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.

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.

Urinary retinol binding protein predicts renal outcome in systemic immunoglobulin light-chain (AL) amyloidosis.

Renal risk stratification in systemic immunoglobulin light-chain (AL) amyloidosis is according to estimated glomerular filtration rate (eGFR) and urinary protein creatinine ratio (uPCR), the latter attributed to glomerular dysfunction, with proximal tubular dysfunction (PTD) little studied. Urinary retinol binding protein 4 (uRBP), a low molecular weight tubular protein and highly sensitive marker of PTD, was prospectively measured in 285 newly diagnosed, untreated patients with systemic AL amyloidosis between August 2017 to August 2018. At diagnosis, the uRBP/creatinine ratio (uRBPCR) correlated with serum creatinine (r = 0·618, P < 0·0001), uPCR (r = 0·422, P < 0·0001) as well as both fractional excretion of phosphate and urate (r = 0·563, P < 0·0001). Log uRBPCR at diagnosis was a strong independent predictor of end-stage renal disease {hazard ratio [HR] 2·65, [95% confidence interval (CI) 1·06-6·64]; P = 0·038}, particularly in patients with an eGFR >30 ml/min/1.73 m2 [HR 4·11, (95% CI 1·45-11·65); P = 0·008] and those who failed to achieve a deep haematological response to chemotherapy within 3 months of diagnosis [HR 6·72, (95% CI 1·83-24·74); P = 0·004], and also predicted renal progression [HR 1·91, (95% CI 1·18-3·07); P = 0·008]. Elevated uRBPCR indicates PTD and predicts renal outcomes independently of eGFR, uPCR and clonal response in systemic AL amyloidosis. The role of uRBPCR as a novel prognostic biomarker merits further study, particularly in monoclonal gammopathies of renal significance.

Longevity of SARS-CoV-2 immune responses in hemodialysis patients and protection against reinfection.

Patients with end stage kidney disease receiving in-center hemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. Following infection, patients receiving ICHD frequently develop circulating antibodies to SARS-CoV-2, even with asymptomatic infection. Here, we investigated the durability and functionality of the immune responses to SARS-CoV-2 infection in patients receiving ICHD. Three hundred and fifty-six such patients were longitudinally screened for SARS-CoV-2 antibodies and underwent routine PCR-testing for symptomatic and asymptomatic infection. Patients were regularly screened for nucleocapsid protein (anti-NP) and receptor binding domain (anti-RBD) antibodies, and those who became seronegative at six months were screened for SARS-CoV-2 specific T-cell responses. One hundred and twenty-nine (36.2%) patients had detectable antibody to anti-NP at time zero, of whom 127 also had detectable anti-RBD. Significantly, at six months, 71/111 (64.0%) and 99/116 (85.3%) remained anti-NP and anti-RBD seropositive, respectively. For patients who retained antibody, both anti-NP and anti-RBD levels were reduced significantly after six months. Eleven patients who were anti-NP seropositive at time zero, had no detectable antibody at six months; of whom eight were found to have SARS-CoV-2 antigen specific T cell responses. Independent of antibody status at six months, patients with baseline positive SARS-CoV-2 serology were significantly less likely to have PCR confirmed infection over the following six months. Thus, patients receiving ICHD mount durable immune responses six months post SARS-CoV-2 infection, with fewer than 3% of patients showing no evidence of humoral or cellular immunity.

Parry-Romberg syndrome in a patient with scleroderma.

Parry-Romberg syndrome (PRS) is characterised by progressive but self-limiting facial hemiatrophy. We describe a 48-year-old woman with a 3-year history of gradually worsening right facial hemiatrophy on a background of scleroderma. Her initial primary concern was alopecia. Within the last year, there was greater prominence of her right zygoma and hyperpigmentation on her forearms and left neck. She also had worsening headaches and neck stiffness in the mornings. A clinical diagnosis of PRS was made and she was subsequently treated with a course of methotrexate. She is due to be followed up by dermatology, rheumatology and maxillofacial surgery with the aim of reconstructive surgery once her symptoms stabilise.

Lateral percutaneous nephrolithotomy: A safe and effective surgical approach.

INTRODUCTION: Percutaneous nephrolithotomy (PCNL) is traditionally performed with the patient in the prone position for large renal calculi. However, anesthetic limitations exist with the prone position. Similarly, the supine position is associated with poorer ergonomics due to the awkward downward position of the renal tract, a smaller window for percutaneous puncture, and a higher risk of anterior calyx puncture. This study aimed to demonstrate the feasibility and safety of lateral-PCNL in managing large renal calculi without the disadvantages of prone and supine positions. METHODS: Retrospectively, 347 lateral-PCNL cases performed from July 2001 to July 2015 were examined. the patient's thorax, abdomen, and pelvis were positioned over a bridge perpendicular to a "broken" table, creating an extended lumbodorsal space. The procedure was evaluated in terms of stone clearance at 3 months' postprocedure, operative time, and complications. RESULTS: Primary stone clearance was achieved in 82.7% of patients. The mean operating time was 97 min. The average time taken to establish the tract and mean radiation time were 4.5 min and 6.93 min, respectively. In total, 2.3% of patients required postoperative transfusion, and 13.5% of patients had postoperative fever. There was one case of hydrothorax, but no bowel perforation. CONCLUSIONS: Our lateral-PCNL technique allows for effective stone clearance due to good stone ergonomics and it should be considered as a safe alternative even in the most routine procedures.

Outcomes following Serial Intragastric Balloon Therapy for Obesity and Nonalcoholic Fatty Liver Disease in a Single Centre.

Background: The incidence of nonalcoholic fatty liver disease (NAFLD) continues to parallel the rise in obesity rates. Endobariatric devices such as the intragastric balloon (IGB) may provide an alternative treatment option. Methods: Outcomes following IGB treatment in 135 patients with obesity and NAFLD (mean baseline weight 117.9 kg; BMI 41.7 kg/m2; HOMA-IR 3.6) were retrospectively examined. Clinical, anthropometric, and biochemical changes were analysed at six months and after consecutive treatment with two and three serial IGBs. Results: After six months, significant changes were seen with weight and BMI (mean reductions of 11.3 kg and 4.1 kg/m2, resp., p < 0.01 for both). Significant improvements were also seen with ALT, GGT, and HOMA-IR, with all changes corresponding with weight loss. Forty-eight patients received two IGBs, and 20 were treated with three serial IGBs. The greatest amount of total weight loss was observed after the first 6 months (mean weight lost 7.4 kg, versus 3.6 kg and 1.9 kg with two and three IGBs, resp.). Conclusions: IGB therapy is an effective, alternative nonsurgical means for weight loss in the management of obesity and NAFLD over the short term, with greatest outcomes observed after six months. Improvements in insulin resistance and hepatic transaminases correlated with weight change.