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BK virus maintains a latent infection that is ubiquitous in humans. It has a propensity for reactivation in the setting of a dysfunctional cellular immune response and is frequently encountered in kidney transplant recipients. Screening for the virus has been effective in preventing progression to nephropathy and graft loss. However, it can be a diagnostic and therapeutic challenge. In this in-depth state-of-the-art review, we will discuss the history of the virus, virology, epidemiology, cellular response, pathogenesis, methods of screening and diagnosis, evidence-based treatment strategies, and upcoming therapeutics, along with the issue of re-transplantation in patients.

Creatine is a natural nitrogenous organic acid that is integral to energy metabolism and crucial for proper cell functioning. The kidneys are involved in the first step of creatine production. With kidney transplantation being the gold-standard treatment for end-stage kidney disease, kidney transplant recipients (KTR) may be at risk of impaired creatine synthesis. We aimed to compare creatine homeostasis between KTR and controls. Plasma and urine concentrations of arginine, glycine, guanidinoacetate, creatine and creatinine were measured in 553 KTR and 168 healthy controls. Creatine intake was assessed using food frequency questionnaires. Iothalamate-measured GFR data were available in subsets of 157 KTR and 167 controls. KTR and controls had comparable body weight, height and creatine intake (all P > 0.05). However, the total creatine pool was 14% lower in KTR as compared to controls (651 ± 178 vs. 753 ± 239 mmol, P < 0.001). The endogenous creatine synthesis rate was 22% lower in KTR as compared to controls (7.8 ± 3.0 vs. 10.0 ± 4.1 mmol per day, P < 0.001). Despite lower GFR, the plasma guanidinoacetate and creatine concentrations were 21% and 41% lower in KTR as compared to controls (both P < 0.001). Urinary excretion of guanidinoacetate and creatine were 66% and 59% lower in KTR as compared to controls (both P < 0.001). In KTR, but not in controls, a higher measured GFR was associated with a higher endogenous creatine synthesis rate (std. beta: 0.21, 95% CI: 0.08; 0.33; P = 0.002), as well as a higher total creatine pool (std. beta: 0.22, 95% CI: 0.11; 0.33; P < 0.001). These associations were fully mediated (93% and 95%; P < 0.001) by urinary guanidinoacetate excretion which is consistent with production of the creatine precursor guanidinoacetate as rate-limiting factor. Our findings highlight that KTR have a disturbed creatine homeostasis as compared to controls. Given the direct relationship of measured GFR with endogenous creatine synthesis rate and the total creatine pool, creatine supplementation might be beneficial in KTR with low kidney function.Trial registration ID: NCT02811835.Trial registration URL: https://clinicaltrials.gov/ct2/show/NCT02811835.

Non-nephrotoxic immunosuppressive strategies that allow reduction of calcineurin-inhibitor exposure without compromising safety or efficacy remain a goal in kidney transplantation. Immunosuppression based on the mammalian-target-of-rapamycin inhibitor everolimus was assessed as a strategy for elimination of calcineurin-inhibitor exposure and optimisation of renal-graft function while maintaining efficacy. In the ZEUS multicentre, open-label study, 503 patients (aged 18–65 years) who had received de-novo kidney transplants were enrolled. After initial treatment with ciclosporin, based on trough concentrations, and enteric-coated mycophenolate sodium (1440 mg/day, orally), corticosteroids (≥5 mg/day prednisolone or equivalent, orally), and basiliximab induction (20 mg, intravenously, on day 0 [2 h before transplantation], and on day 4), 300 (60%) patients were randomly assigned at 4·5 months in a 1:1 ratio to undergo calcineurin-inhibitor elimination (everolimus-based regimen that was based on trough concentrations [6–10 ng/mL] and enteric-coated mycophenolate sodium [1440 mg/day] with corticosteroids), or continue standard ciclosporin-based treatment. Randomisation was done by use of a central, validated system that automated the random assignment of treatment groups to randomisation numbers. The primary objective was to show better renal function (glomerular filtration rate [GFR]; Nankivell formula) with the calcineurin-inhibitor-free everolimus regimen at 12 months after transplantation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00154310. 118 (76%) of 155 everolimus-treated patients and 117 (81%) of 145 ciclosporin-treated patients completed treatment with study drug up to 12 months after transplantation. At this timepoint, the everolimus regimen was associated with a significant improvement in GFR versus the ciclosporin regimen (71·8 mL/min per 1·73 m2vs 61·9 mL/min per 1·73 m2, respectively; mean difference 9·8 mL/min per 1·73 m2, 95% CI −12·2 to −7·5). Rates of biopsy-proven acute rejection were higher in the everolimus group than in the ciclosporin group after randomisation (15 [10%] of 154 vs five [3%] of 146; p=0·036), but similar for the full study period (23 [15%] vs 22 [15%]). Compared with the ciclosporin regimen, higher mean lipid concentrations, slightly increased urinary protein excretion, and lower haemoglobin concentrations were noted with the everolimus regimen; thrombocytopenia, aphthous stomatitis, and diarrhoea also occurred more often in the everolimus group. A higher incidence of hyperuricaemia was noted with ciclosporin. Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety, indicating that this strategy may facilitate improved long-term outcomes in selected patients. Novartis Pharma.

Successful kidney transplantation offers patients with end-stage renal disease the greatest likelihood of survival. However, cardiovascular disease poses a major threat to both graft and patient survival in this cohort. Transplant recipients are unique in their accumulation of a wide range of traditional and non-traditional cardiovascular risk factors. Hypertension, diabetes, dyslipidaemia and obesity are highly prevalent in patients with end-stage renal disease. These risk factors persist following transplantation and are often exacerbated by the drugs used for immunosuppression in organ transplantation. Additional transplant-specific factors such as poor graft function and proteinuria are also associated with increased cardiovascular risk. However, these transplant-related factors remain unaccounted for in current cardiovascular risk prediction models, making it challenging to identify transplant recipients with highest risk. With few interventional trials in this area specific to transplant recipients, strategies to reduce cardiovascular risk are largely extrapolated from other populations. Aggressive management of traditional cardiovascular risk factors remains the cornerstone of prevention, though there is also a potential role for selecting immunosuppression regimens to minimise additional cardiovascular injury.

The first successful kidney transplant in December 1954 between the Herrick brothers ushered in a new field of medicine. Over the almost seventy years, thousands of lives have been saved and patient survival has improved. There is one area of kidney transplant patient care that has been overlooked. Patient quality and ability to participate in life have not been adequately studied. This is due in part to the false narrative of life after kidney transplantation. The false narrative has developed due to the patient voice not being heard due to a variety of factors. The development and implementation of Patient Reported Outcome Measures into clinical practice and clinical trials is the first step ensuring the patient voice is heard systematically. By enabling the patient voice to be heard, I hope this result in a new narrative that is patient centered.

Despite advances in post-transplant management, the long-term survival rate of kidney grafts and patients has not improved as approximately forty percent of transplants fails within ten years after transplantation. Both immunologic and non-immunologic factors contribute to late allograft loss. Chronic kidney transplant rejection (CKTR) is often clinically silent yet progressive allogeneic immune process that leads to cumulative graft injury, deterioration of graft function. Chronic active T cell mediated rejection (TCMR) and chronic active antibody-mediated rejection (ABMR) are classified as two principal subtypes of CKTR. While significant improvements have been made towards a better understanding of cellular and molecular mechanisms and diagnostic classifications of CKTR, lack of early detection, differential diagnosis and effective therapies continue to pose major challenges for long-term management. Recent development of high throughput cellular and molecular biotechnologies has allowed rapid development of new biomarkers associated with chronic renal injury, which not only provide insight into pathogenesis of chronic rejection but also allow for early detection. In parallel, several novel therapeutic strategies have emerged which may hold great promise for improvement of long-term graft and patient survival. With a brief overview of current understanding of pathogenesis, standard diagnosis and challenges in the context of CKTR, this mini-review aims to provide updates and insights into the latest development of promising novel biomarkers for diagnosis and novel therapeutic interventions to prevent and treat CKTR.

To address the need for improved biomarkers for kidney transplant rejection, European Society of Organ Transplantation (ESOT) convened a dedicated working group comprised of experts in kidney transplant biomarkers to review literature pertaining to clinical and subclinical acute rejection to develop guidelines in the screening and diagnosis of acute rejection that were subsequently discussed and voted on during the Consensus Conference that took place in person in Prague. The findings and recommendations of the Working Group on Molecular Biomarkers of Kidney Transplant Rejection are presented in this article.

Background Reproductive function in women with end stage renal disease generally improves after kidney transplant. However, pregnancy remains challenging due to the risk of adverse clinical outcomes. Methods We searched PubMed/MEDLINE, Elsevier EMBASE, Scopus, BIOSIS Previews, ISI Science Citation Index Expanded, and the Cochrane Central Register of Controlled Trials from date of inception through August 2017 for studies reporting pregnancy with kidney transplant. Results Of 1343 unique studies, 87 met inclusion criteria, representing 6712 pregnancies in 4174 kidney transplant recipients. Mean maternal age was 29.6 ± 2.4 years. The live-birth rate was 72.9% (95% CI, 70.0–75.6). The rate of other pregnancy outcomes was as follows: induced abortions (12.4%; 95% CI, 10.4–14.7), miscarriages (15.4%; 95% CI, 13.8–17.2), stillbirths (5.1%; 95% CI, 4.0–6.5), ectopic pregnancies (2.4%; 95% CI, 1.5–3.7), preeclampsia (21.5%; 95% CI, 18.5–24.9), gestational diabetes (5.7%; 95% CI, 3.7–8.9), pregnancy induced hypertension (24.1%; 95% CI, 18.1–31.5), cesarean section (62.6, 95% CI 57.6–67.3), and preterm delivery was 43.1% (95% CI, 38.7–47.6). Mean gestational age was 34.9 weeks, and mean birth weight was 2470 g. The 2–3-year interval following kidney transplant had higher neonatal mortality, and lower rates of live births as compared to > 3 year, and < 2-year interval. The rate of spontaneous abortion was higher in women with mean maternal age < 25 years and > 35 years as compared to women aged 25–34 years. Conclusion Although the outcome of live births is favorable, the risks of maternal and fetal complications are high in kidney transplant recipients and should be considered in patient counseling and clinical decision making.

•Pneumococcal prime-boost vaccination is recommended for transplant recipients/candidates.•23-valent polysaccharide vaccine is additive in kidney transplant recipients/candidates.•In candidates, double dosage vaccines are superior to normal dosage.•Double dosage pneumococcal vaccines are safe. Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients, but is not thoroughly tested in this population. Furthermore, a pneumococcal vaccine dose effect has never been investigated, though observed in healthy adults. To assess whether a double dose of 13-valent pneumococcal conjugate vaccine (PCV13) and of 23-valent pneumococcal polysaccharide vaccine (PPV23) increases the immunogenicity of prime-boost vaccination in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs), a phase 3, randomized, non-blinded trial was conducted. KTRs and WLPs were in parallel groups assigned either normal or double dosage of both vaccines 12 weeks apart. A ′protective response′ was an average geometric mean concentration ≥ 1 mg/L based on 12 vaccine shared serotype-specific IgG antibodies. Furthermore, number of antibodies with ≥ 2-fold rises and individual serotype-specific antibody concentrations were evaluated. Follow-up was 48 weeks. Seventy-four KTRs and 65 WLPs were enrolled. In WLPs, double dosage resulted in a significantly higher proportion of participants with a ′protective response′ (66.7%), 5 weeks after PPV23, compared to normal dosage (35.5%), p = 0.015. KTRs exhibited no dose effect. After PPV23, all four groups had increased their number of serotypes with ≥ 2-fold rises (p ≤ 0.05 for both WLPs groups; p ≤ 0.01 for both KTRs groups). Vaccines were safe, well tolerated and still immunogenic at week 48. Data suggests that double dosage of pneumococcal vaccines used according to the prime-boost strategy might be recommendable for WLPs. Furthermore, our data supports PPV23́s additive effect to PCV13 in KTRs and WLPs. (EudraCT: 2016–004123-23)

Objective The Patient-Reported Outcomes Measurement Information System (PROMIS) aims to address the lack of generalizable and universal measure of patient-reported outcomes to assess health-related quality of life. It has not been validated for patients with chronic kidney disease. We aim to validate the PROMIS-57 and PROMIS-29 questionnaires among kidney transplant recipients. Methods A cross-sectional sample of stable kidney transplant recipients was recruited. Each participant completed PROMIS-57, a 57-question instrument covering seven domains—physical function, anxiety, depression, fatigue, pain, sleep disturbance, and social functioning—alongside validated legacy questionnaires [Patient Health Questionnaire (PHQ9), General Anxiety Disorder (GAD7), Edmonton Symptom Assessment Scale revised (ESASr), and Kidney Disease Quality of Life (KDQoL-36)]. PROMIS-29, a 29-question instrument, is nested within PROMIS-57 and measures the same domains. Structural validity of PROMIS was assessed with confirmatory factor analysis, reported using the Comparative Fit Index (CFI). Construct validity was assessed with known-groups comparisons. Internal consistency was evaluated with Cronbach’s α and convergent validity was assessed with Spearman’s Rho. Test–retest reliability was assessed through the intraclass correlation coefficient (ICC). Results Mean (± SD) age of the 177 participants was 50 (± 17), 57% were male and 55% Caucasian. Internal consistency of each domain was high (Cronbach’s α > 0.88). Confirmatory factor analysis showed good structural validity for most domains (CFI > 0.95, RMSEA < 0.05). Test–retest reliability indicated good agreement (ICC > 0.6). Known-groups comparisons by clinical and socio-demographic differences were found as hypothesized. Conclusions Our results provide evidence that PROMIS-57 and PROMIS-29 are highly reliable and valid instruments among kidney transplant recipients. We propose it as a valuable tool to assess important domains of the illness experience.