Reduction of Extended‐Release Tacrolimus Dose in Low‐Immunological‐Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor‐Specific Antibodies: A Randomized Study

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended‐release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid‐free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C₀) >3 μg/L; group B had no change in TacER dose (TacER C₀ 7–12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent‐to‐treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C₀ was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti‐HLA donor‐specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C₀ should be maintained >7 μg/L during the first year after transplantation in low‐immunological‐risk, steroid‐free KTRs receiving a moderate dose of mycophenolic acid.     

Long‐term follow‐up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin

Cholongitas E, Shusang V, Germani G, Tsochatzis E, Raimondo ML, Marelli L, Senzolo M, Davidson BR, Patch D, Rolles K, Burroughs AK. Long‐term follow‐up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin.
Clin Transplant 2011: 25: 614–624. © 2010 John Wiley & Sons A/S. Abstract: Background: Early withdrawal of steroids after liver transplantation has benefits, but rarely is total avoidance of steroids used. We evaluated long‐term results of patients with ab initio monotherapy with cyclosporin (CYA) vs. tacrolimus (TAC), in randomized and cohort studies. Methods: We evaluated long‐term outcomes in 66 adults randomized to TAC or CYA and 94 subsequent patients who received TAC. Protocol liver biopsies were performed. Rejection was treated with three 1 g/d methylprednisolone. Further rejection after two courses of methylprednisolone was defined as monotherapy failure. Results: Actuarial five‐yr survival was 68% in TAC and 70% CYA. Monotherapy failed in 8% TAC and 13% CYA patients; no rejection in 24% TAC and 19% CYA patients; 42% TAC and 33% CYA patients were not exposed to any steroids. Rejection episodes were less with TAC, compared to CYA: mean 1.8 vs. 2.5, p = 0.042. Chronic rejection occurred in only 4 (11%) CYA patients. During follow‐up of median 97 months (range: 0.06–145), there were 16 (44%) deaths in CYA and 48 (39%) in TAC patients (p > 0.05). Conclusions: TAC monotherapy ab initio is a viable immunosuppressive strategy in liver transplantation and was associated with lower rejection rates and renal complications, compared to CYA.     

Selecting an optimal cutoff value for creatinine in the model for end‐stage liver disease equation

Huo T‐I, Hsu C‐Y, Lin H‐C, Lee P‐C, Lee J‐Y, Lee F‐Y, Hou M‐C, Lee S‐D. Selecting an optimal cutoff value for creatinine in the model for end‐stage liver disease equation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01099.x.
© 2009 John Wiley & Sons A/S. Abstract: Background: The model for end‐stage liver disease (MELD) is used for organ allocation in liver transplantation. The maximal serum creatinine (Cr) level for MELD is set at 4.0 mg/dL; however, there was no outcome data to justify this strategy. Methods: Ninety‐two patients with cirrhosis with Cr level >4 mg/dL were selected from 1438 patients and compared with MELD score‐matched controls for three‐month and six‐month mortality. Results: At three months, patients with Cr level >4 mg/dL had a significantly higher mortality rate than the 184 controls with a lower Cr level (44.6% vs. 29.3%, p = 0.015). This trend was still significant at six months: the mortality rate was 62% in the index group vs. 45.1% in the control group (p = 0.011). The difference between the index and control groups was the smallest (2.5% at three months and 3.4% at six months) when Cr was up‐scaled to 5.5 mg/dL. The predictive accuracy of the MELD was estimated by using area under receiver‐operating characteristic (AUC) curve. Only the cutoff of 5.5 mg/dL at six months displayed a higher AUC (0.753). Conclusions: A cutoff at 5.5 mg/dL may be more appropriate for the MELD. The MELD for patients with cirrhosis with advanced renal insufficiency deserves re‐evaluation.     

Clinical pharmacokinetics of tacrolimus in heart transplantation: new strategies of monitoring

The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart transplant patients in order to find the best sampling time to predict the total exposure and to explore the target range for optimal clinical immunosuppression. Twenty-five full pharmacokinetic studies were performed in 22 heart transplant patients (11 men and 7 women) at less than 1 year posttransplant. The immunosuppressive treatment was steroids plus azathioprine or mycophenolate mofetil and TAC. The mean age was 55 years (36-64 years) and the mean weight 70.49 kg (50-111 kg). After three days of receiving the same dose, eight blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 12 hours postmorning dose. TAC concentrations were measured by microparticle enzyme immunoassay (IMx). Area under the concentration-time curve(AUC(0-12)) was calculated by the trapezoidal rule. Using 0-4 hours TAC blood concentrations, a projected 12 hours AUC (extrapolated AUC(0-4)) was calculated assuming C0 and C12 were comparable. A high interpatient TAC pharmacokinetics variability that was greater during the absorption phase was observed. A Cmax (30.5+/-13.8 ng/mL) was reached at 2.3+/-1.5 h. When target trough levels were achieved (10-20 ng/mL), the mean tacrolimus exposure was 230.6+/-59.2 ng h/mL (120.14-327.7) (n=19). Correlation between AUC(0-12) and C0 was relatively good (r2=0.74). Between individual time points, C4 showed the best correlation (r2=0.88). In any case the best strategy to monitor is to obtain the extrapolated AUC(0-4) (r2=0.98), as a good approach to patients with a poor response to treatment.     

Efficacy and safety of bleselumab in kidney transplant recipients: A phase 2, randomized,open‐label,noninferiority study

This study assessed the efficacy and safety of the anti‐CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate‐release tacrolimus [IR‐TAC]; target minimum blood concentration [C_trough] 4‐11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR‐TAC (0.1 mg/kg per day; target C_trough 4‐11 ng/mL days 0‐30, then 2‐5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3‐5 posttransplant) and corticosteroids. One hundred thirty‐eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR‐TAC [n = 44]). For the primary endpoint (incidence of biopsy‐proven acute rejection [BPAR] at 6 months), bleselumab + IR‐TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] ?8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%‐46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR‐TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit–risk ratio. Most treatment‐emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).     

Detection rate and factors predictive the presence of prostate cancer in patients undergoing ultrasonography‐guided transperineal saturation biopsies of the prostate

Study Type – Diagnostic (case series)
Level of Evidence 4

OBJECTIVES

To assess the prostate cancer detection rate and predictive factors for prostate cancer after transrectal ultrasonography (TRUS)‐guided transperineal saturation re‐biopsies of the prostate, using a 24‐core scheme.

PATIENTS AND METHODS

We evaluated 143 consecutive patients undergoing TRUS‐guided transperineal saturation re‐biopsy of the prostate using a 24‐core scheme. The inclusion criteria were a previous negative biopsy and a prostate‐specific antigen (PSA) level of ≥10.0 ng/mL, or of 4.0–10.0 ng/mL with a free/total ratio of <20% or an abnormal digital rectal examination or previous high‐grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP).

RESULTS

The mean (sd ) age of the patients was 66.5 (6.1) years and the median (interquartile range) PSA level was 9.0 (6.1–12.8) ng/mL. The number of previous biopsies was one in 59% of patients, two in 26% and three or more in 15%. We detected prostate cancer in 26%, ASAP in 5.6% and HGPIN in 2.1%. The cancer detection rate was 47%, 25.5% and 14% for prostate volumes of <40, 40–60 and ≥60 mL, respectively (P = 0.002). On a multivariate analysis the total prostate volume (40–60 vs <40 mL, hazard ratio 5.683; >60 vs <40 mL, hazard ratio 6.965; P = 0.01) was the only significant predictor of prostate cancer at saturation biopsy.

CONCLUSIONS

TRUS‐guided transperineal saturation re‐biopsy of the prostate using a 24‐core scheme resulted in a high cancer detection rate also in patients who had had two or more previous biopsies. The total prostate volume was the only predictor of prostate cancer.     

A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients

The improved pharmacokinetics of Neoral allows the development of an accurate estimate of the full area under the concentration time curve (AUC) from a limited sampling strategy. As no such strategy has been derived from pharmacokinetic data obtained from children on 12-hourly dosing, and as patient convenience demands shorter sampling times, we derived a limited sampling strategy from 45 AUCs obtained from 19 pediatric renal transplant patients by stepwise forward multiple regression, and prospectively tested them on a separate group of 49 AUCs obtained from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained based on the formula: AUC = 444 + 3.69 × C0 + 1.77 × C2 + 4.1 × C4 (mean prediction error ± SD = 0.3 ± 6.4%, 95% confidence interval=–1.7% to 1.9%.) In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly Neoral dosing can be reliably predicted by an early time point-based limited sampling strategy in children. This formula has the advantage of obtaining trough as well as AUC from one brief, convenient sampling period. Received: 7 August 1998 / Revised: 23 November 1998 / Accepted: 25 November 1998     

Massive ascites after living donor liver transplantation with a right lobe graft larger than 0.8% of the recipient’s body weight

Shirouzu Y, Ohya Y, Suda H, Asonuma K, Inomata Y. Massive ascites after living donor liver transplantation with a right lobe graft larger than 0.8% of the recipient’s body weight.
Clin Transplant 2010: 24: 520–527.
© 2009 John Wiley & Sons A/S. Abstract: Background: There are only limited data on post‐transplant ascites unrelated to small‐sized grafts in living donor liver transplantation (LDLT). Methods: The subjects were 59 adult patients who had received right lobe LDLT with a graft weight‐to‐recipient weight ratio (GRWR) > 0.8%. Patients were divided into either Group 1 (n = 14, massive ascites, defined as the production of ascitic fluid > 1000 mL/d that lasted longer than 14 d after LDLT) or Group 2 (n = 45, no development of massive ascites). Patients were followed for a median period of 3.0 yr (range, 0.5–7.5 yr). Results: Group 1 had both higher Model for End‐Stage Liver Disease score and Child‐Pugh score than Group 2. Portal venous flow volume just after reperfusion was significantly greater in Group 1 than Group 2 (307.8 ± 268.8 vs. 176.2 ± 75.0 mL/min/100 g graft weight, respectively; p < 0.05). Post‐transplant infectious complications including ascites infection developed more frequently within the first post‐transplant month in Group 1. Massive ascites was significantly associated with early graft loss (p < 0.05). Conclusion: Post‐transplant massive ascites associated with portal over‐perfusion into the graft liver can develop in patients with a GRWR over 0.8%. Recipients with post‐transplant massive ascites require careful management to prevent infection.     

Efficacy,safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice‐daily tacrolimus‐based regimen to once‐daily tacrolimus extended‐release formulation

The aim of this study was to determine the efficacy, safety, and immunosuppressant adherence in 125 stable liver transplant (LT) patients converted from twice‐daily tacrolimus (TAC BID) to once‐daily TAC (TAC OD). Tacrolimus trough levels, laboratory parameters, metabolic disorders, selected patient reported outcomes, and adverse events were assessed. Mean TAC trough level concentration was 6.1 ± 2.3 ng/ml at study entry, decreased to 5.5 ± 2.1 ng/ml (P = 0.016) and 5.5 ± 2.2 ng/ml (P = 0.019) after 1 and 2 weeks, respectively, and tended to equal the baseline value during further follow‐up. At week 1, TAC concentrations were lower in 62.4% of patients and higher in 36.0% when compared with baseline. Renal and cardiovascular risk factors remained stable and no rejection episodes occurred over 12 months. Adverse events were consistent with the safety profile known from previous studies with TAC BID. Nonadherence measured by the “Basel Assessment of Adherence Scale to Immunosuppressives” was evident in 66.4% at study entry and decreased to 30.9% postconversion (P < 0.0001). Prevalence of nonadherence at baseline was significantly higher in patients converted >2 years after LT and in those ≤60 years of age. Conversion to TAC OD is safe, enhances immunosuppressant adherence and should be accompanied by a close TAC level monitoring during the initial period.     

Therapeutic drug monitoring of tacrolimus in cardiac transplant recipients: a comparison with cyclosporine neoral

This study compares the pharmacokinetics of tacrolimus (TAC) and cyclosporine Neoral (CsA) in cardiac transplant recipients. METHODS: Twenty-six de novo cardiac recipients were prospectively and randomly assigned to receive oral TAC- or CsA-based regimens after 5 to 6 days of rabbit antithymocyte globulin induction. Blood samples were collected at 0 (before the dose) and 0.5, 1, 2, 3, 4, 6, 8, 10, as well as 12 hours after drug administration. The pharmacokinetics of the first dose (PK-1) and at steady state (PK-S, 1 month after transplantation) were analyzed. RESULTS: Comparing the AUC per milligram dose, there was no significant difference between PK-1 and PK-S among TAC (46.0 +/- 24.3 ng x h/mg x mL versus 69.0 +/- 43.9 ng x h/mg x mL, P = .15 by paired t-test), but a significant difference in CsA (25.2 +/- 11.4 ng x h/mg x mL versus 45.4 +/- 12.9 ng x h/mg x mL, P = .0005 by paired t-test). This means better TAC absorption in the early post-heart transplant period. Using a single-point blood level to predict AUC, TAC showed a significantly higher correlation than CsA at all corresponding sampling times. Besides, C12 in both PK-1 and PK-S of TAC displayed good correlations to the AUC (r2 = .895, P = .00 in PK-1 and r2 = .81, P = .00 in PK-S). The TAC trough level was accurate enough to predict the AUC. CONCLUSION: The pharmacokinetic profile of TAC is more reliable than that of CsA in the early post-heart transplant period. A high correlation of trough blood levels with AUC omits the requirement for a multiple sampling strategy to more accurately measure AUC as is needed with CsA.     

Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics

Most calcineurin inhibitor (CNI)‐based protocols reduce blood trough goals approximately 2–3 months post‐transplant in clinically stable kidney transplant recipients. The CNI target trough level to prevent rejection, after reduction, is unknown. Using a multivariate Cox proportional hazards model, we determined the association of time‐varying tacrolimus (TAC) trough levels with acute rejection (AR) occurring in the first 6 months post‐transplant, but specifically we assessed this association after 3 months. A total of 1930 patients received TAC‐based immunosuppression prior to AR in a prospective study. Of the 151 (7.8%) who developed AR, 47 developed AR after 3 months post‐transplant. In an adjusted time‐varying multivariate model, each 1 ng/ml decrease in TAC trough levels was associated with a 7.2% increased risk of AR [hazards ratio (HR) = 1.07, 95% confidence interval (CI) (1.01, 1.14) P = 0.03] in the first 6 months. There was an additional 23% increased risk of AR with each 1 ng/ml decrease in the TAC trough levels in months 3–6 [HR = 1.23, 95% CI (1.06, 1.43) P = 0.008]. In conclusion, lower TAC trough levels were significantly associated with increased risk of AR in the first 6 months post‐transplant with additional risk of AR between months 3 and 6 post‐transplant. The timing and practice of TAC dose reduction should be personalized based on the individual's risk factors.     

Hepatic and cardiac iron overload among patients with end‐stage liver disease referred for liver transplantation

O’Glasser AY, Scott DL, Corless CL, Zaman A, Sasaki A, Gopal DV, Rayhill SC, Orloff SL, Ham JM, Rabkin JM, Flora K, Davies CH, Broberg CS, Schwartz JM. Hepatic and cardiac iron overload among patients with end‐stage liver disease referred for liver transplantation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01136.x.
© 2009 John Wiley & Sons A/S. Abstract: Background: Iron overload is associated with fatal cardiovascular events following liver transplantation. Myocardial iron deposits were observed post‐mortem in patients who died of cardiac events after transplantation at our institution. This observation prompted testing to exclude cardiac iron in subsequent transplant candidates. Aims: To assess the results of testing for iron overload in liver transplant candidates at our institution. Methods: Ferritin, TIBC, and serum iron were measured in cirrhotics referred for transplantation. Patients with transferrin saturation ≥50% and ferritin ≥250 ng/mL underwent liver biopsy graded for iron. Patients with 3–4+ hepatic iron deposits underwent HFE mutation analysis and endomyocardial biopsy with iron staining. Results: Eight hundred and fifty‐six patients were evaluated for liver transplantation between January 1997 and March 2005. Two hundred and eighty‐seven patients (34%) had transferrin saturation ≥50% and ferritin ≥250 ng/mL. Patients with markers of iron overload had more advanced liver disease than those with normal iron indices. One hundred and fifty‐three patients underwent liver biopsy. Twenty‐six patients (17%) had 3–4+ hepatic iron staining. One patient was a C282Y heterozygote. Endomyocardial biopsy was performed in 14 patients of whom nine had cardiac iron deposition. Conclusions: Non‐HFE‐related cardiac iron overload can occur in advanced liver disease We therefore recommend screening for cardiac iron prior to liver transplantation.     

Conversion to low-dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy-guided study

Long-term survival of kidney allografts is primarily limited by a progressive decline in function characterized by the presence of interstitial fibrosis (IF) and tubular atrophy (TA) on biopsy. Since chronic calcineurin-inhibitor (CNI) drug toxicity has been implicated as a significant cause of IF/TA, a major effort in transplantation has been to decrease or eliminate CNI therapy. We now report the clinical and histological consequences of converting renal transplant recipients at 3 months to either very low levels of tacrolimus (TAC; 4-6 ng/mL) or sirolimus (SRL; 6-10 ng/mL) therapy. Fifty-eight enrollees in this prospective randomized trial received low-dose (2.9 ± 0.6 mg/kg) rabbit antithymocyte globulin induction followed by standard doses of TAC (10-15 ng/mL), mycophenolic acid, and low-dose steroids for 3 months. Protocol biopsies were performed at implantation and 3 and 12 months. Six patients had evidence of either borderline changes (n = 5) or grade 1A rejection (n = 1) on the 3-month protocol biopsy and were not randomized. Only one patient had clinically evident rejection that occurred after randomization to SRL. One patient in each group had borderline changes at 12 months. Renal function (estimated glomerular filtration rate) was equivalent in both groups at 12 months (TAC 74 ± 15 vs SRL 66 ± 18 mL/min, P = .22). Chronic allograft damage index scores at 1 year were similar in both groups (TAC 2.8 ± 2.4 vs SRL 2.0 ± 2.7, P = .71). The percentage of patients with IF/TA scores greater than 2 at 1 year was low in both groups (TAC 12% vs SRL 9%, P = .78). Therefore, in a low-risk population defined as having a normal 3-month protocol biopsy, TAC levels can be successfully decreased to very low concentrations. One-year graft function and histology were equally well maintained with either low-dose TAC or SRL immunosuppression.     

Neighborhood Poverty and Kidney Transplantation Among US Asians and Pacific Islanders with End‐Stage Renal Disease

The degree to which low transplant rates among Asians and Pacific Islanders in the United States are confounded by poverty and reduced access to care is unknown. We examined the relationship between neighborhood poverty and kidney transplant rates among 22 152 patients initiating dialysis during 1995–2003 within 1800 ZIP codes in California, Hawaii and the US‐Pacific Islands. Asians and whites on dialysis were distributed across the spectrum of poverty, while Pacific Islanders were clustered in the poorest areas. Overall, worsening neighborhood poverty was associated with lower relative rates of transplant (adjusted HR [95% CI] for areas with ≥20% vs. <5% residents living in poverty, 0.41 [0.32–0.53], p < 0.001). At every level of poverty, Asians and Pacific Islanders experienced lower transplant rates compared with whites. The degree of disparity increased with worsening neighborhood poverty (adjusted HR [95% CI] for Asians–Pacific Islanders vs. whites, 0.64 [0.51–0.80], p < 0.001 for areas with <5% and 0.30 [0.21–0.44], p < 0.001 for areas with ≥20% residents living in poverty; race–poverty level interaction, p = 0.039). High levels of neighborhood poverty are associated with lower transplant rates among Asians and Pacific Islanders compared with whites. Our findings call for studies to identify cultural and local barriers to transplant among Asians and Pacific Islanders, particularly those residing in resource‐poor neighborhoods.     

Adequate Early Cyclosporin Exposure is Critical to Prevent Renal Allograft Rejection: Patients Monitored by Absorption Profiling

This study used receiver operating characteristic analysis to investigate the properties of area under the concentration-time curve during the first 4h after cyclosporin-microemulsion dosing (AUC0-4) and cyclosporin (CyA) levels immediately before and at 2 and 3h after dosing (C0, C2 and C3) to predict the risk of biopsy-proven acute rejection (AR) at 6 months. Ninety-eight kidney transplant recipients treated with CyA-microemulsion-based triple therapy immunosuppression were studied on post-transplant days 3, 5, and 7, and at increasing intervals thereafter. The most sensitive and specific predictor of AR was AUC0-4. Of the single time-point measurements, the measurement properties of C2 were closest to those of AUC0-4, and superior to those of C3. The relationship between C0 and subsequent AR was weak and did not reach statistical significance. On day 3, CyA AUC0-4 > or = 4,400 ng.h/mL and C2 > or = 1,700 ng/mL were each associated with a 92% negative predictive value for rejection in the first 6months. Pharmacokinetic measurements on or after day 5, and measurements on day 3 in patients with delayed graft function, were not predictive of AR. Adequate exposure within the first 3days post transplantation may be critically important in preventing subsequent rejection.     

Roux‐en‐Y gastric bypass is an effective bridge to kidney transplantation: Results from a single center

Body mass index (BMI) > 35‐40 kg/m² is often a contraindication, while Roux‐en‐Y gastric bypass (RYGB) is performed to enable kidney transplantation. This single‐center retrospective study evaluated pre‐ and post‐transplant outcomes of 31 morbidly obese patients with end‐stage renal disease having RYGB before kidney transplantation between July 2009 and June 2014. Fourteen RYGB patients were subsequently transplanted. Nineteen recipients not having GB with a BMI ≥ 36 kg/m² at transplantation were used as historical controls. Mean BMI (±SE) before RYGB was 43.5 ± 0.7 kg/m² (range: 35.4‐50.5 kg/m²); 87.1% (27/31) achieved a BMI < 35 kg/m². The percentage having improved diabetes/hypertension control was 29.0% (9/31); 25.8% (8/31) had complications (mostly minor) after RYGB. Among transplanted patients, blacks/Hispanics comprised 78.6% (11/14) and 84.2% (16/19) of RYGB and controls; 57.1% (8/14) and 63.2% (12/19) had a (mostly long‐standing) pretransplant history of diabetes. While biopsy‐proven acute rejection (BPAR) occurred significantly higher among RYGB vs control patients (6/14 vs 3/19, P = .03), patients developing T‐cell BPAR were also significantly more likely to have a tacrolimus (TAC) trough level < 4.0 ng/mL within 3 weeks of T‐cell BPAR (P = .0007). In Cox's model, the impact of having a TAC level < 4.0 ng/mg remained significant (P = .007) while the effect of RYGB was no longer significant (P = .13). Infections, graft, and patient survival were not significantly different. Despite obvious effectiveness in achieving weight loss, RYGB will need more careful post‐transplant monitoring given the observed higher BPAR rate.     

Salvage high‐intensity focused ultrasound for biopsy‐confirmed local recurrence of prostate cancer after radical prostatectomy

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To present experience in high‐intensity focused ultrasound (HIFU) used as a salvage therapy for biopsy‐confirmed local recurrence at the vesico‐urethral anastomosis after radical prostatectomy (RP).

PATIENTS AND METHODS

From July 2006, four patients diagnosed with prostate cancer recurrence after RP were treated with HIFU, with or without salvage radiotherapy, using the Sonablate® 500 (Focus Surgery, IN, USA). Biochemical failure was defined as in increase in prostate‐specific antigen (PSA) level of >0.2 ng/mL. No patients received any adjuvant therapy after HIFU therapy before reporting failure.

RESULTS

The mean age and initial PSA level before RP was 74 years and 10.0 ng/mL, respectively. After RP, one patient was stage T2aN0M0, two were stage T3N0M0 and the last had an unknown pathological stage. Three patients received external beam radiotherapy as salvage therapy after RP. The mean PSA level before HIFU, tumour volume at the vesico‐urethral lesion and operative duration were 4.3 ng/mL, 4.6 mL and 27 min, respectively. Adenocarcinomas were confirmed by biopsy of the tumour at the vesico‐urethral anastomotic lesion before HIFU. At 24 months of follow‐up, patients 2 and 4 were classified a biochemically disease‐free. Biopsies at the anastomotic site after HIFU in three patients showed no malignancy, with fibrosis. There were no complications.

CONCLUSION

Salvage HIFU for patients with recurrence after RP is feasible, even though they received salvage radiotherapy before HIFU. More patients and a longer follow‐up are needed to evaluate the safety and oncological adequacy of this new approach.     

The ORION Study: Comparison of Two Sirolimus‐Based Regimens versus Tacrolimus and Mycophenolate Mofetil in Renal Allograft Recipients

Safety and efficacy of two sirolimus (SRL)‐based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher‐than‐expected biopsy‐confirmed acute rejections (BCARs), was sponsor‐terminated; therefore, Group 2 two‐year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One‐ and 2‐year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1‐ and 2‐year modified intent‐to‐treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One‐year post hoc analysis of new‐onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between‐group malignancy rates were similar. The SRL‐based regimens were not associated with improved outcomes for kidney transplantation patients.     

Pre‐transplant phospholipase A2 receptor autoantibody concentration is associated with clinically significant recurrence of membranous nephropathy post‐kidney transplantation

Previous studies that have assessed the association of pre‐transplant antiphospholipase A2 receptor autoantibody (PLA2R‐Ab) concentration with a recurrence of membranous nephropathy (rMN) post‐kidney transplant have yielded variable results. We tested 16 consecutive transplant patients with a history of iMN for pre‐transplant PLA2R‐Ab. Enzyme‐linked immunosorbent assay titers (Euroimmun, NJ, USA) >14 RU/mL were considered positive. A receiver operating characteristic (ROC) analysis was performed after combining data from Quintana et al. (n = 21; Transplantation February 2015) to determine a PLA2R‐Ab concentration which could predict rMN. Six of 16 (37%) patients had biopsy‐proven rMN at a median of 3.2 yr post‐transplant. Of these, five of six (83%) had a positive PLA2R‐Ab pre‐transplant with a median of 82 RU/mL (range = 31–1500). The only patient who had rMN with negative PLA2R‐Ab was later diagnosed with B‐cell lymphoma. One hundred percent (n = 10) of patients with no evidence of rMN (median follow‐up = five yr) had negative pre‐transplant PLA2R‐Ab. In a combined ROC analysis (n = 37), a pre‐transplant PLA2R‐Ab > 29 RU/mL predicted rMN with a sensitivity of 85% and a specificity of 92%. Pre‐transplant PLA2R‐Ab could be a useful tool for the prediction of rMN. Patients with rMN in the absence of PLA2R‐Ab should be screened for occult malignancy and/or alternate antigens.