Does the Microbiome Affect the Outcome of Renal Transplantation?

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 vice versa 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.

When politics meets science: What impact might Brexit have on organ donation and transplantation in the United Kingdom?

Brexit may lead to major political, societal, and financial changes-this has significant implications for a tax revenue funded healthcare system such as the United Kingdom's (UK) National Health Service. The complex relationship between European Union (EU) legislation and clinical practice of organ donation and transplantation is poorly understood. However, it is unclear what impact Brexit may have on organ donation and transplantation in the UK and EU. This work aims to describe the current legislative interactions affecting organ donation and transplantation regulation and governance within the UK and EU. We consider the potential impact of Brexit on the practical aspects of transplantation such organ-sharing networks, logistics, and the provision of health care for transplant patients when traveling to the EU from the UK and vice versa, as well as personnel, and research. Successful organ donation and transplantation practices rely on close collaboration and co-operation across Europe and throughout the United Kingdom. The continuation of such relationships, despite the proposed legislative change, will remain a vital and necessary component for the ongoing success of transplantation programs.

Peritoneal inflammation precedes encapsulating peritoneal sclerosis: results from the GLOBAL Fluid Study.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is an uncommon condition, strongly associated with a long duration of peritoneal dialysis (PD), which is itself associated with increased fibrosis in the peritoneal membrane. The peritoneal membrane is inflamed during PD and inflammation is often associated with fibrosis. We hypothesized that patients who subsequently develop EPS might have a more inflamed peritoneal membrane during PD. METHODS: We performed a nested, case-control study identifying all EPS cases in the UK arm of the GLOBAL Fluid Study and matching them by centre and duration of PD with two to three controls. Dialysate and plasma samples were taken during repeated peritoneal equilibration tests prior to cessation of PD from cases and controls. Samples were assayed by electrochemiluminescence immunoassay for interleukin-1ß (IL-1ß), tumour necrosis factor α (TNF-α), interferon-γ (IFN-γ) and IL-6. Results were analysed by linear mixed models adjusted for age and time on PD. RESULTS: Eleven EPS cases were matched with 26 controls. Dialysate TNF-α {0.64 [95% confidence interval (CI) 0.23, 1.05]} and IL-6 [0.79 (95% CI 0.03, 1.56)] were significantly higher in EPS cases, while IL-1ß [1.06 (95% CI -0.11, 2.23)] and IFN-γ [0.62 (95% CI -0.06, 1.29)] showed a similar trend. Only IL-6 was significantly higher in the plasma [0.42 (95% CI 0.07, 0.78)]. Solute transport was not significantly different between cases and controls but did increase in both groups with the duration of PD. CONCLUSIONS: The peritoneal cavity has higher levels of inflammatory cytokines during PD in patients who subsequently develop EPS, but neither inflammatory cytokines nor peritoneal solute transport clearly discriminates EPS cases. Increased systemic inflammation is also evident and is probably driven by increased peritoneal inflammation.

Outcomes of peritoneal dialysis patients and switching to hemodialysis: a competing risks analysis.

BACKGROUND: We performed a review of a large incident peritoneal dialysis cohort to establish the impact of current practice and that of switching to hemodialysis. METHODS: Patients starting peritoneal dialysis between 2004 and 2010 were included and clinical data at start of dialysis recorded. Competing risk analysis and Cox proportional hazards model with time-varying covariate (technique failure) were used. RESULTS: Of 286 patients (median age 57 years) followed for a median of 24.2 months, 76 were transplanted and 102 died. Outcome probabilities at 3 and 5 years respectively were 0.69 and 0.53 for patient survival (or transplantation) and 0.33 and 0.42 for technique failure. Peritonitis caused technique failure in 42%, but ultrafiltration failure accounted only for 6.3%. Davies comorbidity grade, creatinine and obesity (but not residual renal function or age) predicted technique failure. Due to peritonitis deaths, technique failure was an independent predictor of death hazard. When successful switch to hemodialysis (surviving more than 60 days after technique failure) and its timing were analyzed, no adverse impact on survival in adjusted analysis was found. However, hemodialysis via central venous line was associated with an elevated death hazard as compared to staying on peritoneal dialysis, or hemodialysis through a fistula (adjusted analysis hazard ratio 1.97 (1.02 - 3.80)). CONCLUSIONS: Once the patients survive the first 60 days after technique failure, the switch to hemodialysis does not adversely affect patient outcomes. The nature of vascular access has a significant impact on outcome after peritoneal dialysis failure.

Do hemodialysis patients prefer renal-specific or standard oral nutritional supplements?

OBJECTIVE: We investigated whether hemodialysis (HD) patients prefer standard or renal-specific oral nutritional supplements (ONS). DESIGN: Standard ONS Fortisip (Nutricia Clinical Care, Wiltshire, Trowbridge, UK) and renal ONS Renilon (Nutricia Clinical Care) and Nepro (Abbott Laboratories, Ltd., Maidenhead, Berkshire, UK) were compared using single-blind taste tests and face-to-face, interviewer-administered questionnaires. SETTING: This study took place in our HD unit in September 2007. PATIENTS: There were 40 patients, including 24 males, 14 smokers, and 26 Caucasians, aged <30 years (n = 6), 31 to 50 years (n = 13), 51 to 70 years (n = 12), and >70 years (n = 9). INTERVENTION: Patients ranked ONS taste on a Likert scale (1 to 5), and compared flavor options, phosphate-binder requirements, and fluid contribution. MAIN OUTCOME MEASURE: Which factors influenced a patient's choice of ONS? RESULTS: Gender, smoking status, ethnicity, and age influenced patients' choices. The taste of Fortisip and Nepro was liked by 58% (n = 23), versus 28% liking Renilon (n = 11). Renilon was disliked by 35% (n = 14), Nepro was disliked by 30% (n = 12), and Fortisip was disliked by 25% (n = 10). The favorite taste was Fortisip, in 52% (n = 21). However, 21% (n = 4) who preferred the taste of renal ONS would not choose them long-term because of their limited flavor ranges. The lack of phosphate binders with Renilon was a deciding factor in 27% (n = 19/33). The low fluid contribution of renal ONS influenced the choice of 43% (n = 12/28). All factors considered, standard ONS remained most popular for patients aged >70 years. However, in all other subgroups, and particularly males and non-Caucasians, renal ONS became more popular. Many patients (23%; n = 9) would sacrifice taste for the benefits of renal ONS. CONCLUSIONS: Renal ONS are more popular in HD patients because of their low fluid contribution and phosphate-binder requirements, which can influence preference over taste. Patients need information to make informed choices.

How can genetic advances impact on experimental models of encapsulating peritoneal sclerosis?

In this review we discuss how animal models have contributed to the understanding of pathological pathways that may be involved in the development of encapsulating peritoneal sclerosis. We review the various interventional procedures that, so far, have ameliorated disease progression in animals. Reviewing advancements in molecular biology and genetic technologies, we discuss how future experimental models may impact our understanding of the pathogenesis and treatment of this rare but complex disease.

Nutritional management of patients undergoing surgery following diagnosis with encapsulating peritoneal sclerosis.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication of peritoneal dialysis (PD). Gastrointestinal (GI) symptoms affect appetite and dietary intake. Adequate nutrition is especially important if surgical interventions are required. AIM: To investigate the nutritional management of 23 EPS patients that underwent surgical intervention between 1999 and 2005 at Manchester Royal Infirmary, United Kingdom. METHODS: EPS was recognized by GI symptoms and diagnostically confirmed by laparotomy, computed tomographic scanning, or biopsy. RESULTS: Mean time on PD was 74 months (interquartile range 42-89 months). During the 12 months pre-diagnosis, 65% of the group showed significant weight loss (p = 0.0001), with 8 patients losing >10% of body weight; 74% of patients experienced significant albumin decrease (p = 0.001); and 56% of patients experienced GI symptoms during the 6 months pre-diagnosis. Nasogastric (NG) feeding was recommended for 8 patients but continued in only 1. 15 patients (mean albumin 27 g/L) commenced parenteral nutrition (PN); 9 patients recovered, with albumin increasing over the 6-month follow-up. Mean hospital time was 62 days for the group receiving neither NG nor PN, compared with 124.3 for the PN/NG group (p = 0.04). In patients that died of EPS, albumin continued to fall at 3 months post-diagnosis. CONCLUSION: There is currently little guidance for nutritional management of EPS. From this study we recommend (1) a high level of clinical suspicion for EPS, especially if PD patients have weight loss; (2) PN may be better than NG feeding but further studies into dual enteral nutrition and PN are needed; (3) aggressive nutritional supplementation pre- and postoperatively; and (4) dietitians need to recognize the high risk of refeeding syndrome.

Encapsulating peritoneal sclerosis following renal transplantation despite tamoxifen and immunosuppressive therapy.

Encapsulating peritoneal sclerosis (EPS) is a rare disease in patients who have undergone peritoneal dialysis (PD). We report a case of EPS following renal transplantation that highlights important clinical issues. Initially, a presumptive diagnosis of EPS was made following surgical and pathological findings at the time of cholecystectomy. CT imaging at this time did not confirm the diagnosis. The patient continued PD and commenced tamoxifen. Prior to and immediately following transplantation, further CT imaging demonstrated no evidence of EPS. Acute bowel obstruction occurred 5 months post-transplantation and a diagnosis of EPS was made both clinically and on CT imaging, despite immunosuppression and tamoxifen. The role of these therapies in managing EPS post-transplant is discussed, in addition to the need for a high index of clinical suspicion to make the diagnosis.

Interaction between genetic control of vascular endothelial growth factor production and retinoid responsiveness in psoriasis.

Vascular endothelial growth factor (VEGF) promotes angiogenesis, and elevated levels are found in plaques of psoriasis. Two VEGF polymorphisms, +405 and -460, are associated with early-onset psoriasis and are close to the functional activator protein-1 site (+419) through which retinoids, an established systemic therapy for psoriasis, can block production of VEGF. We report that peripheral blood mononuclear cells (PBMCs) and epidermal keratinocytes (KC) from patients with psoriasis demonstrate differential, genotype-dependent, regulation of VEGF. For PBMCs, VEGF genotype distinguishes two groups of patients with psoriasis - "high and low VEGF producers" (P < 0.001). In contrast, KC production of VEGF is not genotype dependent. However, the effects of all-trans retinoic acid (RA) on cellular expression of VEGF are determined by both cell type and genotype. RA inhibits KC production of VEGF in a genotype-dependent manner (P < 0.005) whereas RA stimulates PBMCs production irrespective of VEGF genotype (P < 0.001). We also report that the -460 VEGF polymorphism appears to have a clinical pharmacogenetic role in predicting response or non-response of psoriasis to acitretin (P = 0.01). In future, determination of VEGF gene polymorphisms and thus individual patient VEGF "signatures" may be used as a prognostic factor for psoriasis susceptibility/severity and as a means for optimizing treatment response.

Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end-stage renal failure.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). It is characterized by a progressive, intra-abdominal, inflammatory process resulting in sheets of fibrous tissue that cover, bind, and constrict the viscera, thereby compromising the motility and function of the bowel. Although recent therapeutic approaches have been reported with variable success, the ability to detect reliably at an early stage patients at risk for EPS would be beneficial and allow treatment standardization. The aim of this study was to evaluate the clinical features of EPS and identify possible risk factors for its development in CAPD and APD patients. METHODS: This was a review of all cases of EPS in a single center over the last 5 years. RESULTS: There were 810 CAPD and APD patients, managed in our program over this period. We identified 27 cases of EPS, giving an overall of 3.3% in this population. The mean duration of CAPD before diagnosis of EPS was 72.6 +/- 39.7 months (range 16-172). Sixteen cases required surgical treatment and were classified as severe; others were treated conservatively (mild to moderate group). Ten patients received tamoxifen treatment with apparent benefit. The overall mortality rate was 29.6%. Eight patients from the severe group and the entire moderate group survived on hemodialysis or transplantation at 48.71 and 27.63 months follow-up, respectively. Peritonitis rates were not different between the 2 groups and peritoneal history was unremarkable compared to overall peritonitis rates in the unit. Data on small solute transport were not available in all patients in this retrospective analysis. CONCLUSION: EPS is a serious, life-threatening complication of CAPD. Most cases had PD duration of more than 4 years. Careful monitoring by CT scans of the peritoneal membrane in patients beyond 5 years, and early catheter removal in patients with peritoneal thickening should be considered for long-term CAPD patients. Treatment with tamoxifen may be of benefit in these patients.

VEGF -460 genotype plays an important role in progression to chronic kidney disease stage 5.

BACKGROUND: Changes in renal vasculature, with vascular and interstitial fibrosis, are hallmarks of progression to chronic kidney disease (CKD) stage 5. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. Transforming growth factor-beta1 (TGF-beta1) plays a critical role in promoting extracellular matrix (ECM) deposition and fibrosis. This study investigates whether genetic polymorphisms of VEGF or TGF-beta1 are associated with (i) progressive decline in renal function in patients with glomerular disorders (cohort 1) and (ii) predisposition to CKD stage 5 in a separate group of renal transplant recipients with various primary diseases (cohort 2). METHODS: Two patient groups were studied. Cohort 1 comprised 91 patients with biopsy-proven glomerular disease who were followed-up for 5 years before categorization as either non-progressors (with stable serum creatinine or < or =30% increase over 5 years, n = 39) or progressors (requiring dialysis, transplantation or whose serum creatinine increased by >30% over 5 years, n = 52). Cohort 2 comprised 107 patients with various primary renal diseases, who had reached CKD stage 5 and undergone renal transplantation at the time of study. All patients were genotyped for the VEGF polymorphisms at positions -460 (C/T) and +405 (G/C). Linkage disequilibrium (LD) was established using EHplus. SNPHAP was used to estimate haplotype frequency and to infer haplotypes to all patients. Cohort 1 patients were genotyped for the TGF-beta1 polymorphisms at positions -800, -509, codons 10 and 25. Genotyping was performed by polymerase chain reaction-restriction length polymorphism (PCR-RFLP). RESULTS: In cohort 1, there was a significant increase in frequency of the -460 VEGF CC genotype 30.8 vs 5.1%, P = 0.008; odds ratio (OR), CC vs TT 10.67, 95% confidence interval (CI), 1.94-58.72 and C allele 56.7 vs 37.2%, P = 0.009; OR 2.22, 95% CI, 1.21-4.04, in the progressor patients when compared with the non-progressors. In cohort 2, there was a significant increase in the VEGF -460 CC genotype when compared with healthy volunteers 37 vs 20.8%, P = 0.011; OR CC vs TT 1.59, 95% CI, 0.72-3.51. The -460 and +405 polymorphisms were in LD P < 0.00007. There were significant differences in diplotype (haplotype pair) frequencies in cohort 1 and 2, P = 0.018, which confirmed the importance of the -460C allele. There were no associations between the VEGF +405 or TGF-beta1 polymorphisms and progressive renal disease. CONCLUSION: In this study, we have demonstrated an association between the VEGF -460 polymorphism and progression to CKD stage 5. The function of this polymorphism remains unclear although previous evidence suggests that promoter constructs containing this single nucleotide polymorphism (SNP) have been associated with increased activity. Clearly there is a role for TGF-beta1 in chronic kidney disease. However, this study found no associations with four TGF-beta1 polymorphisms in this cohort.

Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset.

Vascular endothelial growth factor (VEGF)--a stimulus of angiogenesis--is produced by epidermal keratinocytes, and elevated levels have been found in plaques of psoriasis. Polymorphisms in the VEGF gene regulate production of VEGF. We postulated that patients with psoriasis may have altered systemic expression of VEGF consequent upon programming at the genomic level. We investigated the genetic basis of VEGF expression in patients with type 1 (onset before age 40 y) chronic plaque psoriasis compared to healthy controls and also measured plasma levels of VEGF and its receptors flt-1 and KDR. Patients with severe disease, and those with onset of psoriasis between the ages of 20 and 40 y showed significantly increased frequency of the +405 CC genotype (p=0.04 and p=0.02) and the C allele (p=0.03 and p=0.02), respectively, compared to healthy controls. Plasma levels of VEGF and flt-1 were significantly detectable in patients with psoriasis compared with controls (p<0.001); by contrast, mean plasma levels of KDR in psoriatic patients were comparable with controls. These results suggest that alterations in the biology of VEGF may be involved in the pathogenesis of psoriasis. VEGF, flt-1, and KDR could provide attractive targets for future psoriasis therapy.