Vancomycin use for haemodialysis patients-Development of a new dosing protocol.

AIM: To develop a dosing and monitoring protocol to achieve therapeutic vancomycin levels on intermittent haemodialysis. METHODS: We identified 15 vancomycin treatment courses received by patients on intermittent haemodialysis at a district health board in Auckland, New Zealand. Demographic, biochemical and clinical parameters were gathered from their health records. We subsequently devised and implemented a new vancomycin protocol consisting of weight-based loading dose, and subsequent dose titration according to same-day measured pre-dialysis levels. We then re-audited 16 vancomycin treatment courses to assess the performance of the protocol. RESULTS: A significantly higher proportion of vancomycin levels were within the target range (15-20 mg/L) following the implementation of protocol, from 23% to 46% (p < .005). Additionally, a greater proportion of treatment courses had >50% of pre-dialysis levels within the target range, rising from 13% to 56% (p < .01). In the pre-protocol group, 19 out of 117 doses of vancomycin were withheld during treatment, compared to 1 out of 118 doses in the post-protocol group. A total of 62% of total maintenance doses were administered in adherence to protocol. Length of hospital stay and number of positive blood cultures while on treatment were reduced. CONCLUSIONS: Our initial audit revealed deficiencies in our clinical practice in the absence of a local vancomycin protocol for patients receiving intermittent haemodialysis. Following the implementation of our novel protocol, there was an improvement in therapeutic levels and fewer doses were withheld. Our sample size was too small to allow for interpretation of clinical outcome data.

BLISS-LN trial revisited: function matters.

This post hoc analysis of the Belimumab International Study in Lupus Nephritis (BLISS-LN) shows belimumab effectively reduced the time to 30% and 40% decreases in estimated glomerular filtration rate and persistent decreases in estimated glomerular filtration rate. Subgroup analysis found belimumab was most effective in proliferative lupus nephritis, and that there was no apparent benefit from the addition of belimumab in those with baseline nephrotic range proteinuria nor in those receiving cyclophosphamide/azathioprine. These results raise questions about trial end points and their relationship to long-term kidney function, the outcome of most importance to patients, caregivers, and health professionals alike.

Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression.

OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.

Clinical impact of early post-transplant red cell transfusions in kidney transplantation: a systematic review and meta-analysis.

Introduction: Red blood cell transfusions (RBCT) represent a potentially modifiable risk factor for HLA sensitisation and adverse outcomes post transplantation. Evidence of the clinical impact of post-transplant RBCT has been infrequently reported. Herein, we performed a systematic review of available literature to assess the prevalence of RBCT post kidney transplant, and the effect of transfusion on transplant outcomes. Methods: We included studies from 2000 to July 2022, published on Medline, Embase and the Transplant Library. Results: Ten studies were analysed which included a total of 32,817 kidney transplant recipients, with a median transfusion prevalence of 40% (range 18-64%). There was significant heterogeneity between studies in terms of patient and allograft characteristics, immunological risk, and immunosuppression protocols. Analysis of unadjusted outcomes showed that post-transplant RBCTs are associated with inferior patient survival, allograft loss, rejection and donor specific antibodies. Adjusted outcomes were described where available, and supported the adverse associations seen in the unadjusted models in many studies. Discussion: This review demonstrates that RBCT post-transplant are common and maybe associated with inferior outcomes, highlighting the urgent need for high quality prospective evidence of the effect of RBCTs on transplant outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier, CRD42022348763767.

Insight on the Role of Poly(acrylic acid) for Directing Calcium Phosphate Mineralization of Synthetic Polymer Bone Scaffolds.

Bone is a complex tissue with robust mechanical and biological properties originating from its nanoscale composite structure. Although much research has been conducted on designing bioinspired artificial bone, the role of biological macromolecules such as noncollagenous proteins (NCPs) in influencing the formation of biominerals is not fully understood. In this work, we have designed nanofiber shish-kebab (NFSK) structures that can template mineral location by recruiting calcium cations from an ion-rich mineralization solution. Poly(acrylic acid) (PAA) is used as the NCP analogue to understand the role of polyelectrolytes in scaffold mineralization. We demonstrate that the addition of PAA in the mineralization solution suppresses the development of extrafibrillar minerals as well as slows down the accumulation and development of mineral phases within NFSKs. We probe the mechanism behind this effect by monitoring the free calcium ion concentration, investigating the PAA molecular weight effect, and conducting mineralization in membrane-partitioned solutions. Our results suggest the 2-fold effect of PAA as a solution stabilizer and physical barrier on the NFSK surface. This work could shed light on the understanding of the NCP effect in biomineralization.

Comparison of immunogenicity and clinical effectiveness between BNT162b2 and ChAdOx1 SARS-CoV-2 vaccines in people with end-stage kidney disease receiving haemodialysis: A prospective, observational cohort study.

Background: People with end-stage kidney disease, including people on haemodialysis, are susceptible to greater COVID-19 related morbidity and mortality. This study compares the immunogenicity and clinical effectiveness of BNT162B2 versus ChAdOx1 in haemodialysis patients. Methods: In this observational cohort study, 1021 patients were followed-up from time of vaccination until December 2021. All patients underwent weekly RT-PCR screening. Patients were assessed for nucleocapsid(anti-NP) and spike(anti-S) antibodies at timepoints after second(V2) and third(V3) vaccinations. 191 patients were investigated for T-cell responses. Vaccine effectiveness (VE) for prevention of infection, hospitalisation and mortality was evaluated using the formula VE=(1-adjustedHR)x100. Findings: 45.7% (467/1021) had evidence of prior infection. There was no difference in the proportion of infection-naïve patients who seroconverted by vaccine type, but median anti-S antibody titres were higher post-BNT162b2 compared with ChAdOx1; 462(152-1171) and 78(20-213) BAU/ml respectively, p<0.001.  Concomitant immunosuppressant use was a risk factor for non-response, OR 0.12[95% CI 0.05-0.25] p<0.001.  Post-V3 (all BNT162b2), median anti-S antibody titres remained higher in those receiving BNT162b2 versus ChAdOx1 as primary doses; 2756(187-1246) and 1250(439-2635) BAU/ml respectively, p=0.003.Anti-S antibodies waned over time. Hierarchical levels of anti-S post-V2 predicted risk of infection; patients with no/low anti-S being at highest risk. VE for preventing infection, hospitalisation and death was 53% (95% CI 6-75), 77% (95% CI 30-92) and 93% (95% CI 59-99) respectively, with no difference seen by vaccine type. Interpretation: Serum anti-S concentrations predict risk of breakthrough infection. Anti-S responses vary dependent upon clinical features, infection history and vaccine type. Monitoring of serological responses may enable individualised approaches to vaccine boosters in at risk populations. Funding: National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.

Lack of seroresponse to SARS-CoV-2 booster vaccines given early post-transplant in patients primed pre-transplantation.

SARS-CoV-2 vaccines are recommended pre-transplantation, however, waning immunity and evolving variants mandate booster doses. Currently there no data to inform the optimal timing of booster doses post-transplant, in patients primed pre-transplant. We investigated serial serological samples in 204 transplant recipients who received 2 or 3 SARS-CoV-2 vaccines pre-transplant. Spike protein antibody concentrations, [anti-S], were measured on the day of transplantation and following booster doses post-transplant. In infection-naïve patients, post-booster [anti-S] did not change when V3 (1st booster) was given at 116(78-150) days post-transplant, falling from 122(32-574) to 111(34-682) BAU/ml, p=0.78. Similarly, in infection-experienced patients, [anti-S] on Day-0 and post-V3 were 1090(133-3667) and 2207(650-5618) BAU/ml respectively, p=0.26. In patients remaining infection-naïve, [anti-S] increased post-V4 (as 2nd booster) when given at 226(208-295) days post-transplant, rising from 97(34-1074) to 5134(229-5680) BAU/ml, p=0.0016. Whilst in patients who had 3 vaccines pre-transplant, who received V4 (as 1st booster) at 82(49-101) days post-transplant, [anti-S] did not change, falling from 981(396-2666) to 871(242-2092) BAU/ml, p=0.62. Overall, infection pre-transplant and [anti-S] at the time of transplantation predicted post-transplant infection risk. As [Anti-S] fail to respond to SARS-CoV-2 booster vaccines given early post-transplant, passive immunity may be beneficial to protect patients during this period.

The identification of fall risk through tests of mediolateral stability during gait.

INTRODUCTION: Many falls in older adults are due to a loss of mediolateral stability during gait. This investigation examines if a simple beam-walking task can assess fall risk in older adults by taxing mediolateral control during gait. MATERIAL AND METHODS: 50 older adults (65-96 yrs.) and 20 younger adults (20-35 yrs.) walked along three 6 m long beams (12, 9 and 6 cm wide). Distance walked, number of steps and velocity were recorded. Participants also completed the Narrow Path Walking Test on a computerized gait mat and walked unrestricted across the mat. The number of falls in the 6 months pre- and post-testing were recorded. RESULTS: The beam data revealed significant differences between fallers and non-fallers in distance walked and number of steps taken on the 9 cm beam but not on the other beam widths. The coefficient of variation (CV) for step time and step length for unrestricted walking and for the NPWT were also significantly different between fallers and non-fallers. Falls in the 6 months before testing was not correlated with gait velocity but was significantly correlated with the number of steps and the distance walked on the 9 cm beam and with step length and step time CV. Falls in the 6 months following testing were strongly correlated with distance walked on the 9 cm beam. CONCLUSION: This research suggests that examining an older adult's ability to walk on a 9 cm wide beam might contribute significantly to the assessment of that person's fall risk.

Immune responses following 3rd and 4th doses of heterologous and homologous COVID-19 vaccines in kidney transplant recipients.

Background: Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population. Methods: We undertook a single centre cohort study of 724 kidney transplant recipients prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. 322 patients were sampled post-V4 for anti-spike (anti-S), with 69 undergoing assessment of SARS-CoV-2 T-cell responses. All vaccine doses were received post-transplant, only mRNA vaccines were used for V3 and V4 dosing. All participants had serological testing performed post-V2 and at least once prior to their first dose of vaccine. Findings: 586/724 (80.9%) patients were infection-naïve post-V3; 141/2586 (24.1%) remained seronegative at 31 (21-51) days post-V3. Timing of vaccination in relation to transplantation, OR: 0.28 (0.15-0.54), p=0.0001; immunosuppression burden, OR: 0.22 (0.13-0.37), p<0.0001, and a diagnosis of diabetes, OR: 0.49 (0.32-0.75), p=0.001, remained independent risk factors for non-seroconversion. Seropositive patients post-V3 had greater anti-S if primed with BNT162b2 compared with ChAdOx1, p=0.001.Post-V4, 45/239 (18.8%) infection-naïve patients remained seronegative. De novo seroconversion post-V4 occurred in 15/60 (25.0%) patients. There was no difference in anti-S post-V4 by vaccine combination, p=0.50. T-cell responses were poor, with only 11/54 (20.4%) infection-naive patients having detectable T-cell responses post-V4, with no difference seen by vaccine type. Interpretation: A significant proportion of transplant recipients remain seronegative following 3- and 4- doses of SARS-CoV-2 vaccines, with poor T-cell responses, and are likely to have inadequate protection against infection. As such alternative strategies are required to provide protection to this vulnerable group. Funding: MW/PK received study support from Oxford Immunotec.

Identification of Patient Characteristics Associated With SARS-CoV-2 Infection and Outcome in Kidney Transplant Patients Using Serological Screening.

BACKGROUND: From population studies, solid organ transplant recipients are at increased risk of mortality from RT-PCR confirmed COVID-19 infection. The risk factors associated with infection acquisition and mortality in transplant recipients using serological data have not been reported. METHODS: From 1725 maintenance transplant recipients, 855 consecutive patients were screened for SARS-CoV-2 antibodies. Serological screening utilized assays to detect both the N protein and receptor binding domain antibodies. Thirty-three of 855 (3.9%) of the screened patients had prior infection confirmed with RT-PCR. Twenty-one additional patients from our 1725 maintenance cohort with RT-PCR confirmed infection were included in our analysis. RESULTS: Eighty-nine of 855 (10.4%) patients tested positive for SARS-CoV-2 antibodies. Fifty-nine of 89 (66.3%) cases were patients newly identified as exposed, while 30/89 (33.7%) seropositive patients had previous infection confirmed by RT-PCR. A diagnosis of SARS-CoV-2 (RT-PCR or Ab+) was associated with being from a noncaucasoid background, P = 0.015; having a diagnosis of diabetes, P = 0.028 and a history of allograft rejection, P < 0.01. Compared with the RT-PCR+ cohort, patients with serological-proven infection alone were more likely to be receiving tacrolimus monotherapy, P < 0.01, and less likely to have a diagnosis of diabetes, P = 0.012. Seventeen of 113 (15.0%) of all patients with infection (RT-PCR and Ab+) died. Risk factors associated with survival were older age, odds ratio (OR): 1.07 (1.00-1.13), P = 0.041; receiving prednisolone, OR: 5.98 (1.65-21.60), P < 0.01 and the absence of diabetes, OR: 0.27 (0.07-0.99), P = 0.047. CONCLUSIONS: This study identifies risk factors and outcome for COVID-19 infection incorporating data on serologically defined infection and highlights the important contribution of immunosuppression regimen on outcomes.

Resuming Deceased Donor Kidney Transplantation in the COVID-19 Era: What Do Patients Want?

BACKGROUND: The rapidly evolving novel coronavirus 2019 (COVID-19) pandemic bought many kidney transplant (KT) programs to a halt. Integral to resuming KT activity is understanding the perspectives of potential transplant candidates during this highly dynamic time. METHODS: From June 1 to July 7, 2020, a telephone survey of KT candidates on the deceased donor waiting list at Imperial College Renal and Transplant Centre in West London was conducted. The survey captured ongoing COVID-19 exposure risks and patients' views on waitlist (WL) reactivation and undergoing transplantation. RESULTS: Two hundred seven responses were received. Of the respondents, 180 patients (87%) were happy to be reactivated onto the WL; with 141 patients (68%) willing to give consent to transplantation currently, while 53 patients (26%) felt unsure, and 13 patients (6%) would decline a KT. The vast majority of patients had no concerns. In the responses from those who were uncertain or who would decline a KT, concerns about COVID-19 infection and the need for reassurance from transplant units dominated. Universally patients wanted more information about COVID-19 infection risk with KT and the precautions being taken to reduce this risk. CONCLUSIONS: The majority of surveyed patients are in favor of reactivation and receiving a KT despite the ongoing COVID-19 pandemic. Reactivation of candidates cannot be assumed and should take an individualized approach, incorporating clinical risk with patient perspectives. Improved communication with KT candidates is highly requested.

Informing the Risk of Kidney Transplantation Versus Remaining on the Waitlist in the Coronavirus Disease 2019 Era.

INTRODUCTION: There are limited data pertaining to comparative outcomes of remaining on dialysis versus kidney transplantation as the threat of coronavirus disease 2019 (COVID-19) remains. In this study we delineate the differential risks involved using serologic methods to help define exposure rates. METHODS: From a cohort of 1433 patients with end-stage kidney disease (ESKD), we analyzed COVID-19 infection rates and outcomes in 299 waitlist patients compared with 237 transplant recipients within their first year post-transplant. Patients were followed over a 68-day period from the time our transplant program closed due to COVID-19. RESULTS: The overall mortality rates in waitlist and transplant populations were equivalent (P = 0.69). However, COVID-19 infection was more commonly diagnosed in the waitlist patients (P = 0.001), who were more likely to be tested by reverse transcriptase polymerase chain reaction (P = 0.0004). Once infection was confirmed, mortality risk was higher in the transplant patients (P = 0.015). The seroprevalence in dialysis and transplant patients with undetected infection was 18.3% and 4.6%, respectively (P = 0.0001). After adjusting for potential screening bias, the relative risk of death after a diagnosis of COVID-19 remained higher in transplant recipients (hazard ratio = 3.36 [95% confidence interval = 1.19-9.50], P = 0.022). CONCLUSIONS: Although COVID-19 infection was more common in the waitlist patients, a higher COVID-19‒associated mortality rate was seen in the transplant recipients, resulting in comparable overall mortality rates.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow assay for antibody prevalence studies following vaccination: a diagnostic accuracy study.

Background: Lateral flow immunoassays (LFIAs) are able to achieve affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Methods: This was a prospective diagnostic accuracy study. Sampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Two cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following two doses of SARS-CoV-2 vaccine, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination and subsequent follow up. During the participants visit, finger-prick blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG was detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. A total of 186 paired samples were collected. The accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay Results: The LFIA had an estimated sensitivity of 92.0% (114/124; 95% confidence interval [CI] 85.7% to 96.1%) and specificity of 93.6% (58/62; 95% CI 84.3% to 98.2%) using the Abbott assay as reference standard (using the threshold for positivity of 7.10 BAU/ml) Conclusions: Fortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveillance but does not meet criteria for individual testing.

Glomerular Disease and Pregnancy.

Nephrologists are routinely involved in the care of pregnant women with glomerulonephritis. Prepregnancy counseling is vital to inform women of the potential risks of pregnancy and to reduce those risks by optimizing clinical status and medications. In general, for all glomerulonephritides, the best pregnancy outcomes are achieved when the disease is in remission and the woman has preserved renal function with no proteinuria or hypertension. Each glomerulonephritis has specific considerations, for example in lupus nephritis, mycophenolate is teratogenic and must be stopped at least 6 weeks before conception, hydroxychloroquine is recommended for all pregnant women, and flares are frequently encountered and must be treated appropriately. De novo glomerulonephritis should be considered when significant proteinuria is found early in pregnancy or an acute kidney injury with active urine is encountered. Biopsy can be safely undertaken in the first trimester. Treatment is often with corticosteroids, azathioprine, and/or tacrolimus. Rituximab is increasingly used for severe disease. Women with glomerulonephritis should ideally be managed in a joint renal-obstetric clinic. This review details the approach to the care of women with glomerulonephritis from prepregnancy counseling, through antenatal care and delivery, to the postpartum period. Special attention is given to medications and treatment of glomerulonephritis in pregnancy.

Electrospun poly(ε-caprolactone) nanofiber shish kebabs mimic mineralized bony surface features.

Electrospinning of nanofiber is of growing interest especially in bone tissue engineering because of its similar fibrous properties to the extracellular matrix. To this end, we have fabricated polycaprolactone (PCL) nanofiber shish kebab (NFSK) templates. The novelty of this work is the ability to control the mineral orientation and spatial location on the nanofiber, mimicking natural collagen fibers. However, NFSK templates have properties that need to be investigated in terms of cellular response including fiber alignment and crystallization. In this study, MC3T3 E1 preosteoblast cells were seeded onto the templates to determine the effect of both fiber orientation and kebab size on the cell metabolic activity. PCL was electrospun to form aligned and randomly oriented nanofibers, which were then crystallized in a PCL solution in pentyl acetate for 15 and 60 min, resulting in the formation of homopolymer PCL NFSK templates. We evaluated the cell proliferation and alkaline phosphatase activity of MC3T3 E1 cells after 3, 7, and 14 days in coculture. Aligned nanofiber and polymer crystallization both significantly increased the cell proliferation and alkaline phosphatase activity at each time point. The aligned nanofibers and polymer crystallization resulted in the highest metabolic activities of the cells compared to the randomly oriented fibers and noncrystallized controls. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1141-1149, 2019.