transplant patients receiving CMV prophylaxis between August 2003 and August 2011, and analysed valganciclovir dosing, CG-CrCl, CMV viraemia (CMV-PCR <750 copies/mL), leucopenia (<3500/µL) and neutropenia (<1500/µL) in the first year post-transplant. On Days 30 and 60 post-transplant, dosing pattern in relation to estimated creatinine clearance was analysed regarding CMV viraemia, leucopenia and neutropenia. RESULTS: Six hundred and thirty-five patients received valganciclovir prophylaxis that lasted 129 ± 68 days with a mean dose of 248 ± 152 mg/day of whom 112/635 (17.7%) developed CMV viraemia, 166/635 (26.1%) leucopenia and 48/635 (7.6%) neutropenia. CMV resistance within 1 year post-transplant was detected in three patients. Only 137/609 (22.6%) patients received the recommended dose, while n = 426 (70.3%) were underdosed and n = 43 (7.1%) were overdosed at Day 30 post-tx. Risk factors for CMV viraemia were donor positive D (+)/receptor negative R (-) status and short prophylaxis duration, but not low valganciclovir dose. Risk factors for developing leucopenia were D+/R- status and low renal function. No significant differences in dosing frequency were observed in patients developing neutropenia or not (P = 0.584). CONCLUSION: Most patients do not receive the recommended valganciclovir dose. Despite obvious underdosing in a large proportion of patients, effective prophylaxis was maintained and it was not associated as a risk factor for CMV viraemia or leucopenia.

IL-17 Expression in the Time Course of Acute Anti-Thy1 Glomerulonephritis.

BACKGROUND: Interleukin-17 (IL-17) is a new pro-inflammatory cytokine involved in immune response and inflammatory disease. The main source of IL-17 is a subset of CD4+ T-helper cells, but is also secreted by non-immune cells. The present study analyzes expression of IL-17 in the time course of acute anti-thy1 glomerulonephritis and the role of IL-17 as a potential link between inflammation and fibrosis. METHODS: Anti-thy1 glomerulonephritis was induced into male Wistar rats by OX-7 antibody injection. After that, samples were taken on days 1, 5, 10 (matrix expansion phase), 15 and 20 (resolution phase). PBS-injected animals served as controls. Proteinuria and histological matrixes score served as the main markers for disease severity. In in vitro experiments, NRK-52E cells were used. For cytokine expressions, mRNA and protein levels were analyzed by utilizing RT-PCR, in situ hybridization and immunofluorescence. RESULTS: Highest IL-17 mRNA-expression (6.50-fold vs. con; p<0.05) was found on day 5 after induction of anti-thy1 glomerulonephritis along the maximum levels of proteinuria (113 ± 13 mg/d; p<0.001), histological glomerular-matrix accumulation (82%; p<0.001) and TGF-ß1 (2.2-fold; p<0.05), IL-6 mRNA expression (36-fold; p<0.05). IL-17 protein expression co-localized with the endothelial cell marker PECAM in immunofluorescence. In NRK-52E cells, co-administration of TGF-ß1 and IL-6 synergistically up-regulated IL-17 mRNA 4986-fold (p<0.001). CONCLUSIONS: The pro-inflammatory cytokine IL-17 is up-regulated in endothelial cells during the time course of acute anti-thy1 glomerulonephritis. In vitro, NRK-52E cells secrete IL-17 under pro-fibrotic and pro-inflammatory conditions.

The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts that develop de novo thrombotic microangiopathy.

BACKGROUND: Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. METHODS: Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. RESULTS: The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. CONCLUSION: The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses.

Recurrent Primary Focal Segmental Glomerulosclerosis Managed With Intensified Plasma Exchange and Concomitant Monitoring of Soluble Urokinase-Type Plasminogen Activator Receptor-Mediated Podocyte ß3-integrin Activation.

BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) often causes nephrotic proteinuria and frequently results in end-stage renal disease and recurrence after kidney transplantation. Recent studies describe soluble urokinase-type plasminogen activator receptor (suPAR) as a circulating factor implicated in FSGS. METHODS: This single-center study included 12 adult patients with histologically proven primary FSGS (n = 2) or recurrent FSGS after transplantation (n = 10). The effect of plasma exchange (PE) on clinical outcome, suPAR levels, and in vitro podocyte ß3-integrin activation was investigated over a median of 11 (6-18) sessions of PE. RESULTS: The course of treatment was monitored in a total of 70 sessions of PE, which partly eliminated suPAR, with a mean reduction of 37 ± 12% of serum concentration per session. However, a substantial rebound was observed between sessions, with suPAR levels reaching 99 ± 22% of the pretreatment levels after a median of 4 days. Podocyte ß3-integrin activation dropped significantly after PE but rebounded within 4 days concomitant with a rising suPAR level. In 11 of 12 patients, multimodal treatment (including extensive PE) reduced proteinuria significantly (from 5.3 [2.0-7.8] to 1.0 [0.4-1.6] g/d), indicating clinical efficacy of the therapy. One patient suffered allograft loss due to FSGS recurrence. A persisting response was independent of a lasting reduction in the level of total suPAR because there was no sustained significant change in suPAR levels before and after the course of intensified treatment (3814 ± 908 to 3595 ± 521 pg/mL; P = 0.496). CONCLUSIONS: We conclude that multimodal therapy including extensive PE was associated with stabilization of recurrent FSGS and a temporary lowering of plasma suPAR as well as podocyte ß3-integrin activation. Whether a sustained lowering of total suPAR results in further improved outcomes requires additional study.

No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study.

AIMS: Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA exposure. Data from healthy volunteers suggest a significant drug-drug interaction (DDA) between pantoprazole and MPA. In transplant patients, a decreased MPA area under the concentration-time curve (AUC) may lead to higher IMPDH activity, which may lead to higher acute rejection risk. Therefore this DDA was evaluated in renal transplant patients under maintenance immunosuppressive therapy. METHODS: In this single-centre, open, randomized, four-sequence, four-treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC0-12 h (dAUC) was analysed in 20 renal transplant patients (>6 months post-transplantation) receiving MMF (1-2 g day(-1) ) and EC-MPS in combination with ciclosporin. The major metabolite MPA glucuronide (MPAG) and the IMPDH activity were also examined. RESULTS: MMF + PAN intake led to a lowest mean dAUC for MPA of 41.46 ng h ml(-1) mg(-1) [95% confidence interval (CI) 32.38, 50.54], while MPA exposure was highest for EC-MPS + PAN [dAUC: 46.30 ng h ml(-1) mg(-1) (95% CI 37.11, 55.49)]. Differences in dAUC and dose-adjusted maximum concentration (dCmax) were not significant. Only for MMF [dAUC: 41.46 ng h ml(-1) mg(-1) (95% CI 32.38, 50.54)] and EC-MPS [dAUC: 43.39 ng h ml(-1) mg(-1) (95% CI 33.44, 53.34)] bioequivalence was established for dAUC [geometric mean ratio: 101.25% (90% CI 84.60, 121.17)]. Simultaneous EC-MPS + PAN intake led to an earlier time to Cmax (tmax) [median: 2.0 h (min-max: 0.5-10.0)] than EC-MPS intake alone [3 h (1.5-12.0); P = 0.037]. Tmax was not affected for MMF [1.0 h (0.5-5.0)] ± pantoprazole [1.0 h (0.5-6.0), P = 0.928). No impact on MPAG pharmacokinetics or IMPDH activity was found. CONCLUSION: Pantoprazole influences EC-MPS and MMF pharmacokinetics but as it had no impact on MPA pharmacodynamics, the immunosuppressive effect of the drug was not impaired.

Renal allograft loss caused by cardiorenal syndrome: frequency and diagnosis.

BACKGROUND: Scientific interest in cardiorenal syndrome (CRS) affecting the native kidneys is increasing. In contrast, no relevant literature exists on CRS after kidney transplantation. METHODS: Prompted by the clinical course of a renal allograft recipient, who lost his graft because of CRS, we systematically investigated the frequency, the clinical appearance, the underlying cardiac pathophysiology, and the renal pathology of patients with graft loss caused by CRS between 2006 and 2011 at our center. RESULTS: We identified seven cases of graft loss caused by CRS, six cases of CRS type II, and one case of CRS type I. The proportion of death-censored graft losses caused by CRS was 4.6% (7/152 patients). Median graft survival after diagnosis was 6 (1-62) months. Clinically, all patients suffered from repeated episodes of decreasing renal function together with severe volume overload necessitating multiple hospitalizations (range, 23-308 days) and ultrafiltration treatments (range, 4-45). Cardiac investigation revealed a combination of left heart failure, right heart failure and moderate-to-severe tricuspid regurgitation in 5/6 CRS type II patients. Renal allograft pathology showed the same pattern of tubular injury in all biopsy specimens: microvesicular tubular epithelial cytoplasmatic vacuolization and luminal dilatation with flattening of the epithelium. CONCLUSION: We propose that the diagnosis of CRS after renal transplantation should be based on the following triad: (i) otherwise unexplained decrease of renal function together with severe volume overload; (ii) functionally relevant heart disease, predominantly left heart failure in combination with right heart failure, and tricuspid regurgitation; and (iii) a typical histopathologic pattern of tubular injury.

Designation of T-cell-mediated rejection type Ib and IIa reflects the type of rejection rather than the severity in the Banff classification.

OBJECTIVES: Whether T-cell-mediated rejection Banff classification type Ib (severe tubulointerstitial rejection) and type IIa (mild vascular rejection) are associated with responses to antirejection therapy and long-term graft survival are unclear. MATERIALS AND METHODS: One hundred ten patients were enrolled who had at least 1 episode of T-cell-mediated rejection and whose highest T-cell-mediated rejection severity was T-cell-mediated rejection type Ib or IIa. RESULTS: T-cell-mediated rejection Ib occurred significantly later than T-cell-mediated rejection IIa (P < .001). The proportion of partial/no response to antirejection therapy was comparable between the 2 groups (P = .83). Up to 8-year posttransplant, death-censored graft survival rate of the T-cell-mediated rejection Ib group was similar to that of the T-cell-mediated rejection IIa group (P = .51). Early T-cell-mediated rejection IIa had a statistically higher death-censored graft survival rate than did late T-cell-mediated rejection IIa (P < .001), while no significant difference in the death-censored graft survival was found between early and late T-cell-mediated rejection Ib (P = .11) or between early T-cell-mediated rejection Ib and early T-cell-mediated rejection IIa (P = .11) or between late T-cell-mediated rejection Ib and late T-cell-mediated rejection IIa (P = .07). Furthermore, the T-cell-mediated rejection IIa with isolated v1 lesion (v1, i0-1, t0-1) showed a similar death-censored graft survival rate compared to T-cell-mediated rejection IIa with intensive tubulointerstitial inflammation (v1, i2-3, t2-3). The timing of rejection, graft number, the number of indicated biopsies and the presence of ci/ct lesions were associated with long-term graft loss. CONCLUSIONS: The designation of T-cell-mediated rejection type Ib and IIa reflects the different type rather than the distinct severity of rejection and has no independent prognostic significance.

Treatment with sirolimus is associated with less weight gain after kidney transplantation.

BACKGROUND: Immunosuppression after kidney transplantation has been associated with weight gain. The aim was to evaluate if sirolimus (SRL) had a different effect on weight gain than calcineurin inhibitor (CNI). METHODS: Data on body weight in different patient populations were analyzed at several time points: (a) SRL (CNI-free) versus cyclosporine A (CsA) treatment de novo, (b) CsA+SRL versus CsA (SRL-free) treatment de novo, (c) SRL+tacrolimus elimination at 3 months versus SRL+mycophenolate mofetil versus tacrolimus+mycophenolate mofetil de novo, and (d) conversion from CNI to SRL versus CNI in maintenance patients. RESULTS: Patients were analyzed from de novo transplantation trials (n=1863) and from the conversion study (n=742). At baseline, weight in the SRL-containing and SRL-free treatment arms was not different, but weight gain was significantly less pronounced in SRL in de novo treatment (group 1: 2.8±4.6 vs. 6.2±6.6 kg every 2 years, P=0.020; group 2: 6.1±9.5 vs. 9.6±9.1 kg every 2 years, P<0.001; and group 3: 3.7±7.0 vs. 3.5±6.2 vs. 5.9±9.0 kg every 1 year, P=0.042). In the conversion study, patients lost weight in the SRL arm and gained weight in the CNI arm (-1.0±6.0 vs. +1.0±5.1 kg every 2 years; P<0.001). CONCLUSION: SRL treatment is associated with less weight gain de novo as well as in late conversion.

Tubular von Hippel-Lindau knockout protects against rhabdomyolysis-induced AKI.

Renal hypoxia occurs in AKI of various etiologies, but adaptation to hypoxia, mediated by hypoxia-inducible factor (HIF), is incomplete in these conditions. Preconditional HIF activation protects against renal ischemia-reperfusion injury, yet the mechanisms involved are largely unknown, and HIF-mediated renoprotection has not been examined in other causes of AKI. Here, we show that selective activation of HIF in renal tubules, through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO), protects from rhabdomyolysis-induced AKI. In this model, HIF activation correlated inversely with tubular injury. Specifically, VHL deletion attenuated the increased levels of serum creatinine/urea, caspase-3 protein, and tubular necrosis induced by rhabdomyolysis in wild-type mice. Moreover, HIF activation in nephron segments at risk for injury occurred only in VHL-KO animals. At day 1 after rhabdomyolysis, when tubular injury may be reversible, the HIF-mediated renoprotection in VHL-KO mice was associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal, as demonstrated by quantitative PCR, pathway enrichment analysis, and immunohistochemistry. In conclusion, a HIF-mediated shift toward improved energy supply may protect against acute tubular injury in various forms of AKI.

Pharmacokinetics of aliskiren in patients with end-stage renal disease undergoing haemodialysis.

BACKGROUND AND OBJECTIVES: Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis. METHODS: Six ESRD patients and six matched healthy volunteers were enrolled in an open-label, parallel-group, single-sequence study. The ESRD patients underwent two treatment periods where 300 mg of aliskiren was administered 48 or 1 h before a standardized haemodialysis session (4 h, 1.4 m(2) high-flux filter, blood flow 300 mL/min, dialysate flow 500 mL/min). Washout was >10 days between both periods. Blood and dialysis samples were taken for up to 96 h postdose to determine aliskiren concentrations. RESULTS: Compared with the healthy subjects (1681 ± 1034 ng·h/mL), the area under the plasma concentration-time curve (AUC) from time zero to infinity was 61% (haemodialysis at 48 h) and 41% (haemodialysis at 1 h) higher in ESRD patients receiving single-dose aliskiren 300 mg. The maximum (peak) plasma drug concentration (481 ± 497 ng/mL in healthy subjects) was 17% higher (haemodialysis at 48 h) and 16% lower (haemodialysis at 1 h). In both treatment periods, dialysis clearance was below 2% of oral clearance and the mean fraction eliminated from circulation was 10 and 12% in period 1 and 2, respectively. Drug AUCs were similar in ESRD patients receiving aliskiren 1 or 48 h before dialysis. No severe adverse events occurred. CONCLUSION: The exposure of aliskiren is moderately higher in ESRD patients. Only a minor portion is removed by a typical haemodialysis session. Aliskiren exposure is not significantly affected by intermittent haemodialysis, suggesting that no dose adjustment is necessary in this population.

An evaluation of sirolimus in renal transplantation.

INTRODUCTION: Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs. AREAS COVERED: The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role. EXPERT OPINION: Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit.

Impact of biological gender and soluble guanylate cyclase stimulation on renal recovery after relief of unilateral ureteral obstruction.

PURPOSE: Gender difference and nitric oxide deficiency contribute to the progression of many chronic kidney diseases. In a model of unilateral ureteral obstruction relief we analyzed the impact of biological gender and nitric oxide/cyclic guanosine monophosphate signaling stimulation on renal disease severity and restoration. MATERIALS AND METHODS: Female and male rats underwent sham surgery or unilateral ureteral obstruction. After 5-day unilateral ureteral obstruction female and male rats were assigned to obstruction relief alone or obstruction relief plus 7-day treatment with the soluble guanylate cyclase stimulator BAY 41-8543. RESULTS: Compared to male rats with obstruction relief renal disease was less severe in female rats, which had significantly less tubulointerstitial matrix accumulation and tubular atrophy. In each gender group α1 and ß1-soluble guanylate cyclase was comparably and significantly increased but female rats produced significantly more cyclic guanosine monophosphate after treatment with the soluble guanylate cyclase stimulator. In each group BAY 41-8543 treatment was associated with significant amelioration of renal matrix protein expansion, macrophage infiltration, tubular apoptosis and atrophy. CONCLUSIONS: Female gender is protective for unilateral ureteral obstruction relief. This was linked to higher sensitivity of the soluble guanylate cyclase enzyme and cyclic guanosine monophosphate production in response to BAY 41-8543. In these female and male rats enhancing the signaling of nitric oxide/cyclic guanosine monophosphate with BAY 41-8543 significantly accelerated the restoration of renal architecture after obstruction relief and largely ameliorated the differences in disease severity due to the gender disparity.

Weight gain in long-term survivors of kidney or liver transplantation--another paradigm of sarcopenic obesity?

OBJECTIVE: Obesity in transplant recipients is a frequent phenomenon but data from body composition analyses in long-term survivors are limited. Body composition and energy metabolism were studied in patients after liver (LTX) and kidney (KTX) transplantation and patients with liver cirrhosis (LCI) or on chronic hemodialysis (HD) and compared to healthy controls. METHODS: In 42 patients 50.0 mo (median; range 17.1-100.6) after LTX and 30 patients 93.0 mo (31.2-180.1) after KTX as wells as in LCI (n = 39) or HD (n = 10) patients mid-arm muscle and fat area, body cell mass, and phase angle (bioimpedance analysis), and resting energy expenditure (indirect calorimetry, REE(CALO)) were measured. RESULTS: Obesity was more prevalent in LTX (17%) than LCI (3%) and in KTX (27%) than in HD (10%). In LTX and KTX, phase angle was higher than in end-stage disease (LTX 5.6° [4.1-7.2] versus LCI 4.4° [2.9-7.3], P < 0.001; KTX 5.9° [4.4-8.7] versus HD 4.3° [2.9-6.8]) but was lower in all patient groups than in controls (7.1°; 4.6-8.9; P < 0.001). In LCI and HD REE(CALO) was higher than predicted, while in LTX and KTX REE(CALO) was not different from predicted REE. CONCLUSIONS: Despite excellent graft function, many long-term LTX or KTX survivors exhibit a phenotype of sarcopenic obesity with increased fat but low muscle mass. This abnormal body composition is observed despite normalization of the hypermetabolism found in chronic disease and cannot be explained by overeating. The role of appropriate nutrition and physiotherapy after transplantation merits further investigation.

Immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix(®)) in renal transplant recipients.

BACKGROUND: In the course of the influenza A H1N1 pandemic, transplanted patients were recommended to receive vaccination. In the present study, we evaluated the immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix®) in renal allograft recipients. METHODS: Sixty patients and 22 healthy controls participated in a prospective observational study and received a single dose of Pandemrix®. H1N1 antibody titres as well as anti-HLA antibodies were determined before and after vaccination. In 19 patients, a booster vaccination was performed and the outcome of all vaccinated renal allograft recipients (n = 107) in our clinic was reviewed. RESULTS: Two out of sixty patients had an elevated influenza A H1N1 titre before vaccination. Of the remaining 58 patients, only 20/58 (34.5%) developed a protective immune response in contrast to 20/22 (91%) of the control group. After booster vaccination, a protective titre was present in 8/19 (42%) of patients. Of the 107 patients, 6 (5.6%) developed new donor-specific HLA antibodies after vaccination. CONCLUSIONS: These data suggest that Pandemrix® does not provide a protective immune response in the majority of kidney transplant recipients. Therefore, for new vaccines, efficacy as well as safety profiles should be evaluated in this subgroup of patients.

Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies).

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Pretransplant cardiovascular evaluation and posttransplant cardiovascular risk.

Modern immunosuppression has expanded access to kidney transplantation by limiting the risk of rejection. However, cardiovascular disease (CVD) remains the principal cause of death with a functioning graft, threatening the long-term survival of transplant recipients. The article reviews the leading risk factors for cardiovascular morbidity both before and after kidney transplantation. Evidence linking poor renal function to CVD is discussed. The function of immunosuppression in exacerbating the risk of both nephrotoxicity and CVD is explored through means of a clinical case study. Underlying kidney disease, hypertension, hyperlipidemia, and diabetes are recognized risk factors for CVD both before and after kidney transplantation. Worsening kidney function and posttransplant immunosuppression exacerbate the risk. Although underlying medical conditions and demographic factors are not easily modifiable, immunosuppression has been recognized as a suitable target. Multiple risk factors converge to increase the risk of cardiovascular events and cardiovascular mortality after kidney transplantation. Clinicians are charged with isolating and treating modifiable risk factors to reduce the risk to long-term survival.

Enteric-coated mycophenolate sodium.

IMPORTANCE OF THE FIELD: Mycophenolic acid (MPA) therapy is a fundamental component of most post-transplant immunosuppressive regimens. Side effects, however, are common and frequently necessitate dose reductions or discontinuations. AREAS COVERED IN THIS REVIEW: Enteric-coated mycophenolate sodium (EC-MPS) is designed to improve the gastrointestinal (GI) tolerability of MPA. This review assesses the pharmacology, efficacy and safety of EC-MPS. WHAT THE READER WILL GAIN: An understanding of the use of EC-MPS in solid organ transplantation and the key trials examining the GI impact of EC-MPS versus the immediate-release mycophenolate mofetil (MMF) formulation. The article also addresses the possible impact of proton pump inhibitor therapy, and the optimal MPA dose with different concomitant immunosuppressants. TAKE HOME MESSAGE: Evidence from blinded trials using standard reporting measures or patient-reported outcomes has not confirmed a significant improvement in the GI symptom burden using EC-MPS. Several open-label studies, however, have consistently shown an improvement in GI tolerability with EC-MPS, which can permit restoration of the optimal MPA dose. EC-MPS has equal efficacy and possibly a different tolerability profile to MMF, thus offering a choice to physicians and their patients, particularly those experiencing MMF-related GI symptoms, diabetic patients or those in whom an MPA dose reduction is required.

The 'blood group O problem' in kidney transplantation--time to change?

BACKGROUND: Patients with blood group O have disadvantages in the allocation of deceased donor organs in the Eurotransplant Kidney Allocation System and fewer ABO-compatible living donors. In order to investigate the consequences of this dilemma, we analysed the outcome of patients with blood group O in our transplantation programme. METHODS: A single-centre analysis of 1186 waitlisted patients for first deceased donor kidney transplantations between 1996 and 2008 was performed, and the mechanisms of blood group-dependent differences for graft and recipient outcome were assessed. RESULTS: Median follow-up time until death or end of observation for all waitlisted patients was 66 months (range, 0-158 months) and for 589 recipients of a kidney graft was 61 months (range, 0-158 months). Patients with blood group O had significantly longer waiting times for deceased donor kidney grafts, compared to non-group O recipients (median waiting time, 85 vs 59 months). As a consequence, blood group O patients had an increased risk for death without transplantation (13.1% for O patients vs 9.6% for non-O patients; P < 0.05). Despite a good human leukocyte antigen match, graft outcome tended to be worse in O recipients; 14.1% (95% CI, 8.2-19.9%) of all O kidneys from deceased donors were transplanted into non-O recipients, leading to the accumulation of O recipients on the waiting list. CONCLUSIONS: The export of blood group O donor kidneys to other blood groups leads to longer waiting times, to a higher death rate and to accumulation of blood group O patients on the waiting list, which will further aggravate the problem in the future. Our results should prompt further research on the issues associated with blood group O. Current allocation systems and living donor kidney exchange programmes should be re-evaluated to address this problem.

Does endothelin B receptor deficiency ameliorate the induction of peritoneal fibrosis in experimental peritoneal dialysis?

BACKGROUND: Peritoneal fibrosis is a serious complication of peritoneal dialysis (PD); however, the mechanisms are poorly understood. The endothelin system exhibits potent pro-fibrotic properties and is known to be stimulated in peritoneal fibrosis. Thus, our study aimed at elucidating the impact of the endothelin B (ETB) receptor on peritoneal membrane thickening by means of an ETB-deficient rat model (ETB(-)(/)(-)) in experimental PD. METHODS: Wild-type (WT) and ETB(-/-) rats were randomly allocated to four groups (each group n = 10): (i) WT Sham, (ii) WT PD, (iii) ETB(-/-) Sham and (iv) ETB(-/-) PD. All animals underwent surgical implantation of a port for intraperitoneal administration and 1 week of habituation to the procedure by administration of 2 ml of saline once daily. Afterwards, all animals were switched to 12 weeks of 15 ml of saline (Sham groups) or commercially available PD fluid containing 3.86% glucose (PD groups) administered twice daily. Afterwards, animals were sacrificed, and samples from visceral as well as parietal peritoneum were obtained. The samples were stained with Sirius-Red, and at 10 different sites per sample, peritoneal membrane thickness was measured using computer-aided histomorphometry devices. RESULTS: Mean peritoneal membrane thickness was increased by PD in both WT and ETB(-/-) rats versus respective Sham controls (WT Sham: 22.3 +/- 0.7 microm/ETB Sham: 22.3 +/- 0.9 microm versus WT PD: 26.5 +/- 1.5 microm/ETB PD: 28.7 +/- 1.2 microm; P < 0.05, respectively). However, no difference in peritoneal membrane thickness was detected between WT PD and ETB(-/-) PD groups. CONCLUSION: Our study demonstrates that PD increases peritoneal membrane thickness in a rat model, but deficiency of the ETB receptor has no detectable impact on this process.