Publications by authors named "Titus Augustine"

74 Publications

Surgical management of Encapsulating Peritoneal Sclerosis (EPS) in children: international case series and literature review.

Pediatr Nephrol 2021 Aug 26. Epub 2021 Aug 26.

Department of Renal and Pancreas Transplantation, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Oxford Road, Manchester, M13 9WL, UK.

Background: Encapsulating Peritoneal Sclerosis (EPS) is a rare phenomenon in paediatric patients with kidney failure treated with peritoneal dialysis (PD). This study highlights clinical challenges in the management of EPS, with particular emphasis on peri-operative considerations and surgical technique.

Methods: Retrospective analysis of all paediatric patients with EPS treated at the Manchester Centre for Transplantation.

Results: Four patients were included with a median duration of 78 months on PD. All patients had recurrent peritonitis (> 3 episodes), and all had symptoms within three months of a change of dialysis modality from PD to haemodialysis or transplant. In Manchester, care was delivered by a multi-disciplinary team, including surgeons delivering the adult EPS surgical service with a particular focus on nutritional optimisation, sepsis control, and wound management. The surgery involved laparotomy, lavage, and enterolysis of the small bowel + / - stoma formation, depending on intra-abdominal contamination. Two patients had a formal stoma, which were reversed at three and six months, respectively. Two patients underwent primary closure of the abdomen, whereas two patients had re-look procedures at 48 h with secondary closure. One patient had a post-operative wound infection, which was managed medically. One patient's stoma became detached, leading to an intra-abdominal collection requiring re-laparotomy. The median length of stay was 25 days, and patients were discharged once enteral feeding was established. All patients remained free of recurrence with normal gut function and currently two out of four have functioning transplants.

Conclusions: This series demonstrates 100% survival and parenteral feed independence following EPS surgery. Post-operative morbidity was common; however, with individualised experience-based decision-making and relevant additional interventions, patients made full recoveries. Health and development post-surgery continued, allowing the potential for transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.
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http://dx.doi.org/10.1007/s00467-021-05243-0DOI Listing
August 2021

Staggered Dual Kidney Transplantation.

Prog Transplant 2021 Sep 10;31(3):263-266. Epub 2021 Jun 10.

Department of Renal and Pancreas Transplantation, Manchester Royal Infirmary, 5293Manchester University NHS Foundation Trust, Manchester, United Kingdom.

We describe a case where a patient received a successful dual kidney transplantation in a staggered fashion. Two kidneys from a deceased donor were accepted for 2 separate primary intended recipients, however, due to unforeseen circumstances, both kidneys were eventually transplanted in a staggered fashion into an alternate single recipient. The intention behind this method was to enhance the patient's renal function and to prevent the wastage of a kidney. Despite the significantly prolonged cold ischemia times, the recipient has excellent dual graft function after 3 years. The positive outcome underpins the effectiveness of donor kidneys even with prolonged cold ischemia times outside established best practice guidelines. It also reinforces the effectiveness of dual kidney transplantation. Transplant professionals encounter complex situations occasionally where an established evidence-base or aids to decision-making are limited. This case reflects challenges in decision-making, patient counselling and consent, especially when the opportunity for the staggered dual kidney transplantation, with potential increased morbidity, came about as another recipient declined a usable kidney. It also highlights the widely differing risk appetites of different patients. Crucially, it optimised the donation process and procurement of 2 kidneys while preventing wastage. To our knowledge, this is the first report of a staggered dual kidney transplantation in a single recipient.
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http://dx.doi.org/10.1177/15269248211024606DOI Listing
September 2021

No evidence of improvement in neuropathy after renal transplantation in patients with end stage kidney disease.

J Peripher Nerv Syst 2021 Sep 10;26(3):269-275. Epub 2021 Jun 10.

Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health, University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, Manchester, UK.

To assess the impact of renal transplantation on peripheral nerve damage in patients with chronic kidney disease (CKD). Fifteen patients with CKD (eGFR <15 mL/min/1.73 m ) underwent longitudinal assessment after renal transplantation (age: 56.88 ± 2.53 years, eGFR: 46.82 ± 4.86) and were compared with 15 age-matched controls (age: 58.25 ± 2.18 years, eGFR: 86.0 ± 2.0). The neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration perception threshold (VPT), cold and warm sensation threshold (CST and WST), cold and heat induced pain (CIP and HIP), deep breathing heart rate variability (DB-HRV), nerve conduction studies and corneal confocal microscopy (CCM) to quantify small nerve fibre pathology, were undertaken within 1-month of renal transplantation (baseline) and at 6, 12 and 24 months of follow up. There was no significant difference in NSP (P = .1), NDS (P = .3), VPT (P = .6), CST (P = .2), CIP (P = .08), HIP (P = .1), DB-HRV (P = .9) and sural (P = .4) and peroneal (P = .1) nerve amplitude between patients with CKD and controls at baseline. However, sural (P = .04), peroneal (P = .002) and tibial (P = .007) nerve conduction velocity and tibial nerve amplitude (P = .03) were significantly lower, WST (P = .02) was significantly higher and corneal nerve fibre density (P = .004) was significantly lower in patients with CKD compared with controls. There was no significant change in NSP, NDS, quantitative sensory testing, DB-HRV, nerve conduction or CCM parameters 24 months after renal transplantation. There is evidence of small and large fibre neuropathy in patients with CKD, but no change up to 24 months after successful renal transplantation.
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http://dx.doi.org/10.1111/jns.12456DOI Listing
September 2021

Endovascular coiling in the treatment of patients with renal artery aneurysms.

J Vasc Surg Cases Innov Tech 2021 Jun 18;7(2):307-310. Epub 2021 Apr 18.

Department of Renal and Pancreas Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom.

Endovascular coiling is a percutaneous endovascular technique used in the management of arterial aneurysms with high success rates and minimal associated morbidity. We present a series of three patients with incidental renal artery aneurysms treated successfully with endovascular coiling, despite comorbidities. One patient had an aneurysm associated with a solitary kidney. The decision to use this technique becomes critical when the aneurysm involves a single functioning kidney. Each renal artery aneurysm was successfully coiled by combining vascular and neurointerventional techniques. The results from the present case series also highlight the challenges faced in therapeutic decision-making in complex situations with limited error margins.
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http://dx.doi.org/10.1016/j.jvscit.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121767PMC
June 2021

Transplant Options for Patients With Diabetes and Advanced Kidney Disease: A Review.

Am J Kidney Dis 2021 09 14;78(3):418-428. Epub 2021 May 14.

Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address:

Optimal glycemic control in kidney transplant recipients with diabetes is associated with improved morbidity and better patient and allograft survival. Transplant options for patients with diabetes requiring insulin therapy and chronic kidney disease who are suitable candidates for kidney transplantation should include consideration of β-cell replacement therapy: pancreas or islet transplantation. International variation related to national regulatory policies exists in offering one or both options to suitable candidates and is further affected by pancreas/islet allocation policies and transplant waiting list dynamics. The selection of appropriate candidates depends on patient age, coexistent morbidities, the timing of referral to the transplant center (predialysis versus on dialysis) and availability of living kidney donors. Therefore, early referral (estimated glomerular filtration rate < 30 mL/min/1.73 m) is of the utmost importance to ensure adequate time for informed decision making and thorough pretransplant evaluation. Obesity, cardiovascular disease, peripheral vascular disease, smoking, and frailty are some of the conditions that need to be addressed before acceptance on the transplant list, and ideally before dialysis becoming imminent. This review offers insights into selection of pancreas/islet transplant candidates by transplant centers and an update on posttransplant outcomes, which may have practice implications for referring nephrologists.
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http://dx.doi.org/10.1053/j.ajkd.2021.02.339DOI Listing
September 2021

Radiological initial treatment of vascular catastrophes in pancreas transplantation: Review of current literature.

Transplant Rev (Orlando) 2021 07 18;35(3):100624. Epub 2021 Apr 18.

Manchester University Hospitals NHS Foundation Trust, Department of Renal and Pancreatic Transplantation, Manchester Academic Health Science Centre, Manchester, Greater Manchester, M13 9WL, UK.

Background: Arterio-enteric fistula (AEF) is a rare but potentially devastating complication of solid organ pancreatic transplantation. Traditional management has been to remove the pancreas-duodenum allograft and control the vascular defect. Interventional radiological (IR) techniques present a new method of managing AEF related haemorrhage without re-operation and the potential to preserve graft function. This paper examines the available literature to assess efficacy and safety of this novel approach.

Methods: Aggregate results tables were constructed from 28 cases identified in the English language literature where IR was used in the management of AEF following pancreas transplantation. Outcomes recorded were death, re-bleeding, surgical intervention required and post intervention graft function. These were analysed with respect to technical factors and graft function at time of presentation.

Results: 28 cases of AEF managed by IR methods were identified. Mortality was high at 17.9%. 78.6% of all AEFs were present in failed pancreas allografts. Median time from transplant to bleeding event was 29 months. There was a trend of bleeding event occurring within 12 months of allograft failure or rejection. Of the AEFs present in functioning grafts, graft salvage rate was 33% from available data. Coil embolization or use of haemostatic compressed sponge as primary intervention was associated with a higher rate of re-bleeding and death versus arterial stenting. Arterial stenting resulted in a higher rate of distal ischaemia requiring surgical re-vascularisation. All deaths occurred in patients who did not have a transplant pancreatectomy as part of their definitive treatment.

Conclusion: IR can be an effective way to manage bleeding in the context of AEF associated with pancreas transplantation. If patient condition allows, it should be the first-choice intervention to manage AEF associated bleeding. Use of arterial stenting is more effective in controlling and preventing further bleeding. In a non-functioning graft, transplant pancreatectomy should be strongly considered, possibly in conjunction with or following arterial stenting.
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http://dx.doi.org/10.1016/j.trre.2021.100624DOI Listing
July 2021

Training digitally competent clinicians.

BMJ 2021 03 25;372:n757. Epub 2021 Mar 25.

Department of Renal and Pancreatic Transplantation, Manchester Academic Health Science Centre, Manchester, UK.

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http://dx.doi.org/10.1136/bmj.n757DOI Listing
March 2021

Donor insulin therapy in intensive care predicts early outcomes after pancreas transplantation.

Diabetologia 2021 Jun 4;64(6):1375-1384. Epub 2021 Mar 4.

Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

Aims/hypothesis: Approximately 50% of organ donors develop hyperglycaemia in intensive care, which is managed with insulin therapy. We aimed to determine the relationships between donor insulin use (DIU) and graft failure in pancreas transplantation.

Methods: UK Transplant Registry organ donor data were linked with national data from the UK solid pancreas transplant programme. All pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Logistic regression models determined associations between DIU and causes of graft failure within 3 months. Area under the receiver operating characteristic curve (aROC) and net reclassification improvement (NRI) assessed the added value of DIU as a predictor of graft failure.

Results: In 2168 pancreas transplant recipients, 1112 (51%) donors were insulin-treated. DIU was associated with a higher risk of graft loss from isolated islet failure: OR (95% CI), 1.79 (1.05, 3.07), p = 0.03, and this relationship was duration/dose dependent. DIU was also associated with a higher risk of graft loss from anastomotic leak (2.72 [1.07, 6.92], p = 0.04) and a lower risk of graft loss from thrombosis (0.62 [0.39, 0.96], p = 0.03), although duration/dose-dependent relationships were only identified in pancreas transplant alone/pancreas after kidney transplant recipients with grafts failing due to thrombosis (0.86 [0.74, 0.99], p = 0.03). The relationships between donor insulin characteristics and isolated islet failure remained significant after adjusting for potential confounders: DIU 1.75 (1.02, 2.99), p = 0.04; duration 1.08 (1.01, 1.16), p = 0.03. In multivariable analyses, donor insulin characteristics remained significant predictors of lower risk of graft thrombosis in pancreas transplant alone/pancreas after kidney transplant recipients: DIU, 0.34 (0.13, 0.90), p = 0.03; insulin duration/dose, 0.02 (0.001, 0.85), p = 0.04. When data on insulin were added to models predicting isolated islet failure, a significant improvement in discrimination and risk reclassification was observed in all models: no DIU aROC 0.56; DIU aROC 0.57, p = 0.86; NRI 0.28, p < 0.00001; insulin duration aROC 0.60, p = 0.47; NRI 0.35, p < 0.00001.

Conclusions/interpretation: DIU predicts graft survival in pancreas transplant recipients. This assessment could help improve donor selection and thereby improve patient and graft outcomes.
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http://dx.doi.org/10.1007/s00125-021-05411-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099796PMC
June 2021

Adoption of clinical risk prediction tools is limited by a lack of integration with electronic health records.

BMJ Health Care Inform 2021 02;28(1)

Department of Renal and Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.

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http://dx.doi.org/10.1136/bmjhci-2020-100253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898839PMC
February 2021

The use of health information technology in renal transplantation: A systematic review.

Transplant Rev (Orlando) 2021 04 10;35(2):100607. Epub 2021 Feb 10.

Manchester University Hospitals NHS Foundation Trust, Department of Renal and Pancreatic Transplantation, Manchester Academic Health Science Centre, Manchester, Greater Manchester, M13 9WL, UK; University of Manchester Faculty of Biology, Medicine and Health, Division of Diabetes, Endocrinology and Gastroenterology, Manchester, Greater Manchester, M13 9PT, UK.

Renal transplantation is a complex, multi-disciplinary and cross-center service. Clinical pathways naturally traverse specialty and organizational boundaries as patients transition from chronic kidney disease to renal failure and ultimately transplantation. Health information technology (IT) has the potential to support transplant care by improving access to data, information sharing and communication. This novel review aimed to identify and characterize health IT solutions in renal transplantation, and where possible evaluate any intended benefits. A systematic literature review was conducted of studies covering any part of the clinical pathway, with end-users being clinical staff or patients. Interventions were characterized and evaluated for achieved benefits using the World Health Organization (WHO) Classification of Digital Health Interventions and the mixed methods assessment tool (MMAT) was used to determine the quality of experimental studies. Of 4498 articles, 12 descriptive and 6 experimental studies met the inclusion criteria. Median MMAT percentage score of experimental studies was 64 (i.q.r. 57 to 74.8). The most frequent functionality of technology involved overcoming communication roadblocks and improving access to data. Intended benefits included improving information management and supporting workflow, however only one study reported evaluated results. Six patient-facing applications that primarily addressed adherence-to-treatment were identified, five of which were evaluated for intended benefits, showing overall positive results. Overall, despite transplantation being well suited to health IT interventions, this review demonstrates a scarcity of literature in this field. A small number of clinician- and patient-facing IT solutions have been reported, albeit mostly in non-experimental studies. Due to this lack of formal evaluation, the effectiveness of solutions remains unclear. High-quality evaluative studies are required to develop effective IT solutions that improve clinical care.
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http://dx.doi.org/10.1016/j.trre.2021.100607DOI Listing
April 2021

Associations between human leukocyte antigens and renal function.

Sci Rep 2021 Feb 4;11(1):3158. Epub 2021 Feb 4.

Transplantation Laboratory, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK.

Human leukocyte antigens (HLA) have been associated with renal function, but previous studies report contradictory findings with little consensus on the exact nature or impact of this observation. This study included 401,307 white British subjects aged 39-73 when they were recruited by UK Biobank. Subjects' HLA types were imputed using HLA*IMP:02 software. Regression analysis was used to compare 362 imputed HLA types with estimated glomerular filtration rate (eGFR) as a primary outcome and clinical indications as secondary outcome measures. 22 imputed HLA types were associated with increased eGFR (and therefore increased renal function). Decreased eGFR (decreased renal function) was associated with 11 imputed HLA types, seven of which were also associated with increased risk of end-stage renal disease and/or chronic kidney disease. Many of these HLA types are commonly inherited together in established haplotypes, for example: HLA-A*01:01, B*08:01, C*07:01, DRB1*03:01, DQB1*02:01. This haplotype has a population frequency of 9.5% in England and each allele was associated with decreased renal function. 33 imputed HLA types were associated with kidney function in white British subjects. Linkage disequilibrium in HLA heritance suggests that this is not random and particularly affects carriers of established haplotypes. This could have important applications for the diagnosis and treatment of renal disease and global population health.
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http://dx.doi.org/10.1038/s41598-021-82361-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862310PMC
February 2021

Does the Microbiome Affect the Outcome of Renal Transplantation?

Front Cell Infect Microbiol 2020 23;10:558644. Epub 2020 Dec 23.

School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.

The role of the human microbiome in health and disease is becoming increasingly apparent. Emerging evidence suggests that the microbiome is affected by solid organ transplantation. Kidney transplantation is the gold standard treatment for End-Stage Renal Disease (ESRD), the advanced stage of Chronic Kidney Disease (CKD). The question of how ESRD and transplantation affect the microbiome and includes how the microbiome is affected by increased concentrations of toxins such as urea and creatinine (which are elevated in ESRD), whether restoration of renal function following transplantation alters the composition of the microbiome, and the impact of lifelong administration of immunosuppressive drugs on the microbiome. Changes in microbiome composition and activity have been reported in ESRD and in therapeutic immunosuppression, but the effect on the outcome of transplantation is not well-understood. Here, we consider the current evidence that changes in kidney function and immunosuppression following transplantation influence the oral, gut, and urinary microbiomes in kidney transplant patients. The potential for changes in these microbiomes to lead to disease, systemic inflammation, or rejection of the organ itself is discussed, along with the possibility that restoration of kidney function might re-establish orthobiosis.
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http://dx.doi.org/10.3389/fcimb.2020.558644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785772PMC
June 2021

A Successful Treatment of Encapsulating Peritoneal Sclerosis in an Adolescent Boy on Long-term Peritoneal Dialysis: A Case Report.

Prague Med Rep 2020 ;121(4):254-261

Department of Transplant and Endocrine Surgery, Manchester Royal Infirmary, Manchester University Foundation Trust; An United Kingdom National Specialized Centre for Surgery for Encapsulating Peritoneal Sclerosis, Manchester, United Kingdom.

Encapsulating peritoneal sclerosis (EPS) is a rare life-threatening complication associated with peritoneal dialysis (PD). EPS is characterized by progressive fibrosis and sclerosis of the peritoneum, with the formation of a membrane and tethering of loops of the small intestine resulting in intestinal obstruction. It is very rare in children. We present a case of a 16-year-old adolescent boy who developed EPS seven years after being placed on continuous ambulatory peritoneal dialysis (CAPD) complicated by several episodes of bacterial peritonitis. The diagnosis was based on clinical, radiological, intraoperative and histopathological findings. The patient was successfully treated with surgical enterolysis. During a 7-year follow-up, there have been no further episodes of small bowel obstruction documented. He still continues to be on regular hemodialysis and is awaiting a deceased donor kidney transplant. EPS is a long-term complication of peritoneal dialysis and is typically seen in adults. Rare cases may be seen in the pediatric population and require an appropriate surgical approach that is effective and lifesaving for these patients.
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http://dx.doi.org/10.14712/23362936.2020.22DOI Listing
January 2021

Kidney Transplantation From a 5-Day-Old Donor With a Single Functioning Kidney.

Exp Clin Transplant 2020 11;18(6):732-736

From the Department of Renal and Pancreas Transplantation, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Unitek Kingdom.

Kidney transplant restores renal function in eligible patients with end-stage renal failure who require renal replacement therapy. There remains a significant disparity between the demand and supply of suitable kidneys for transplant. In recent years, pediatric donors have formed an important area for expansion of the donor pool. However, neonatal donation (< 28 days) remains an underutilized resource. We describe a case of en bloc kidney transplant from a 5-day-old donor after circulatory death into an adult recipient. One kidney thrombosed almost immediately, leaving a single 4.5-cm, poorly functioning kidney. Eighteen months after transplant, the recipient has shown good function with the estimated glomerular filtration rate continuing to improve. This case demonstrates that a single neonatal kidney can grow and adapt to provide adequate renal function in an adult. This experience suggests that a single kidney from a neonate can sustain renal function in adults, and every effort should be made to maximize their use in transplant.
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http://dx.doi.org/10.6002/ect.2020.0254DOI Listing
November 2020

Non-invasive cardiac stress studies may not offer significant benefit in pre-kidney transplant evaluation: A retrospective cohort study.

PLoS One 2020 28;15(10):e0240912. Epub 2020 Oct 28.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Hope Hospital, Salford, United Kingdom.

Background: Screening with cardiac non-invasive stress studies (NISS) prior to listing for kidney transplantation can help in identifying treatable coronary disease and is considered an integral part of pre-kidney transplant evaluation. However, few studies assessed their effectiveness in all patients evaluated for transplantation in clinical practice. To evaluate the role of NISS in pre-kidney transplant evaluation we analyzed their impact prior to waitlisting in 1053 adult CKD-5 patients consecutively evaluated in Greater Manchester, UK during a 6-year period.

Methods: 918 waitlisted patients were grouped based on presence or absence of Diabetes or Cardio-Vascular Disease (CVD): Group-1 (255 DM-/CVD-/NISS-), Group-2 (368 DM-/CVD-/NISS+) and Group-3 (295 with DM or CVD).

Results: Group-2 patients had longer 'time-to-listing' (5.5months in Group-1 vs 6.9months in 'Normal-NISS' vs 9.9months in 'Abnormal-NISS', p<0.01) but none with 'Abnormal-NISS' needed coronary revascularization before listing. NISS was followed by revascularization in 8 Group-3 patients (3%). In multi-variate analyses, there was no association of NISS on death or MACE in listed patients. During follow up, Transplantation was the most significant factor associated with improved outcomes in all subgroups (HR:0.97, p<0.001). 135 patients were considered unsuitable for waitlisting, with NISS influencing management in 11 of these patients (8%).

Conclusions: Pre-kidney transplant evaluation with NISS influenced clinical management in 19 of 1053 (2%) patients. Screening with NISS added limited benefit but contributes to significant delays in listing and adding resource implications. Further studies are needed to assess clinical and cost effectiveness of NISS in pretransplant evaluation to optimize outcomes and resources.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240912PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592791PMC
December 2020

Encapsulating Peritoneal Sclerosis: A Case Report and Literature Review.

Am J Case Rep 2020 Oct 4;21:e925341. Epub 2020 Oct 4.

Department of General Surgery, Sultan Qaboos University Hospital, Muscat, Oman.

BACKGROUND Encapsulating peritoneal sclerosis (EPS) is a rare, life-threatening, and serious complication of long-term peritoneal dialysis (PD). No evidence-based management strategy has been established until now. Surgical management, including enterolysis and excision of the sclerotic and obstructing adhesions, should be considered as soon as conservative management fails to work. We report a case of EPS soon after transplantation in a patient with end-stage kidney disease who had been on long-term PD. CASE REPORT A 26-year-old man had been found to have advanced chronic kidney disease secondary to glomerulonephritis on pre-employment investigation. He was on continuous ambulatory PD for 5 years, after which he underwent a living donor renal transplant from his full HLA-matched sibling. He did well postoperatively, with excellent graft function. One month after transplantation, he repeatedly presented to our Emergency Department with signs and symptoms of complete small-bowel obstruction. Computed tomography of the abdomen showed features of small-bowel obstruction secondary to interloop adhesions. The patient was initially managed conservatively; however, as his condition continued to deteriorate, an exploratory laparotomy was carried out. Operative findings were suggestive of early EPS localized to the terminal ileum. Total enterolysis along with peritonectomy was performed along with resection of the diseased and obstructing terminal ileum. The patient did well, and he was discharged home day 10 postoperatively. CONCLUSIONS EPS remains a serious and fatal complication of long-term PD. Early definitive diagnosis, treatment, and ultimately surgical intervention may be required to prevent the morbidity and mortality associated with this condition.
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http://dx.doi.org/10.12659/AJCR.925341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545366PMC
October 2020

Human leukocyte antigen associations with renal function among ethnic minorities in the United Kingdom.

HLA 2020 12 5;96(6):697-708. Epub 2020 Nov 5.

Transplantation Laboratory, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK.

Human leukocyte antigens (HLA) have been associated with renal function, but previous studies report contradictory findings. There has been a lack of research into how HLA affects renal function in Black, Asian and Minority Ethnic (BAME) people in the UK, despite BAME people being disproportionately affected by renal dysfunction. This study included >27 000 UK Biobank subjects of six ethnicities (>12 100 Irish, >5400 Indian, >4000 Black Caribbean, >3000 Black African, >1600 Pakistani, and >1400 Chinese) aged 39 to 73. Subjects' high-resolution HLA genotypes were imputed using HLA*IMP:02 software. Regression analysis was used to compare 108 imputed HLA alleles with two measures of estimated glomerular filtration rate (eGFR): one based on serum creatinine; one based on serum cystatin. Secondary analysis compared CKD stage 2 subjects to healthy controls. Nine imputed HLA alleles were associated with eGFR (adjusted P < .05). Six associations were based on creatinine in Black African subjects: HLA-B*53:01 (beta = -2.628, adjusted P = 4.69 × 10 ); C*04:01 (beta = -1.667, adjusted P = .0269); DPA1*02:01 (beta = -1.569, adjusted P = .0182); and DPA1*02:02 (beta = -1.716, adjusted P = .0251) were linked to decreased renal function, while DRB1*03:01 (beta = 3.200, adjusted P = 3.99 × 10 ) and DPA1*01:03 (beta = 2.276, adjusted P = 2.31 × 10 ) were linked to increased renal function. Two of these (HLA-B*53:01 and C*04:01) are commonly inherited together. In Irish subjects, HLA-DRB1*04:01 (beta = 1.075, adjusted P = .0138) was linked to increased eGFR (based on cystatin); in Indian subjects, HLA-DRB1*03:01 (beta = -1.72, adjusted P = 4.78 × 10 ) and DQB1*02:01 (beta = -1.755, adjusted P = 2.26 × 10 )were associated with decreased eGFR (based on cystatin). No associations were found in the other three ethnic groups. Nine HLA alleles appear to be associated with kidney function in BAME people in the UK. This could have applications for the diagnosis and treatment of renal disease and could help reduce health inequalities in the UK.
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http://dx.doi.org/10.1111/tan.14078DOI Listing
December 2020

Peri-transplant glycaemic control as a predictor of pancreas transplant survival.

Diabetes Obes Metab 2021 01 5;23(1):49-57. Epub 2020 Oct 5.

Department of Renal and Pancreas Transplantation, Manchester University NHSFT, Manchester, UK.

Aims: The relationship between peri-transplant glycaemic control and outcomes following pancreas transplantation is unknown. We aimed to relate peri-transplant glycaemic control to pancreas graft survival and to develop a framework for defining early graft dysfunction.

Methods: Peri-transplant glycaemic control profiles over the first 5 days postoperatively were determined by an area under the curve [AUC; average daily glucose level (mmol/L) × time (days)] and the coefficient of variation of mean daily glucose levels. Peri-transplant hyperglycaemia was defined as an AUC ≥35 mmol/day/L (daily mean blood glucose ≥7 mmol/L). Risks of graft failure associated with glycaemic control and variability and peri-transplant hyperglycaemia were determined using covariate-adjusted Cox regression.

Results: We collected 7606 glucose readings over 5 days postoperatively from 123 pancreas transplant recipients. Glucose AUC was a significant predictor of graft failure during 3.6 years of follow-up (unadjusted HR [95% confidence interval] 1.17 [1.06-1.30], P = .002). Death censored non-technical graft failure occurred in eight (10%) recipients with peri-transplant normoglycaemia, and eight (25%) recipients with peri-transplant hyperglycaemia such that hyperglycaemia predicted a 3-fold higher risk of graft failure [HR (95% confidence interval): 3.0 (1.1-8.0); P = .028].

Conclusion: Peri-transplant hyperglycaemia is strongly associated with graft loss and could be a valuable tool guiding individualized graft monitoring and treatment. The 5-day peri-transplant glucose AUC provides a robust and responsive framework for comparing graft function.
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http://dx.doi.org/10.1111/dom.14181DOI Listing
January 2021

Talaromycosis in a renal transplant recipient returning from South China.

Transpl Infect Dis 2021 Feb 31;23(1):e13447. Epub 2020 Aug 31.

Department of Renal and Pancreas Transplantation, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Oxford Road, Manchester, UK.

Talaromycosis is a fungal infection endemic in Southeast Asia. We report a case of a renal transplant recipient who developed infection after a trip to South China. She presented with constitutional symptoms and was found to have an FDG-avid lung mass. Histopathology demonstrated small yeast cells and culture grew Talaromyces marneffei. The patient was treated with 2 weeks of liposomal amphotericin B followed by itraconazole. The dose of tacrolimus was significantly reduced because of the interaction with itraconazole. Mycophenolate mofetil was discontinued. After 12 months of treatment, the mass had completely resolved. Talaromycosis has mainly been reported in patients with AIDS and is uncommon among solid organ transplant recipients. The immune response against T. marneffei infection is mediated predominantly by T cells and macrophages. The diagnosis may not be suspected outside of endemic areas. We propose a therapeutic approach in transplant patients by extrapolating the evidence from the HIV literature and following practices applied to other endemic mycoses.
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http://dx.doi.org/10.1111/tid.13447DOI Listing
February 2021

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy.

EBioMedicine 2020 Aug 21;58:102899. Epub 2020 Jul 21.

Transplantační laboratoř, Institut klinické a experimentální medicíny (IKEM), Vídeňská 1958/9, 140 21 Praha 4, Czech Republic.

Background: Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs.

Methods: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression.

Findings: IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88-0⋅94) in cross-validation and 0⋅97 (0⋅93-1⋅00) in six months follow-up samples.

Interpretation: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial.

Funding: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas' Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007-2013 [HEALTH-F5-2010-260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19-06-00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].
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http://dx.doi.org/10.1016/j.ebiom.2020.102899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374249PMC
August 2020

The impact of the COVID-19 pandemic on renal transplantation in the UK.

Clin Med (Lond) 2020 07 25;20(4):e82-e86. Epub 2020 May 25.

Manchester University Hospitals NHS Foundation Trust, Manchester, UK and University of Manchester, Manchester, UK.

COVID-19 is impacting provision of renal transplantation in the UK with a reduction in clinical activity. Publicly available Renal Registry and NHS Blood and Transplant reports were analysed to model the number of missed transplant opportunities, waiting list size and change in dialysis population over a six-month period starting 5 March 2020. An estimated 1,670 kidney transplant opportunities may be lost, which will lead to 6,317 active patients on the kidney-alone waiting list, compared to 4,649 based on usual activity estimates. This will result in 1,324 additional patients on dialysis who would otherwise have been transplanted. COVID-19 will lead to a marked loss of transplant opportunities and a significantly larger national waiting list. The existing strain on dialysis capacity will be exacerbated as patients remain on dialysis as the only available form of renal replacement therapy. These findings will help inform policy and service specific strategies.
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http://dx.doi.org/10.7861/clinmed.2020-0183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385760PMC
July 2020

Donor insulin use predicts beta-cell function after islet transplantation.

Diabetes Obes Metab 2020 10 14;22(10):1874-1879. Epub 2020 Jun 14.

Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

Insulin is routinely used to manage hyperglycaemia in organ donors and during the peri-transplant period in islet transplant recipients. However, it is unknown whether donor insulin use (DIU) predicts beta-cell dysfunction after islet transplantation. We reviewed data from the UK Transplant Registry and the UK Islet Transplant Consortium; all first-time transplants during 2008-2016 were included. Linear regression models determined associations between DIU, median and coefficient of variation (CV) peri-transplant glucose levels and 3-month islet graft function. In 91 islet cell transplant recipients, DIU was associated with lower islet function assessed by BETA-2 scores (β [SE] -3.5 [1.5], P = .02), higher 3-month post-transplant HbA1c levels (5.4 [2.6] mmol/mol, P = .04) and lower fasting C-peptide levels (-107.9 [46.1] pmol/l, P = .02). Glucose at 10 512 time points was recorded during the first 5 days peri-transplant: the median (IQR) daily glucose level was 7.9 (7.0-8.9) mmol/L and glucose CV was 28% (21%-35%). Neither median glucose levels nor glucose CV predicted outcomes post-transplantation. Data on DIU predicts beta-cell dysfunction 3 months after islet transplantation and could help improve donor selection and transplant outcomes.
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http://dx.doi.org/10.1111/dom.14088DOI Listing
October 2020

Living donor kidney transplantation: Let's talk about it.

Clin Med (Lond) 2020 05;20(3):346-348

Manchester University Hospitals NHS Foundation Trust, Manchester, UK and University of Manchester, Manchester, UK.

Transplantation is the preferred treatment option for end-stage renal disease as it offers superior results and patient reported outcomes in comparison to dialysis. Patients treated with a transplant live longer, healthier and more independent lives. Transplantation is also more cost-effective, reducing the overall burden of renal disease. Despite the rising incidence of renal failure, the uptake of living donor kidney transplantation has been static across the UK for several years. Among transplantation, living donation offers a number of advantages compared with deceased donor transplantation. The procedure is more likely to be performed pre-dialysis and the elective nature allows for better perioperative planning. Awareness for living donation processes among healthcare professionals, patients and the public appears to be poor. Sharing information regarding the process will help educate colleagues, dispel myths and, crucially, allow patients the opportunity to talk about this treatment option with their hospital doctor.
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http://dx.doi.org/10.7861/clinmed.2020-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354017PMC
May 2020

Post-Transplantation Diabetes Mellitus.

Diabetes Ther 2020 Apr 24;11(4):779-801. Epub 2020 Feb 24.

Manchester University NHS Foundation Trust, Manchester, UK.

Solid organ transplantation (SOT) is an established therapeutic option for chronic disease resulting from end-stage organ dysfunction. Long-term use of immunosuppression is associated with post-transplantation diabetes mellitus (PTDM), placing patients at increased risk of infections, cardiovascular disease and mortality. The incidence rates for PTDM have varied from 10 to 40% between different studies. Diagnostic criteria have evolved over the years, as a greater understating of PTDM has been reached. There are differences in pathophysiology and clinical course of type 2 diabetes and PTDM. Hence, managing this condition can be a challenge for a diabetes physician, as there are several factors to consider when tailoring therapy for post-transplant patients to achieve better glycaemic as well as long-term transplant outcomes. This article is a detailed review of PTDM, examining the pathogenesis, diagnostic criteria and management in light of the current evidence. The therapeutic options are discussed in the context of their safety and potential drug-drug interactions with immunosuppressive agents.
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http://dx.doi.org/10.1007/s13300-020-00790-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136383PMC
April 2020

Monthly variance in UK renal transplantation activity: a national retrospective cohort study.

BMJ Open 2019 09 17;9(9):e028786. Epub 2019 Sep 17.

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Objective: To identify whether renal transplant activity varies in a reproducible manner across the year.

Design: Retrospective cohort study using NHS Blood and Transplant data.

Setting: All renal transplant centres in the UK.

Participants: A total of 24 270 patients who underwent renal transplantation between 2005 and 2014.

Primary Outcome: Monthly transplant activity was analysed to see if transplant activity showed variation during the year.

Secondary Outcome: The number of organs rejected due to healthcare capacity was analysed to see if this affected transplantation rates.

Results: Analysis of national transplant data revealed a reproducible yearly variance in transplant activity. This activity increased in late autumn and early winter (p=0.05) and could be attributed to increased rates of living (October and November) and deceased organ donation (November and December). An increase in deceased donation was attributed to a rise in donors following cerebrovascular accidents and hypoxic brain injury. Other causes of death (infections and road traffic accidents) were more seasonal in nature peaking in the winter or summer, respectively. Only 1.4% of transplants to intended recipients were redirected due to a lack of healthcare capacity, suggesting that capacity pressures in the National Health Service did not significantly affect transplant activity.

Conclusion: UK renal transplant activity peaks in late autumn/winter in contrast to other countries. Currently, healthcare capacity, though under strain, does not affect transplant activity; however, this may change if transplantation activity increases in line with national strategies as the spike in transplant activity coincides with peak activity in the national healthcare system.
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http://dx.doi.org/10.1136/bmjopen-2018-028786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756352PMC
September 2019

Living donor kidney transplantation: often a missed opportunity.

Br J Gen Pract 2019 Sep 29;69(686):428-429. Epub 2019 Aug 29.

Central Manchester University Hospitals NHS Foundation Trust, Department of Renal and Pancreatic Transplantation, Manchester, UK.

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http://dx.doi.org/10.3399/bjgp19X705173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715493PMC
September 2019

Single stage hand assisted laparoscopic and trans thoracic excision of multifocal paraaortic and cardiac paragangliomas.

J Surg Case Rep 2019 Jun 20;2019(6):rjz169. Epub 2019 Jun 20.

Department of Transplant and Endocrine Surgery, Manchester University Foundation Trust.

A 26-year-old male, with a family history of Paraganglioma Syndrome 4 (PGL4) presented with an 18-month history of paroxysmal headaches, a one-month history of frequent diaphoresis, anxiety attacks and unintentional weight loss of one stone in 2 months. Physical examination and vital parameters were normal. Laboratory studies showed significant elevation of plasma normetanephrines and 3-methoxytyramine while DNA molecular analysis confirmed pathogenic mutation in the SDHB gene and genetic transmission of PGL4. Imaging studies demonstrated a left para-aortic mass in the mid-abdomen and a mediastinal paraganglioma between the root of aorta and origin of the main pulmonary artery, encroaching the right ventricle. After adequate alpha blockade, the patient underwent a combined sequential hand-assisted laparoscopic resection of the abdominal tumour followed by midline sternotomy and resection of the second lesion at the root of the aorta, complicated by the need for emergency cardiopulmonary bypass due to perforation of right ventricular wall.
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http://dx.doi.org/10.1093/jscr/rjz169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585381PMC
June 2019

Early nerve fibre regeneration in individuals with type 1 diabetes after simultaneous pancreas and kidney transplantation.

Diabetologia 2019 08 7;62(8):1478-1487. Epub 2019 Jun 7.

Institute of Cardiovascular Sciences, University of Manchester and Central Manchester NHS Foundation Trust, Core Technology Facility, Grafton Street, Manchester, M13 9NT, UK.

Aims/hypothesis: The study aimed to assess the impact on neuropathy of simultaneous pancreas and kidney transplantation (SPK) in individuals with type 1 diabetes.

Methods: This longitudinal observational study examined neuropathic symptoms, deficits, quantitative sensory testing, neurophysiology, corneal confocal microscopy and skin biopsy results in 32 healthy (non-diabetic) control participants, 29 individuals with type 1 diabetes and severe diabetic peripheral neuropathy [DPN] and 36 individuals with type 1 diabetes after SPK.

Results: Following SPK, HbA, eGFR, triacylglycerols and HDL improved significantly (all p < 0.05). Compared with the DPN group, which remained unchanged over the 36 month study period, corneal confocal microscopy assessments improved over 36 months following SPK, with increasing corneal nerve fibre density of 5/mm (95% CI 1.8, 8.2; p = 0.003) and corneal nerve fibre length of 3.2 mm/mm (95% CI 0.9, 5.5; p = 0.006). The Neuropathy Symptom Profile and peroneal nerve conduction velocity also improved significantly by 36 months compared with DPN (2.5; 95% CI 0.7, 4.3; p = 0.008 and 4.7 m/s; 95% CI 2.2, 7.4; p = 0.0004, respectively), but with a temporal delay compared with the corneal confocal microscopy assessments. Intraepidermal nerve fibre density did not change following SPK; however, mean dendritic length improved significantly at 12 (p = 0.020) and 36 (p = 0.019) months. In contrast, there were no changes in the Neuropathy Disability Score, quantitative sensory testing or cardiac autonomic function assessments. Except for a small decrease in corneal nerve fibre density in the healthy control group, there were no changes in any other neuropathy measure in the healthy control or DPN groups over 36 months.

Conclusions/interpretation: SPK is associated with early and maintained small nerve fibre regeneration in the cornea and skin, followed by an improvement in neuropathic symptoms and peroneal nerve conduction velocity.
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http://dx.doi.org/10.1007/s00125-019-4897-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647173PMC
August 2019

Insulin therapy in organ donation and transplantation.

Diabetes Obes Metab 2019 07 14;21(7):1521-1528. Epub 2019 Apr 14.

Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Medicine, Biology and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Hyperglycaemia is common in hospitalized individuals, and is often caused by physiological stress associated with critical illness or major surgery. Insulin therapy is an established treatment for hyperglycaemia and acute hyperkalaemia, and has also been used for myocardial dysfunction resistant to inotropic support. Insulin is commonly used in both organ donors and transplant recipients for hyperglycaemia, but the underlying knowledge base supporting its use remains limited. Insulin therapy plays an important yet poorly understood role in both organ donation and transplantation. Tight glycaemic control has been extensively studied in critical care over the past 15 years; however, this has not yet translated into the field of transplantation, where patients are more unwell and where improved outcomes remain an ongoing challenge. Insulin therapy and optimization of glycaemic control represent important areas for future hypothesis-driven research into organ donation and transplantation, such as amelioration of ischaemia-reperfusion injury, rejection and infection.
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http://dx.doi.org/10.1111/dom.13728DOI Listing
July 2019
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