Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor‐specific antibodies in the first year of kidney transplantation

De novo donor‐specific antibodies (dnDSAs) have been associated with reduced graft survival. Tacrolimus (TAC)–based regimens are the most common among immunosuppressive approaches used in in clinical practice today, yet an optimal therapeutic dose to prevent dnDSAs has not been established. We evaluated mean TAC C₀ (tacrolimus trough concentration) and TAC time in therapeutic range for the risk of dnDSAs in a cohort of 538 patients in the first year after kidney transplantation. A mean TAC C₀ < 8 ng/mL was associated with dnDSAs by 6 months (odds ratio [OR] 2.51, 95% confidence interval [CI] 1.32–4.79, P = .005) and by 12 months (OR 2.32, 95% CI 1.30–4.15, P = .004), and there was a graded increase in risk with lower mean TAC C₀. TAC time in the therapeutic range of <60% was associated with dnDSAs (OR 2.05, 95% CI 1.28‐3.30, P = .003) and acute rejection (hazard ratio [HR] 4.18, 95% CI 2.31–7.58, P < .001) by 12 months and death‐censored graft loss by 5 years (HR 3.12, 95% CI 1.53–6.37, P = .002). TAC minimization may come at a cost of higher rates of dnDSAs, and TAC time in therapeutic range may be a valuable strategy to stratify patients at increased risk of adverse outcomes.     

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).     

Ten‐year observational follow‐up of a randomized trial comparing cyclosporine and tacrolimus therapy combined with steroid withdrawal in living‐donor renal transplantation

Although various strategies for steroid withdrawal after transplantation have been attempted, there are few reports of the long‐term results of steroid withdrawal regimens in kidney transplantation. Earlier, we reported on a 5‐year prospective, randomized, single‐center trial comparing the safety and efficacy of cyclosporine (CsA) plus mycophenolate mofetil (MMF) with that of tacrolimus (TAC) plus MMF, when steroids were withdrawn 6 months after kidney transplantation in low‐risk patients. We now report the 10‐year observational data on the study population. We collected data from the database of the Organ Transplantation Center, Samsung Medical Center for 5 years after completion of the original study (TAC group n = 62; CsA group n = 55). The 10‐year patient survival, death‐censored graft survival, and acute rejection‐free survival did not differ between groups (98% vs 96%; P = 0.49, 78% vs 85%; P = 0.75 and 84% vs 76%; P = 0.14 in the TAC group vs CsA group, respectively). In low‐risk patients, there was no difference in long‐term patient and graft survival between TAC‐ and CsA‐based late steroid withdrawal regimens that included MMF treatment. More long‐term randomized clinical trials are needed to clarify the benefits of late steroid withdrawal in kidney transplantation.     

Outcomes and risk stratification for late antibody‐mediated rejection in recipients of ABO‐incompatible kidney transplants: a retrospective study

The required intensity of monitoring for antibody‐mediated rejection (AMR) after of ABO‐incompatible (ABOi) kidney transplantation is not clearly formulized. We retrospectively evaluated a single‐center cohort of 115 ABO‐incompatible (ABOi) kidney transplant recipients, of which 32% were also HLA incompatible (ABOi/HLAi) with their donors. We used an adjusted negative binomial model to evaluate risk factors for late AMR. Using this model, we risk‐stratified patients into high‐ and low‐risk groups for the development of late AMR; 26% of patients had at least one AMR episode; 49% of AMR episodes occurred within 30‐days after transplant and were considered early AMR. Patients with an early AMR episode had a 5.5‐fold greater incidence of developing late AMR [IRR = 5.5, (95% CI: 1.5–19.3), P = 0.01]. ABOi/HLAi recipients trended toward increased late AMR risk [IRR = 1.9, (95% CI: 0.5–6.6), P = 0.3]. High‐risk recipients (those with an early AMR or those who were ABOi/HLAi) had a sixfold increased incidence of late AMR [IRR = 6.3, (95% CI: 1.6–24.6), P = 0.008] versus low‐risk recipients. The overall incidence of late AMR was 20.8% vs. 1.5% in low‐risk recipients. Changes in anti‐A/B titer did not correlate with late AMR (IRR = 0.9 per log titer increase, P = 0.7). This risk‐stratification scheme uses information available within 30 days of ABOi transplantation to determine risk for late AMR and can help direct longitudinal follow‐up for individual patients.     

Randomized trial of 3 maintenance regimens (TAC/SRL vs. TAC/MMF vs. CSA/SRL) with low-dose corticosteroids in primary kidney transplantation: 18-year results

A randomized trial of 150 primary kidney transplant recipients, initiated in May 2000, compared tacrolimus (TAC)/sirolimus (SRL) vs. TAC/mycophenolate mofetil (MMF) vs. cyclosporine microemulsion (CSA)/SRL (N = 50/group). All patients received daclizumab induction and maintenance corticosteroids. With current median follow-up of 18 years post-transplant, biopsy-proven acute rejection (BPAR) occurred less often in TAC/MMF (26% (13/50)), vs. the TAC/SRL (36% (18/50)) and CSA/SRL (34% (17/50)) arms combined (p = .23), with statistical significance favoring TAC/MMF (p = .05) after controlling for the multivariable (Cox model) effects of recipient age, recipient race/ethnicity, and donor age. First BPAR rate was clearly more favorable for TAC/MMF after stratifying patients by having 0–1 (N = 72) vs. 2–3 (N = 78) unfavorable baseline characteristics (recipient age <50 years, African American or Hispanic recipient, and donor age ≥50 years) (p = .02). Mean estimated glomerular filtration rate (eGFR), using the CKD-EPI formula, was consistently higher for TAC/MMF, particularly after controlling for the multivariable effect of donor age, throughout the first 96 months post-transplant (p ≤ .008). These differences were translated into an observed more favorable graft failure due to immunologic cause (CAI/TG) rate for TAC/MMF (p = .06), although no significant differences in overall death-uncensored graft loss were observed. Previously reported significantly higher study drug discontinuation and requirement for antilipid therapy rates in the SRL-assigned arms were maintained over time. Overall, these results at 18 years post-transplant more definitively show that TAC/MMF should be the gold standard for achieving optimal, long-term maintenance immunosuppression in kidney transplantation.     

Adherence to antiretroviral therapy for HIV in sub‐Saharan Africa and Asia: a comparative analysis of two regional cohorts

Introduction : Our understanding of how to achieve optimal long‐term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV‐positive persons receiving ART who were enrolled in a bi‐regional cohort in sub‐Saharan Africa and Asia. Methods : This multicentre prospective study of adults starting first‐line ART assessed patient‐reported adherence at follow‐up clinic visits using a 30‐day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six‐month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. Results : Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort (p < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06–1.53; p = 0.009), younger age (OR 0.8 per 10 year increase; 0.8–0.9; p = 0.003), use of concomitant medication (OR 1.8, 1.0–3.2; p = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1–1.7; p = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4–0.9; p = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9–2.6; p = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low‐ and lower‐middle‐income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3–2.0; p < 0.001), compared to those in upper‐middle or high‐income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3–7.7; p < 0.001) and Asia (OR 9.0, 95% CI 5.0–16.2; p < 0.001). Patient‐reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. Conclusions : Psychosocial factors and health system resources may explain regional differences. Adherence‐enhancing interventions should address patient‐reported barriers tailored to local settings, prioritizing the first years of ART.     

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.     

Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients

Tedesco‐Silva H, Felipe CR, Park SI, Pinheiro‐Machado PG, Garcia R, Slade A, Schmouder R, Medina‐Pestana JO. Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients.
Clin Transplant 2010: 24: E116–E123.
© 2009 John Wiley & Sons A/S. Abstract: The delayed release of mycophenolic acid (MPA) from enteric‐coated mycophenolate sodium (EC‐MPS, myfortic^®) may have an impact on the variability of MPA trough (C_{0 h}) levels. A randomized, two‐period crossover study was performed in 24 maintenance renal transplants to evaluate the inter‐ and intrasubject variability of MPA predose levels from EC‐MPS and mycophenolate mofetil (MMF, CellCept^®), both in combination with cyclosporine. Patients received EC‐MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at ?1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1–80.3) and 54.4% (40.0–86.8) for EC‐MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1–72.9) and 42.8% (37.9–49.2). High MPA C_{0 h} levels >10 μg/mL were rarely observed with both EC‐MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)_{0–3 h} was comparable between treatments, while MPA C_{0 h} was on average 46% higher with EC‐MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC‐MPS and MMF therapy given the large intrasubject variability in MPA C_{0 h} levels with both treatments.     

Association of the c.‐9C>T and c.368A>G transitions in H2BFWT gene with male infertility in an Iranian population

The H2BFWT (H2B family, member W, testis specific) gene is a testis‐specific histone which is involved in the spermatogenesis process. This study aimed to investigate the association of H2BFWT gene c.‐9C>T and c.368A>G polymorphisms with male infertility in an Iranian population. The 232 independent individuals, including 109 infertile men and 123 healthy controls, were recruited from IVF centre (Kashan, Iran). The allele types of c.‐9C>T and c.368A>G polymorphisms were detected by using PCR‐RFLP method. In overall analysis, we found that the c.‐9T (OR: 1.75, 95% CI: 1.04–2.95, p = .035) and c.368G (OR: 1.71, 95% CI: 1.02–2.89, p = .042) alleles are associated with male infertility. The c.‐9T allele was also associated with nonobstructive azoospermia (OR: 2.08, 95% CI: 1.01–4.25, p = .046), while c.368G allele was associated with oligozoospermia (OR: 2.10, 95% CI: 1.15–3.85, p = .016). It is concluded that H2BFWT gene c.‐9C>T and c.368A>G polymorphisms might be genetic risk factors for idiopathic male infertility.     

CAG‐repeat polymorphisms in the polymerase γ gene and male infertility: a meta‐analysis

CAG‐repeat in the polymerase γ (POLG) gene encoding polymerase γ for mitochondria is important to spermatogenesis. Compared with a few researchers who raised alteration of CAG‐repeat‐affected male reproductive ability, others did not find the association between CAG‐repeat polymorphisms and male infertility. Therefore, a comprehensive meta‐analysis is necessary to determine the association; 13 case–control studies were screened out using keywords search. From these studies, characteristics were extracted for conducting meta‐analysis. Odds ratio (OR) and 95% confidence interval (CI) were used to describe the results; the results indicated that CAG‐repeat allele was not a risk factor to male infertility (pooled OR = 1.03, 95% CI: 0.79–1.34, P = 0.828). Four different genetic comparisons also demonstrated a negative result: heterozygote comparison (not 10/10 versus 10/10. Pooled OR = 0.99, 95% CI: 0.77–1.27, P = 0.948), homozygote comparison (not 10/not 10 versus 10/10. Pooled OR = 1.08, 95% CI: 0.56–2.06, P = 0.816), the recessive genetic comparison (not 10/not 10 versus not 10/10 + 10/10. Pooled OR = 1.07, 95% CI: 0.58–1.95, P = 0.829) and the dominant genetic comparison (not 10/not 10 + not 10/10 versus 10/10. Pooled OR = 0.97, 95% CI: 0.72–1.29, P = 0.804); based on current researches, this meta‐analysis demonstrated no apparent association between POLG‐CAG‐repeat and male infertility. Similarly, CAG‐repeat was not a sensitive site to male infertility.     

Sirolimus vs mycophenolate mofetil (MMF) in primary combined pancreas and kidney transplantation. Results of a long‐term prospective randomized study

The study was intended to compare pancreas graft survival rates in two groups of pancreas and kidney transplant recipients prospectively randomized to treatment either with sirolimus or MMF. From 2002 to 2013, 238 type 1 diabetic recipients with end‐stage kidney disease were randomized 1:1 to sirolimus or MMF treatment. Noncensored pancreas survival at 5 years was 76.4 and 71.6% for sirolimus and MMF groups, respectively (P > .05). Death‐censored pancreas survival was better in the sirolimus group (P = .037). After removal of early graft losses pancreas survival did not differ between groups (MMF 83.1% vs sirolimus 91.6%, P = .11). Nonsignificantly more grafts were lost due to rejection in the MMF group (10 vs 5; P = .19). Cumulative patient 5‐year survival was 96% in the MMF group and 91% in the sirolimus group (P > .05). Five‐year cumulative noncensored kidney graft survival rates did not statistically differ (85.6% in the sirolimus group and 88.8% in MMF group). Recipients treated with MMF had significantly more episodes of gastrointestinal bleeding (7 vs 0, P = .007). More recipients in the sirolimus group required corrective surgery due to incisional hernias (21 vs 12, P = .019). ClinicalTrials No.: NCT 03582878.     

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression‐related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C₀/D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post‐operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C₀/D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1‐8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07‐0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.     

Effect of Wuzhi preparations on tacrolimus in CYP3A5 expressers during the early period after transplantation: A real-life experience from heart transplant recipients

BackgroundGenetic polymorphisms and drug interactions are associated with tacrolimus exposure. This study aimed to evaluate the effect of Wuzhi (WZ) preparations on tacrolimus (TAC) concentration and dose requirements in heart transplant recipients with the CYP3A5*1 allele during the early period after transplantation.MethodsA total of 167 adult heart transplant recipients with the CYP3A5*1 allele were included and divided into the WZ group (n = 115) and the WZ-free group (n = 52). Blood trough concentrations of TAC were detected and the dose-adjusted concentration (C₀/D) and dose requirement for achieving the TAC therapeutic range were compared between the two groups. The change in C₀/D and dose of TAC were evaluated before and after co-administration with WZ preparations.ResultsNo significant differences in TAC C₀/D and dose requirement were observed between the WZ and WZ-free groups. However, the TAC C₀/D in the WZ group was significantly increased an average of 2.10-fold after co-administration of WZ. Moreover, the degree of elevation was related to the dose of the active ingredient (Schisantherin A). Furthermore, ALT, AST, and TB levels were significantly reduced after administration of WZ preparations.ConclusionCo-administration of the WZ/TAC preparation, in heart transplant recipients carrying the CYP3A5*1 allele, considerably increased TAC concentration (C₀/D) while decreased high levels of leading indicators in the liver function. More importantly, the effect of the WZ/TAC preparation on C₀/D was a dose-dependent event. However, our finding needs to be further confirmed in a larger sample size.     

Perioperative administration of high‐dose recombinant human erythropoietin for delayed graft function prevention in kidney transplantation: a meta‐analysis

Delayed graft function (DGF) due to ischemia–reperfusion injury is a major early complication of kidney transplantation (KT). Recombinant human erythropoietin (rHuEPO) has been shown to exert nephroprotective action in animal models. We conducted a meta‐analysis to explore the impact of rHuEPO on DGF in KT. Eligible studies comparing perioperative high‐dose rHuEPO with placebo or no therapy for prevention of DGF were identified through MEDLINE, CENTRAL, and Transplant Library. Their design and data were assessed by two independent reviewers. Among 737 examined studies, four randomized controlled trials, involving 356 recipients of kidney allografts from deceased donors, fulfilled inclusion criteria. Statistical heterogeneity across studies was not significant (P = 0.98, I² = 0%). In a random effects model, no significant difference was found in the occurrence of DGF (odds ratio: 0,74, 95% CI: 0.47–1.18, P = 0.21). At 4 weeks after KT, the rHuEPO group exhibited higher systolic blood pressure (mean difference: 6.47 mmHg, 95% CI: 1.25–11.68, P = 0.02). Perioperative, high‐dose rHuEPO administration does not prevent DGF in deceased donor KT. Furthermore, it is associated with higher systolic blood pressure leading to safety concerns. Nonerythropoietic rHuEPO derivatives, designed for nephroprotective action without increasing cardiovascular risk, might prove an alternative but still are at early stages of development.     

Comparison of Sirolimus Combined With Tacrolimus and Mycophenolate Mofetil Combined With Tacrolimus in Kidney Transplantation Recipients: A Meta-Analysis

Purpose

The study was designed to compare the outcomes of sirolimus (SRL) combined with tacrolimus (TAC) and mycophenolate mofetil (MMF) combined with TAC in kidney transplantation recipients.

The impact of surveillance and rapid reduction in immunosuppression to control BK virus‐related graft injury in kidney transplantation

We prospectively screened 609 consecutive kidney (538) and kidney‐pancreas (71) transplant recipients for BK viremia over a 4‐year interval using polymerase chain reaction viral load detection and protocol kidney biopsies. We found that BK viremia is common at our center: total cases 26.7%, cases during first year 21.3% (mean 4 months), and recipients with ≥10 000 copies/ml 12.3%. We found few predictive clinical or demographic risk factors for any BK viremia or viral loads ≥10,000 copies/ml, other than prior treatment of biopsy confirmed acute rejection and/or higher immunosuppressive blood levels of tacrolimus (P = 0.001) or mycophenolate mofetil (P = 0.007). Viral loads at diagnosis (<10 000 copies/ml) demonstrated little impact on graft function or survival. However, rising copy numbers demand early reductions in immunosuppressive drug doses of at least 30–50%. Viral loads >185 000 copies/ml at diagnosis were predictive of BK virus‐associated nephropathy (BKVAN; OR: 113.25, 95% CI: 17.22–744.6, P < 0.001). Surveillance for BK viremia and rapid reduction of immunosuppression limited the incidence of BKVAN to 1.3%. The addition of leflunomide or ciprofloxacin to immunosuppressive dose reduction did not result in greater rates of viral clearance. These data support the role of early surveillance for BK viremia to limit the impact on transplant outcome, although the most effective schedule for screening awaits further investigation.     

Failure of abdominal wall closure after intestinal transplantation: Identifying high‐risk recipients

Open abdomen and fascial dehiscence after intestinal transplantation increase morbidity. This study aims to identify recipient and donor factors associated with failure to achieve sustained primary closure (failed‐SPC) of the abdomen after intestinal transplant. We conducted a single‐center retrospective study of 96 intestinal transplants between 2013 and 2018. Thirty‐eight (40%) were adult patients, and 58 were pediatric patients. Median age at transplantation was 36.0 and 5.8 years, respectively. Failed‐SPC occurred in 31 (32%) patients. Identified risk factors of failed‐SPC included preexisting enterocutaneous fistula (OR: 6.8, CI: 2.4‐19.6, P = .0003), isolated intestinal graft (OR: 3.4, CI: 1.24‐9.47, P = .02), male sex in adults (OR: 3.93, CI: 1.43‐10.8, P = .009), and age over four years (OR: 6.22, CI: 1.7‐22.7, P = .004). There was no association with primary diagnosis and prior transplant with failed‐SPC. Donor‐to‐recipient size ratios did not predict failed‐SPC. There was an association between failed‐SPC and extended median hospital stay (100 vs 57 days, P = .007) and increased time to enteral autonomy in pediatric patients. There is a relationship between failed‐SPC and a higher rate of laparotomy (OR: 21.4, CI: 2.78‐178.2, P = .0003) and fistula formation posttransplant (OR: 11.4, CI: 2.83‐45.84, P = .0005) in pediatric patients. Given inferior outcomes with failed‐SPC, high‐risk recipients require careful evaluation.     

A Randomized Trial to Assess the Impact of Early Steroid Withdrawal on Growth in Pediatric Renal Transplantation: The TWIST Study

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n = 98) or tacrolimus, MMF and standard‐dose steroids (TAC/MMF/STR, n = 98). Mean change in height SDS was 0.16 ± 0.32 with TAC/MMF/DAC and 0.03 ± 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04–0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05–0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy‐proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.     

Bilateral is superior to unilateral varicocelectomy in infertile men with bilateral varicocele: Systematic review and meta‐analysis

To investigate whether bilateral surgery can bring more benefits to infertile patients with bilateral varicocele than unilateral surgery. A search of PubMed, Web of Science, EMBASE and the Cochrane Library on 13 January 2019 was conducted to identify studies published in English that used varicocelectomy. The protocol of the present meta‐analysis was pre‐published on PROSPERO (registration number CRD42019093894). Primary outcomes were spontaneous pregnancy rates. A total of eleven articles were finally enrolled in, with a total of 1,743 patients. Spontaneous pregnancy rate was higher in patient with bilateral varicocelectomy than unilateral varicocelectomy with an odds ratio (OR) of 1.89 (95% CI 1.52–2.35; I² = 0%; p < .00001). The results indicated bilateral is superior than unilateral varicocelectomy concerning sperm concentration (SMD: 2.88 × 10⁶/ml; 95% CI: 1.06, 4.70; I² = 93%), sperm motility (SMD: 5.08; 95% CI: 2.65, 7.50; I² = 0%), progression of sperm motility (SMD: 6.48; 95% CI: 5.16, 7.81; I² = 0%) and sperm morphology (SMD: 2.38%; 95% CI: 0.72, 4.03; I² = 94%) between bilateral and unilateral varicocelectomy. Bilateral varicocelectomy may be superior to unilateral in regard to spontaneous pregnancy rate and sperm motility for infertile male with bilateral varicocele (both left clinical and right subclinical varicocele and bilateral clinical varicocele).     

Prevalence of abdominal aortic calcifications in older living renal donors and its effect on graft function and histology

We assessed the prevalence of abdominal aortic calcification (AAC) in older living kidney donors and its effect on recipient eGFR and graft histology. A total of 292 consecutive living pairs with donor age ≥50 from 2003 to 2013 were identified (mean age 56; range 50–78; F/M: 1.8). Donor AAC was determined by prenephrectomy unenhanced CT. Recipient eGFR and spot urine protein: creatinine ratios (UPCRs) were recorded. A total of 180 recipients had 6‐month protocol biopsies. AAC was present in 40.7% of donors, and they were older (58.6 versus 54.7 years old, P < 0.0001) and more likely to be male (77.6% vs. 37.3%, P = 0.004). There was no significant difference in eGFR or spot UPCR up to 36 months in recipients of allografts from donors with versus without AAC. At 6‐month biopsy, there was a higher percentage of allografts with vascular fibrous intimal thickening and arteriolar hyaline thickening from donors with versus without AAC (vascular fibrous intimal thickening: 38.8% vs. 7.1% and arteriolar hyaline thickening: 35.8% vs. 7.1%; P < 0.001 for both). The presence of donor AAC predicts the presence of vascular disease [vascular fibrous intimal thickening (OR: 7.2; CI:2.9–17.9) and arteriolar hyaline thickening (OR:5.7; CI:2.3–14.1)] in allografts at 6 months. Donor AAC is predictive of renal vascular disease and may help to improve the screening of potential donors and inform post‐transplant management.