2% and 10.3%. The S-Cr level did not increase further and was stable at 2.8 mg/dL. The patient was discharged from our hospital on day 58. After leaving hospital, in spite of the above therapy, his S-Cr level was not decreased less than 2.7 mg/dL. The additional biopsy was performed 2 years after kidney transplantation and found the obstinate mild peritubular capillaritis and mild capillary basement membrane thickening. Further analysis showed de novo anti-DQ4 antibodies increased to 14 315 on MFI values. Again, for treatment of the

obstinate refractory AMR, we performed an additional three sessions of PEX and IVIG. In addition, we administered rituximab (200 mg/body) because his CD19/20 level increased to 1.5% and 2%. His S-Cr beta-catenin pathway level was still high at the S-Cr level

of 2.8 mg/dL 30 months after kidney transplantation. In this study, we report a refractory case of JNK inhibitor purchase PCAR accompanied by acute AMR. This case report helps to inform at least two debates: (1) the difficulties of diagnosis and management of PCAR when it is accompanied by AMR; and (2) the difficulties of diagnosis of AMR when it is resultant of anti-HLA-DQ antibody in ABO-incompatible kidney transplantation, because HLA-DQ antigen screening is not always required. PCAR is characterized by the presence of mature plasma cells that comprise more than 10% of the inflammatory cell infiltration in a renal graft.[1] This pathologic finding is noted in approximately 5–14% of patients with biopsy-proven acute rejection. Although therapy for this condition has not been generally established, graft survival is poor.[2] To diagnose PCAR, physicians should pay attention to PTLD

caused by Epstein-Barr (EB) viral infection, because the treatment for PTLD is contrary to that for PCAR.[4] In our case, we confirmed that there was no monoclonality for kappa and lambda by immunohistochemistry. In addition, EBER staining was negative by in situ hybridization. Authorities stated that there could be an AMR variant of PCAR. C4d-positive PCAR with circulating DSAbs responds adequately to treatment aimed at AMR, such as rituximab and IVIG combination of therapy. On the other hand, C4d-negative PCAR is intractable to treatment. In our case, treatment aimed at AMR showed good response. Current anti-humoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cells. Matthew et al. reported that bortezomib therapy may be effective for treating mixed rejection (AMR and acute T cell-mediated rejection) with minimal toxicity and for sustaining reduction of DSAb and non-DSAb levels.[5] In this context, a strategy for treating PCAR needs to be established in the future. The importance of HLA matching in kidney transplantation is well recognized, with HLA-DR compatibility having the greatest influence on outcome.

In a 1964 review lecture, Renkin [15] analyzed the available data on the transport of macromolecules Everolimus nmr between plasma and lymph and considered how well they could be accounted for by ultrafiltration through Grotte’s large pores and by transcytosis by vesicles. By so doing, he showed that if vesicular transport were responsible for macromolecular permeability, it could be described in quantitative terms and these terms placed restrictions on the numbers and behavior of the vesicles. Renkin’s review stimulated considerable experimental work by both physiologists and electron microscopists in the late 1960s and throughout the 1970s. Trans-endothelial channels were reported to be formed by a chain of fused

vesicles [23], and some analyses GPCR Compound Library suggested both convective and non-convective mechanisms of macromolecular transport

operated in parallel. Convective transport and non-convective transport were interpreted in terms of large pores and transcytosis, respectively. In 1979, however, Rippe et al. [16], working on isolated perfused rat hind limb preparations, published a definitive set of experiments providing strong evidence that, in this preparation, the movement of serum albumin from plasma to tissue occurred entirely by convection. In the same year, Bundgaard et al. [3] published the first of a series of papers in which electron micrographs showed that all the vesicles in capillary endothelium were arranged in fused clusters, which communicated with caveolae at either the luminal or abluminal surface of the cells, but never at both. In their later papers, they [9] reconstructed three-dimensional models of the vesicle clusters from TEMs of ultra-thin C225 serial sections. It was argued [2,6] that the vesicle clusters

were static structures incompatible with transcytosis because single unattached vesicles were never present, and this was inconsistent with the simple model of transcytosis. It was not, however, inconsistent with the later fusion–fission model [5]. Furthermore, they found no evidence of channels formed as connections between chains or clusters of vesicles opening on to both luminal and abluminal cell surfaces. To account for the appearance of a blood-borne label in abluminal vesicles, it was proposed that the label had entered the abluminal vesicles from the interstitial fluid, having crossed the endothelium by a nearby intercellular cleft, which lay just out of the plane of section. A few years later, direct evidence rebutting this last argument was reported. Wagner and Chen [24] used terbium as a tracer of transport from blood to tissue in the rete mirabile of the eel. By making TEMs from serial sections, they showed that the tracer reached the abluminal surface via vesicles when no intercellular clefts were in the vicinity. Furthermore, the terbium density decreased with distance from a discharging caveola.

To assess responses

to GAD65 epitopes that could be processed and presented from intact protein, CD4+ T cells were primed by stimulation with GAD65 protein and then screened using tetramers loaded with each of the antigenic peptides identified by tetramer-guided epitope mapping. Briefly, 2·5 × 106 ‘no-touch’ Microbead-enriched CD4+ T cells were stimulated with 1·2 × 105 GAD65 protein loaded monocytes in one well of a 48-well plate. CD14+ monocytes were isolated and pulsed with recombinant GAD65 protein as in the protein-stimulated proliferation assays. At least four replicate wells (of a 48-well plate) were set up for each subject. The T cells were cultured for 14 days, adding fresh media and interleukin-2

as needed starting on day 7. Expanded cells were stained AZD5363 supplier with HLA-DR0401 tetramers loaded with each antigenic selleck chemicals GAD65 peptide. Again, tetramer responses were considered positive when distinct staining that was more than twofold above background (this was set to 0·2% and subtracted) was observed. As described in the Materials and methods section, the tetramer-guided epitope mapping approach was used to comprehensively investigate DR0401-restricted epitopes within GAD65. Peptide pools spanning the entire GAD65 sequence were used to stimulate CD25-depleted T cells from multiple donors with DR0401 haplotypes. Consistent with the representative results shown in Fig. 1(a), a total of 17 different peptides (from 11 peptide pools) elicited a positive response from at least one of the subjects tested. With the exception of pool #6, the antigenic peptides

within each of these peptide pools could be identified using tetramers loaded with individual peptides. The antigenic peptide from pool #6 could not be identified using this approach. However, peptide p26 (GAD201–220) from pool #6 was identified as the antigenic peptide by means of a proliferation assay (Fig. 1b) and was further confirmed by stimulating Selleck Pazopanib of CD4+ T cells with the individual GAD201–220 peptide and staining with the DR0401/GAD#6 pooled tetramer (data not shown). The peptide sequences containing these epitopes are summarized in Table 1. The 17 antigenic peptides identified included five pairs of adjacent, overlapping peptides. It seemed likely that some of these adjacent overlapping peptides contain a single, shared antigenic sequence. To delineate the antigenic sequences within these adjacent overlapping peptides, we generated tetramer-positive T-cell lines for at least one peptide from each pair. As shown in Fig. 2, we assessed the proliferation of these lines in response to each of the adjacent peptides. These results suggested that three pairs of overlapping peptides (GAD105–124 and GAD113–132, GAD265–284 and GAD273–292, GAD545–564 and GAD553–572) appear to contain distinct antigenic sequences, because T-cell lines only proliferated in response to one of the peptides.

01). In conclusion, neurological deteriorations of diabetic rats were alleviated with PGE1, which is associated with inhibition of NGF and enhancement of VEGF at the entrapment site. © 2014 Wiley Periodicals, Inc. Microsurgery 34:568–575, 2014. “
“Medicinal leech therapy (MLT) to salvage venous congestion in native skin and local flaps is commonly practiced. However, the role of MLT in compromised regional and free flaps remains unclear. Leeches were used in 39 patients to treat venous congestion in native skin (n = 5), local flaps (n = 6), regional flaps (n

= 14), and free flaps (n = 14). There were no total losses in patients with compromised native skin or local flaps. One patient who had received a radial forearm RAD001 mouse free flap expired before flap outcome could be assessed, and was excluded from analysis. Of the remaining 27 regional and free flaps, 33.3% were salvaged, 33.3% were partially salvaged, and 33.3% were lost. Means of 38.3 ± 34.0, 101.0 ± 11.2, selleck compound and 157.9 ± 224.4 leeches and 1.7 ± 3.6, 3.2 ± 4.4, and 5.6 ± 5.2 units of blood were required for the salvaged, partially salvaged, and lost groups, respectively. Twenty-two patients required blood transfusion (57.9%). No patients developed wound infection with Aeromonas hydrophilia. Two patients developed donor site hematomas, and four patients developed recipient site hematomas. MLT is efficacious in congested native

skin and local flaps. Some regional and free flaps can be totally orpartially salvaged. However, the morbidity of MLT must be weighed against the risks of flap loss. © 2012 Wiley Periodicals, Inc. Microsurgery, Tenofovir concentration 2012. “
“The purpose of this study was to evaluate the effect of direct administration of nerve growth factor (NGF) into an epineural

conduit across a short nerve gap (10 mm) in a rabbit sciatic nerve model. The animals were divided into two groups. In group 1, n = 6, a 10-mm defect was created in the sciatic nerve and bridged with an epineural flap. A dose of 1 μg of NGF was locally administered daily for the first 21 days. NGF administration was made inside the epineural flap using a silicone reservoir connected to a silicone tube. In group 2, n = 6, the 10-mm defect was bridged with a nerve graft. This group did not receive any further treatment. At 13 weeks, all animals, before euthanasia, underwent electromyography (EMG) studies and then specimen sent for histology morphometric analysis. NGF administration ensured a significantly increased average number of myelinated axons per μm2 (P = 0.028) and promoted fiber maturation (P = 0.031) and better EMG results (P = 0.046 for latency P = 0.048 for amplitude), compared with the control group. Although nerve grafts remain the gold standard for peripheral nerve repair, NGF-treated epineural conduits represent a good alternative, particularly when an unfavorable environment for nerve grafts is present. © 2011 Wiley-Liss, Inc.

OHASHI YASUSHI1, TAI REIBIN1, AOKI TOSHIYUKI1, MIZUIRI SONOO2, OGURA TOYOKO3, TANAKA YOSHIHIDE1, OKADA TAKAYUKI1, AIKAWA ATSUSHI1, SAKAI KEN1 1Department of Nephrology, School of Medicine, Faculty of Medicine, Toho University, Tokyo; 2Division of Nephrology, Ichiyokai Harada Hospital, Hiroshima; 3Department of Nutrition, Toho University Omori Medical Center, Tokyo Introduction: Fluid imbalance due to sodium

retention and malnutrition Rucaparib chemical structure can be characterized by the ratio of extracellular water (ECW) to intracellular water (ICW). Our objectives are to investigate whether fluid imbalance between ICW and ECW is a risk factor for adverse outcomes. Methods: Body fluid composition was measured in 149 patients with chronic kidney disease from 2005 to 2009, who were followed until death, loss to follow-up, or August 2013. Patients were categorized according to the ECW/ICW ratio tertile. The ratio of ECW to total body water, calculated by the Watson formula, was used as an indicator of ECW excess. Main outcomes were adverse Talazoparib supplier renal outcomes, as defined by a decline of 50% or more

from baseline glomerular filtration rate or initiation of renal replacement therapy, cardiovascular events, and all-cause mortality. Results: Patients with higher tertile tended to be older and have diabetes mellitus, treatment-resistant hypertension, ECW excess, decreased protein intake per calorie, lower renal function, hypoalbuminemia, and higher proteinuria and furosemide usage (P < 0.01). Compared with patients in the lowest tertile during a median 4.9-year follow-up, those in the highest tertile had the worst adverse renal outcomes (15.9 vs. 5.1 per 100 patient-years, P < 0.001), cardiovascular events (4.1 vs. 0.3 per 100 patient-years, P = 0.002), and mortality (11.2 vs. 1.3 per 100 patient-years, P < 0.001)

by Kaplan–Meier survival analysis. The adjusted hazard ratio (95% confidence intervals) for adverse renal outcomes, cardiovascular events, and all-cause mortality were 1.15 (1.03–1.26, P = 0.011), 1.12 (0.93–1.31, P = 0.217), and 1.29 (1.11–1.50, P < 0.001), respectively. Conclusion: Fluid Etofibrate imbalance between ICW and ECW, driven by cell volume decrease and ECW excess, was associated with adverse renal outcomes and mortality. These findings emphasize the importance of cell volume retention as well as appropriate extracellular volume. CHEN SZU-CHIA1, HUANG JIUN-CHI1,2, CHANG JER-MING1,2, HWANG SHANG-JYH1, CHEN HUNG-CHUN1 1Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital; 2Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Introduction: The P wave parameters measured by 12-lead electrocardiogram (ECG) are commonly used as noninvasive tool to assess for left atrial enlargement.

In contrast, when combined with TGF-β and IL-23, the cytokines IL-6 or IL-21 can induce Th17 cells, which produce IL-17, IL-21, and IL-22, express the lineage-specific transcription factor ROR-γt, and protect from extracellular bacterial and fungal infections. Finally, naïve FOXP3+ Treg cells under Th1 or Th2 inflammatory conditions acquire effector function and have anti-inflammatory properties. Although all T-cell subsets mentioned above have protective

functions under physiological conditions, uncontrolled responses of the respective Th subsets may cause immunopathology. Thus, Th1 and Th17 cells have been implicated in autoimmune tissue inflammation, including autoimmune encephalomyelitis and inflammatory bowel disease, ITF2357 nmr whereas Tfh cells contribute to a lupus-like syndrome, and Th2 as well as Th9 cells to allergy and asthma [32-35]. Although early studies Raf inhibition have demonstrated the T-cell intrinsic importance of IRF4 for Th2-cell differentiation [36-39], its role for Th1-cell development is less clear. Contradictory data show either diminished [36, 38] or normal [37]

IFN-γ production by Irf4–/– Th cells cultured under Th1 conditions in vitro. In an infectious model with the intracellular protozoon Leishmania major, in which Th1 responses promote healing and parasite clearance, whereas Th2-driven responses cause chronic disease [40], Irf4–/– mice failed to control the infection. However, this defect could not solely be explained by impaired Th1-cell differentiation, because the responding T cells also completely failed to develop a Th2-cell phenotype. Furthermore, disease susceptibility correlated with extraordinarily enhanced apoptosis of Irf4–/– Thiamet G CD4+ T cells, which was reflected in almost total loss of cellularity in the draining lymph node (LN) [41]. Th2-cell differentiation can be compromised

in vivo not only as a result of the T-cell intrinsic loss-of-function of IRF4 but also owing to T-cell extrinsic defects in IRF4-controlled functions, such as DC development [5]. Within T cells, IRF4 controls Th2-cell differentiation through several mechanisms (Fig. 1A). First, IRF4 promotes IL-4 production directly by binding to the IL-4 promoter in cooperation with the transcription factors NFATc2 in mouse [36] or NFATc1 in human cells [39]. Second, IRF4 is important for the upregulation of GATA3, and overexpression of GATA3 partially rescued IL-4 production in Irf4–/– Th2 cells, suggesting a crucial role of IRF4-dependent GATA3 expression for Th2-cell differentiation [38]. Third, IRF4 is important for the expression of growth factor independent 1 (Gfi1), a transcription factor that regulates IL-2-mediated Th2-cell expansion [37]. Given that BATF is required for Th2-cell development [42, 43] and that AICEs have been found in Th2 cells [16], it is highly probable that IRF4 also regulates Th2-cell differentiation in cooperation with BATF–JUN heterodimers.

Parallels exist between falciparum malaria and other severe illnesses such as sepsis and influenza, where inflammatory cytokines as well as chemokines are important mediators of pathogenesis [1,2]. Chemokines bridge innate and adaptive immunity [3], regulate chemotactic recruitment of inflammatory cells, leucocyte activation, angiogenesis and haematopoiesis, and in addition may also regulate host immune responses decisively during intracellular as well as intestinal protozoan parasite infections [4–8]. Recent studies have shown that the profile of chemokine expression and their serum levels varied with disease severity in children with acute

Plasmodium falciparum malaria; notably, the beta-chemokines EGFR targets macrophage

inflammatory protein (MIP)-1α/CCL3 and MIP-1β/CCL4 were elevated, while regulated upon activation normal T cell expressed and secreted (RANTES)/C–C ligand 5 (CCL5) appeared to be suppressed [9]. Resolution of P. falciparum infection requires proinflammatory immune responses that facilitate parasite clearance, while failure to regulate this inflammation leads to immune-mediated pathology, but the sequelae of disease aggravation or its resolution still require further study for a better understanding of pathogenesis as well as the prevention of malaria disease. The early production of proinflammatory T helper type 1 (Th1) cytokines, including tumour necrosis factor (TNF), interleukin (IL)-12 and possibly interferon (IFN)-γ may limit the progression from uncomplicated malaria to severe and life-threatening complications, but TNF can cause pathology if produced excessively [10–12]. Several Selleckchem Selumetinib studies support the idea that Th1 responses are important for clearance of P. falciparum malaria, and enhanced serum levels of IL-6 and IL-10 were observed in patients with severe P. falciparum malaria [13]. In young African children who presented with either mild or severe P. falciparum malaria, the acute-phase plasma IL-12 and IFN-alpha (IFN-α) levels, as well as the whole-blood production capacity of IL-12, were lower in children with severe rather than

mild malaria, and IL-12 levels were correlated inversely with parasitaemia [14]. Further, TNF-α and IL-10 levels were significantly higher in those with severe malaria, Metalloexopeptidase being correlated positively with parasitaemia, and children with severe anaemia had the highest levels of TNF in serum [13]. The cytokine and chemokine imbalance measured in serum were suggested as useful markers for progression of cerebral malaria with fatal outcome; patients who died from malaria tropica had higher amounts of IL-6, IL-10 and TNF-α levels than those who survived; moreover, cerebral malaria (CM) was related to an inflammatory cascade characterized by dysregulation in the production of IP-10, IL-8, MIP-1β, platelet-derived growth factor (PDGF)-β, IL-1Rα, Fas-L, soluble TNF-receptor 1 (sTNF-R1) and sTNF-R2 [15].

In particular, modelling exercises performed to evaluate the potential impact

of new therapies for the treatment of HAE [either performed by or presented to Health Technology Assessment (HTA) agencies, such as AWMSG, SMC and NICE] will benefit from the data collected, where there is a paucity of available evidence relating to the burden of disease of this rare condition in the United Kingdom. There are limitations to this audit, in that data have not been obtained on every patient Obeticholic Acid with HAE in the United Kingdom. It is possible that there may be centres where the patient characteristics or medical practice are different, which might thus influence the findings. The paediatric data set is small, and analysis of a larger data set in children would be helpful. The audit has established a baseline for a wide range of parameters for HAE patients in the United Kingdom. Areas for improvement in practice were identified when compared Caspases apoptosis with the original consensus documents, such as monitoring of lipids, liver function tests and hepatitis serology. There has been rapid progress in the development of guidelines, and as practice may change with the availability

of more effective therapies it will thus be important to re-audit to investigate possible improvements for patients. There are also a range of therapies at different stages of development which may also impact upon how HAE is treated in the future. The area of quality

of life assessment would be optimized with the use of a disease-specific tool. The use of existing and developing databases as well as, potentially, smartphone applications may also facilitate real-time data entry and analysis. Lessons were also learned as to how best to obtain clear high-quality data. Questionnaires should be simple and quick to complete, given the pressures on clinical most time. Where possible, data should be numerical to make analysis more straightforward and linked to stated guideline criteria. Adults and children need to be assessed separately, recognizing the many differences in practice, disease severity (children reaching adolescence may experience increased attack frequency), development and impact on family life that exist between these groups. The future for patients with HAE and AAE, however, looks bright not only with the current range of treatments available but with an intense focus of research into angioedema.

In addition to conventional treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) agents, participants were randomly assigned to receive Tangshen formula (TSF) or matching placebo for 24 weeks. The urinary

and plasmic L-FABP, renal function, UAER for patients with microalbuminuria, 24 h urinary protein level (24 h UP) for patients with macroalbuminuria were measured. Results: In microalbuminuria patients, TSF displayed a significant decrease in UAER (TSF 97.89 ± 52.89 ug/min VS placebo 109.03 ± 75.62 ug/min, P < 0.05) after 24-week treatment. Levels of urinary L-FABP in TSF group were significant lower than that in Placebo group both after 12 weeks and 24 weeks treatment (6.83 ± 2.87 ug/ml VS 11.08 ± 3.29 ug/ml, P < 0.01 and 6.04 ± 2.95 ug/ml VS 9.21 ± 4.38 ug/ml, P < 0.05, respectively).

In macroabluminuria patients, 24 h UP at 12th week obviously decreased Selleckchem CHIR 99021 than baseline in TSF group (12th week 0.37(0.06,0.90)g/24 h VS baseline 0.73(0.50,1.07)g/24 h, P < 0.05). TSF group showed a significant decreased in urinary L-FABP (12 weeks, 1.21 ± 0.26 ug/ml VS 1.65 ± 0.33 ug/ml, P < 0.05; 24 weeks, 1.42 ± 0.46 ug/ml VS 1.91 ± 0.48 ug/ml, P < 0.05). Levels of urinary L-FABP significantly increased according to the severity of diabetic kidney disease (normoalbuminuria patients 5.916(5.152,7.824)ug/ml VS microalbuminuria patients 11.444(6.775,13.441)ug/ml VS macroabluminuria patients 18.471(10.873,23.391)ug/ml, P < 0.05). Conclusion: Urinary L-FABP levels appear to be associated with the severity of DKD, and administration LY294002 of TSF in addition to conventional therapy is demonstrated to be effective in reducing urinary protein and urinary L-FABP. Acknowledgements: This work was supported by the International Science and Technology Cooperation Program of China (Grant no.2011DFA31860, Grant no.2006DFB31480), the National Basic Research Program of China (973 Program, Grant ID-8 no.2006CB504602) and the National Natural Science Foundation of China (Grant no.81130066). GUAN SIAO-SYUN1,2, SHEU MEEI-LING3, WU CHENG-TIEN1,

CHIANG CHIH-KANG4,5, LIU SHING-HWA1 1Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; 2Institute of Nuclear Energy Research, Atomic Energy Council, Executive Yuan, Taoyuan, Taiwan; 3Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan; 4Departments of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taiwan; 5Departments of Internal Medicine, National Taiwan University College of Medicine, Taiwan Introduction: Diabetic nephropathy is known to be the most common cause of chronic kidney disease. Advanced glycation end products (AGEs) have been suggested to play an important role in diabetic nephropathy, including renal fibrosis.

5 mg s/c bd). Levomepromazine can be used if symptoms persist however it is more sedating.

Starting dose 3.125 mg subcutaneously bd or tds – contact Palliative Care team for advice. Metoclopramide CAL-101 chemical structure should be used with caution due to accumulation and potentially increased risk of extrapyramidal side effects[8] (although may be more useful in patients with gastroparesis – maximum 30 mg per 24 hours). Cyclizine may cause hypotension or arrhythmia in patients with cardiac co-morbidities (although this was when used intravenously)[9] so is not recommended. Constipation: Respiratory Tract Secretions: It is important to determine the cause of secretions – anticholinergic medication is unlikely to improve fluid overload/acute pulmonary oedema or secretions ACP-196 purchase due to lower respiratory tract infection. Explanation to the family is crucial as the patient is often not distressed by the secretions and treatment can have undesirable side effects such as dry mouth and urinary retention. Glycopyrrolate does not cross the blood-brain barrier therefore does not cause sedation or delirium as hyoscinehydrobromide can (not recommended), thus it is first choice. Dose should be reduced to 50% of normal due to increased anti-cholinergic side effects[2,

10] (e.g. 100–200 μg prn s/c q4h). Terminal agitation: Midazolam may be used for agitation in the dying phase. Dose and timing interval adjustments may be required in advanced kidney disease due to accumulation of conjugated metabolites.[11] Clonazepam (0.5 mg bdsubcut or sublingual), haloperidol and levomepromazine (6.25–12.5 mg prn – maximum 200 mg per 24 hours) can also be used. Pruritus: If the Palbociclib patient is able to swallow, low dose gabapentin can be considered 9100 mg every second day). If the patient is unconscious,

midazolam or clonazepam can be used. Pain and dyspnoea: Opioid prescribing can be difficult given that most opioids have metabolites which are renally excreted and accumulate in renal failure, and that some patients may be on opioids prior to entering the terminal phase. This means in practice that opioid choice and dose/interval must be individualized to each patient. Morphine and oxycodone have metabolites which accumulate and can be toxic, and thus cannot be recommended.[12] Hydromorphone has been controversial as its metabolite hydromorphone-3-gluconoride accumulates in renal failure and is known to be neuroexcitatory in rats, however evidence in humans is lacking. It is not recommended in the UK guidelines, however is likely to be safer than morphine or oxycodone. Generally fentanyl is the safest opioid to use given that its renally excreted metabolites are inactive,[2, 13] however given its short half-life, can be impractical. In an opioid-naïve patient, 25 μg subcutaneously prn q2 hourly is an appropriate starting dose.