Tacrolimus, Mycophenolate Mofetil, and Low-Dose Steroids With or Without Interleukin-2 Receptor Antibody Induction Therapy: A Retrospective Cohort Analysis.

BACKGROUND: Selective interleukin-2 receptor (IL2R) blockade is one option to decrease acute rejection rates in kidney transplant recipients. However, there are little data on the impact of basiliximab in a triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and low-dose steroids). Thus, this analysis aims at investigating the impact of basiliximab induction on rejection rates and immediate graft function following kidney transplantation. METHODS: Basiliximab was introduced in our center according to our center's policy in the beginning of 2011. Patients who received basiliximab (n = 83) were compared with patients without induction therapy (n = 65) transplanted before the introduction of IL2R antibody induction. RESULTS: The use of basiliximab as induction therapy decreased the incidence of biopsy-proven acute rejection (BPAR) within the 1st year after transplantation (21.5% vs 14.5%; P = .283). Overall rejection episodes (including BPAR and borderline rejection) were significantly reduced in patients with basiliximab compared with patients without (41.5% vs 24.1%; P = .033). However, graft function (incidence of delayed graft function, primary nonfunction, slow graft function, and serum creatinine decline) and overall outcome (patient and graft survivals) were similar in both groups. CONCLUSIONS: We found a favorable impact of basiliximab induction therapy on early acute rejection rate. The impact on long-term outcome must be addressed in further randomized controlled trials.

Assessing the TP53 marker type in patients treated with or without neoadjuvant chemotherapy for resectable colorectal liver metastases: a p53 Research Group study.

The type of a biomarker - whether it is prognostic or predictive - is frequently not known, although such information is crucial for assessing the clinical value of a marker. In order to evaluate the type of marker TP53 is, we identified a cohort of 76 patients with colorectal liver metastases (CLM), homogeneously staged as resectable, who had been treated either with or without fluorouracil-based neoadjuvant chemotherapy. The TP53 genotype was assessed retrospectively from paraffin-embedded, diagnostic tumour biopsies using a standardised, p53 gene-specific sequencing protocol (mark53(®) kit). The overall median survival was 44.2 months, and the overall TP53 mutation frequency was 55%. A significant interaction was observed between chemotherapy and TP53 status (P = 0.045). To illustrate this effect, the 51 patients with and the 25 patients without neoadjuvant chemotherapy were described separately. In patients with neoadjuvant chemotherapy, mutated TP53 was significantly associated with poor survival (P = 0.0025), resulting in five-year survival rates of 22%, compared to 60% in patients with normal TP53. The hazard ratio was 3.12 (95% confidence intervals (CI): 1.46-6.95) to the disadvantage of TP53-mutated patients and 5.49 (P = 0.0001; 95% CI: 2.28-13.24) after adjustment for known prognostic factors. In patients treated with surgery alone, a mutated TP53 did not have a negative effect on survival (P = 0.54). A mutated TP53 status independently predicted survival disadvantage in CLM patients in the presence, but not in the absence, of neoadjuvant chemotherapy. Our data suggest that TP53 might be a pure predictive marker.

Fasting and postprandial liver glycogen content in patients with type 1 diabetes mellitus after successful pancreas-kidney transplantation with systemic venous insulin delivery.

BACKGROUND: In patients with type 1 diabetes mellitus (T1DM), insulin is usually replaced systemically (subcutaneously) and not via the physiological portal route. According to previous studies, the liver's capacity to store glycogen is reduced in T1DM patients, but it remains unclear whether this is due to hyperglycaemia, or whether the route of insulin supply could contribute to this phenomenon. T1DM patients after successful pancreas-kidney transplantation with systemic venous drainage (T1DM-PKT) represent a suitable human model to further investigate this question, because they are normoglycaemic, but their liver receives insulin from the pancreas transplant via the systemic route. MATERIALS AND METHODS: In nine T1DM-PKT, nine controls without diabetes (CON) and seven patients with T1DM (T1DM), liver glycogen content was measured at fasting and after two standardized meals employing (13) C-nuclear-magnetic-resonance-spectroscopy. Circulating glucose and glucoregulatory hormones were measured repeatedly throughout the study day. RESULTS: The mean and fasting concentrations of peripheral plasma glucose, insulin, glucagon and C-peptide were comparable between T1DM-PKT and CON, whereas T1DM were hyperglycaemic and hyperinsulinaemic (P < 0·05 vs T1DM-PKT and CON). Total liver glycogen content at fasting and after breakfast did not differ in the three groups. After lunch, T1DM-PKT and T1DM had a 14% and 21% lower total liver glycogen content than CON (P < 0·02). CONCLUSION: In spite of normalized glycaemic control, postprandial liver glycogen content was reduced in T1DM-PKT with systemic venous drainage. Thus, not even optimized systemic insulin substitution is able to resolve the defect in postprandial liver glycogen storage seen in T1DM patients.

Long-term exposure to belatacept in recipients of extended criteria donor kidneys.

Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein-Barr virus (EBV(-)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m(2) . Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time.

Value of routine voiding cystourethrography after renal transplantation.

The impact of vesicoureteral reflux (VUR) on renal allograft outcomes is debatable, with small cohort studies reporting controversial results. The objective of this retrospective study was to evaluate long-term clinical effects of early VUR in a large cohort of kidney transplant patients. Posttransplantation voiding cystourethrography was used to evaluate 646 consecutive kidney transplant recipients before discharge. The study endpoints included VUR grade, death-censored graft or patient survival, renal function, proteinuria and occurrence of urinary tract infections (UTIs). Of the 646 recipients, 263 (40.7%) were diagnosed with VUR. VUR grade II was most common (19.8%), followed by grades III (10.2%), I (7.9%) and IV (2.8%). VUR was less common in transplantations performed by experienced compared to inexperienced surgeons (36% vs. 48%; p = 0.004). VUR did not affect death-censored graft or patient survival and was not associated with proteinuria or occurrence of UTIs. Patients with VUR had a lower eGFR at 1 year after transplantation than did patients without VUR (60 vs. 52 mL/min/1.73 m(2) ; p = 0.02), although this difference was not observed at 3 and 5 years after transplantation. We conclude that early VUR, a common finding among renal transplant patients, may not have a meaningful impact on long-term transplant outcomes.

Simultaneous pancreas-kidney transplantation nine years after liver transplantation--a case report.

In this case report we have described a patient suffering from sclerosing cholangitis, diabetes mellitus type I, and consequent end-stage renal disease who was successfully treated with simultaneous pancreas and kidney transplantation 9 years after orthotopic liver transplantation.

Peritransplant immunoadsorption for positive crossmatch deceased donor kidney transplantation.

Various desensitization protocols were shown to enable successful living donor kidney transplantation across a positive complement-dependent cytotoxicity crossmatch (CDCXM). Positive crossmatch transplantation, however, is less well established for deceased donor transplantation. We report a cohort of 68 deceased donor renal allograft recipients who, on the basis of broad sensitization (lymphocytotoxic panel reactivity ≥40%), were subjected to a protocol of peritransplant immunoadsorption (IA). Treatment consisted of a single session of immediate pretransplant IA (protein A) followed by posttransplant IA and antilymphocyte antibody therapy. Twenty-one patients had a positive CDCXM, which could be rendered negative by pretransplant apheresis. Solid phase HLA antibody detection revealed preformed donor-specific antibodies (DSA) in all 21 CDCXM-positive and in 30 CDCXM-negative recipients. At 5 years, overall graft survival, death-censored graft survival and patient survival were 63%, 76% and 87%, respectively, without any differences between CDCXM-positive, CDCXM-negative/DSA-positive and CDCXM-negative/DSA-negative recipients. Furthermore, groups did not differ regarding rates of antibody-mediated rejection (24% vs. 30% vs. 24%, p = 0.84), cellular rejection (14% vs. 23% vs. 18%, p = 0.7) or allograft function (median 5-year serum creatinine: 1.3 vs. 1.8 vs. 1.7 mg/dL, p = 0.62). Our results suggest that peritransplant IA is an effective strategy for rapid desensitization in deceased donor transplantation.

Outcome of hepaticojejunostomy for biliary tract obstruction following liver transplantation.

BACKGROUND: Strictures and concrements are the most common biliary complications following liver transplantation. Endoscopic treatment might not lead to a definitive cure in all patients, especially in strictures involving the biliary bifurcation. The aim of this study was to determine the efficacy and the long-term outcome of hepaticojejunostomy (HJS) for post-transplant biliary tract obstruction. MATERIAL AND METHODS: Thirty-seven patients were retrospectively studied for resolving of cholestasis and the incidence of recurring biliary obstruction. RESULTS: Surgery was performed because of anastomotic strictures in 11, ischemic strictures at the donor common bile duct in seven, strictures involving the bile duct bifurcation in 10, hepatolithiasis without strictures in one and biliary cast formation diagnosed by endoscopic retrograde cholangiography or T-tube cholangiography in eight patients. Cholestasis instantly improved in 82% of the patients. After a long-term follow-up of median 33 months (range 3-149), 28 of the patients (76%) required no further intervention for recurring biliary obstruction following HJS. Anastomotic strictures were observed in six (16%), recurring biliary concrements in two patients (5%). CONCLUSION: HJS did prevent recurrent biliary obstruction in the majority of the patients. We therefore recommend early HJS for complicated post-transplant biliary tract obstruction not treatable by a limited number of endoscopic interventions.

Short-term effects of high-dose zoledronic acid treatment on bone mineralization density distribution after orthotopic liver transplantation.

Patients with "hepatic" bone disease exhibit increased fracture incidence. The effects on bone material properties, their changes due to orthotopic liver transplantation (OLT), as well as zolendronate (ZOL) treatment have not yet been investigated. We studied bone mineralization density distribution (BMDD) in paired transiliacal biopsies (at and 6 months after OLT) from patients (control CON n = 18, treatment group ZOL n = 21, the latter treated with i.v. ZOL at doses of 4 mg/month) for how bone at the material level was affected by the "hepatic" disease in general, as well as by OLT and ZOL in particular. (1) BMDD parameters at baseline reflected disturbed bone matrix mineralization in "hepatic" bone disease combined with low turnover. Trabecular bone displayed a decrease in mean and most frequent calcium concentration (Ca(MEAN) -2.9% and Ca(PEAK) -2.8%, respectively; both P < 0.001), increased heterogeneity of mineralization (Ca(WIDTH) +12.2%, P = 0.01), and increased percentage of bone areas with low mineralization (Ca(LOW) +32.4%, P = 0.02) compared to normal; however, there were no differences compared to cortical bone. (2) Six months after OLT, ZOL-treated trabecular bone displayed reduced Ca(LOW) (-32.0%, P = 0.047), cortical bone increased Ca(MEAN) (+4.2%, P = 0.009), increased Ca(PEAK) (+3.3%, P = 0.040), and decreased Ca(LOW) (-55.7, P = 0.038) compared to CON and increased Ca(MEAN) compared to baseline (+1.9, P = 0.032) without any signs of hyper- or defective mineralization. These changes as consequence of the antiresorptive action of ZOL visible already after 6 months result in beneficial effects on bone matrix mineralization, likely contributing to the significant decrease in fracture incidence observed in these patients 2 years post transplantation.

Prophylactic bisphosphonate treatment prevents bone fractures after liver transplantation.

A randomized controlled prospective open-label single center trial was performed. At the time of transplantation patients were randomly assigned to one of two treatment arms: The study group of 47 patients received zoledronic acid (ZOL, 8 infusions at 4 mg during the first 12 months after LT), calcium (1000 mg/d) and vitamin D (800 IE/d). The control group consisted of 49 patients who received calcium and vitamin D at same doses (CON). The incidence of bone fractures or death was predefined as the primary endpoint. Secondary endpoints included bone mineral density (BMD), serum biochemical markers of bone metabolism, parameters of trabecular bone histomorphometry and mineralization density distribution (BMDD). Patients were followed up for 24 months. Analysis was performed on an intention-to-treat basis. The primary endpoint fracture or death was reached in 26% of patients in the ZOL group and 46% in the CON group (p = 0.047, log rank test). Densitometry results were different between the groups at the femoral neck at 6 months after LT (mean+/-SD BMD ZOL: 0.80 +/- 0.19 g/cm2 vs. CON: 0.73 +/- 0.14 g/cm2, p = 0.036). Mixed linear models of biochemical bone markers showed less increase of osteocalcin in the ZOL group and histomorphometry and BMDD indicated a reduction in bone turnover. Prophylactic treatment with the bisphosphonate zoledronic acid reduces bone turnover and fractures after liver transplantation.