The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease.

For a number of years, there has been increasing interest in the concept of directly targeting intestinal phosphate transport to control hyperphosphatemia in chronic kidney disease. However, progress has been slow due to the paucity of information on the mechanisms involved in intestinal phosphate absorption. This editorial highlights the most recent developments in our understanding of this process and the role of the intestine in the maintenance of phosphate balance

Management of chronic renal allograft dysfunction and when to re-transplant

Despite the advances in renal transplantation over the last decades, chronic allograft dysfunction remains the largest concern for patients, their families, clinicians and other members of the multi-disciplinary team. Although we have made progress in improving patient and renal allograft survival within the first year after transplantation, the rate of transplant failure with requirement for commencement of dialysis or re-transplantation has essentially remained unchanged. It is important that paediatric and adult nephrologists and transplant surgeons, not only manage their patients and their renal transplants but provide the best chronic kidney disease management during the time of decline of renal allograft function. The gold standard for patients with Stage V chronic kidney disease is to have pre-emptive living donor transplants, where possible and the same is true for healthy renal transplant recipients with declining renal allograft function. The consideration for children and young people as they embark on their end-stage kidney disease journey is the risk-benefit profile of giving the best immunologically matched and good quality renal allografts as they may require multiple renal transplantation operations during their lifetime

Putative tissue location and function of the SLC5 family member SGLT3

NEW FINDINGS: What is the topic of this review? This review summarizes the evidence on the localization, electrophysiological properties, agonist specificity and putative physiological role of sodium-glucose transporter 3 (SGLT3). What advances does it highlight? Published information is reviewed in some detail by comparing human and rodent isoforms, as well as advances in testing hypotheses for the physiological role of SGLT3 as a glucose sensor or incretin release mediator. We provide a critical overview of available published data and discuss a putative functional role for SGLT3 in human and mouse physiology. Sodium-glucose transporter 3 (SGLT3) has attracted interest because of its putative role as a glucose sensor, rather than a sugar transporter, in contrast to its co-family members SGLT1 and SGLT2. Significant progress has been made in characterizing the electrophysiological properties in vitro of the single human SGLT3 isoform and the two mouse isoforms, SGLT3a and SGLT3b. Although early reports indicated SGLT3 expression in the small intestinal myenteric and submucosal neurones, hypothalamic neurones, portal vein and kidney, a lack of reliable antibodies has left unanswered its exact tissue and cellular localization. Several hypotheses for a role of SGLT3 in glucose sensing, gastric emptying, glucagon-like peptide-1 release and post-Roux-en-Y gastric bypass remodelling have been explored, but so far there is only limited and indirect supportive evidence using non-specific agonists/antagonists, with no firm conclusions. There are no published or available data in knockout animals, and translation is difficult because of its different isoforms in human versus rodent, as well as a lack of selective agonists or antagonists, all of which make SGLT3 challenging to study. However, its unique electrophysiological properties, ubiquitous expression at the mRNA level, enrichment in the small intestine and potential, but uncertain, physiological role demand more attention. The purpose of this overview and review of SGLT3 biology is to provide an update, highlight the gaps in our knowledge and try to signpost potential ways forward to define its likely function in vivo

Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model

B cells have been reported to promote graft rejection through alloantibody production. However, there is growing evidence that B cells can contribute to the maintenance of tolerance. Here, we used a mouse model of MHC-class I mismatched skin transplantation to investigate the contribution of B cells to graft survival. We demonstrate that adoptive transfer of B cells prolongs skin graft survival but only when the B cells were isolated from mice housed in low sterility "conventional" (CV) facilities and not from mice housed in pathogen free facilities (SPF). However, prolongation of skin graft survival was lost when B cells were isolated from IL-10 deficient mice housed in CV facilities. The suppressive function of B cells isolated from mice housed in CV facilities correlated with an anti-inflammatory environment and with the presence of a different gut microflora compared to mice maintained in SPF facilities. Treatment of mice in the CV facility with antibiotics abrogated the regulatory capacity of B cells. Finally, we identified transitional B cells isolated from CV facilities as possessing the regulatory function. These findings demonstrate that B cells, and in particular transitional B cells, can promote prolongation of graft survival, a function dependent on licensing by gut microflora

Post-prandial adjustments in renal phosphate excretion do not involve a gut-derived phosphaturic factor

To date, the role of the small intestine in regulating post-prandial phosphate homeostasis has remained unclear and controversial. Previous studies have proposed the presence of a gut-derived phosphaturic factor that acts independently of changes in plasma phosphate concentration or parathyroid hormone (PTH) level; however, these early studies used duodenal luminal phosphate concentrations in the molar range and therefore the physiological relevance of this is uncertain. In the present study, we used both in vivo and in vitro approaches to investigate the presence of this putative ‘intestinal phosphatonin’. Instillation of 1.3M phosphate into the duodenum rapidly induced phosphaturia, but in contrast to previous reports, this was associated with significant hyperphosphataemia and elevated PTH level; however, there was not the expected decrease in abundance of the renal sodium-phosphate cotransporter NaPi-IIa. Instillation of a physiological (10mM) phosphate load had no effect on plasma phosphate concentration, PTH level or phosphate excretion. Moreover, phosphate uptake by opossum kidney cells was unaffected after incubation with serosal fluid collected from intestinal segments perfused with different phosphate concentrations. Taken together, these findings do not support the concept of a gut-derived phosphaturic factor that can mediate rapid signalling between gut and kidney, leading to increased urinary phosphate excretion, as part of normal phosphate homeostasis

Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon

Despite the importance of extracellular phosphate in many essential biological processes, the mechanisms of phosphate transport across the epithelium of different intestinal segments remain unclear. We have used an in vitro method to investigate phosphate transport at the brush border membrane (BBM) of intact intestinal segments and an in vivo method to study transepithelial phosphate absorption. We have used micromolar phosphate concentrations known to favor NaPi-IIb-mediated transport, and millimolar concentrations that are representative of the levels we have measured in luminal contents, to compare the extent of Na(+)-dependent and Na(+)-independent phosphate transport along the rat duodenum, jejunum, ileum, and proximal and distal colon. Our findings confirm that overall the jejunum is the main site of phosphate absorption; however, at millimolar concentrations, absorption shows ~30% Na(+)-dependency, suggesting that transport is unlikely to be mediated exclusively by the Na(+)-dependent NaPi-IIb co-transporter. In the ileum, studies in vitro confirmed that relatively low levels of phosphate transport occur at the BBM of this segment, although significant Na(+)-dependent transport was detected using millimolar levels of phosphate in vivo. Since NaPi-IIb protein is not detectable at the rat ileal BBM, our data suggest the presence of an as yet unidentified Na(+)-dependent uptake pathway in this intestinal segment in vivo. In addition, we have confirmed that the colon has a significant capacity for phosphate absorption. Overall, this study highlights the complexities of intestinal phosphate absorption that can be revealed using different phosphate concentrations and experimental techniques

The size-brightness correspondence:evidence for crosstalk among aligned conceptual feature dimensions

The same core set of cross-sensory correspondences connecting stimulus features across different sensory channels are observed regardless of the modality of the stimulus with which the correspondences are probed. This observation suggests that correspondences involve modality-independent representations of aligned conceptual feature dimensions, and predicts a size-brightness correspondence, in which smaller is aligned with brighter. This suggestion accommodates cross-sensory congruity effects where contrasting feature values are specified verbally rather than perceptually (e.g., where the words WHITE and BLACK interact with the classification of high and low pitch sounds). Experiment 1 brings these two issues together in assessing a conceptual basis for correspondences. The names of bright/white and dark/black substances were presented in a speeded brightness classification task in which the two alternative response keys differed in size. A size-brightness congruity effect was confirmed, with substance names classified more quickly when the relative size of the response key needing to be pressed was congruent with the brightness of the named substance (e.g., when yoghurt was classified as a bright substance by pressing the smaller of two keys). Experiment 2 assesses the proposed conceptual basis for this congruity effect by requiring the same named substances to be classified according to their edibility (with all of the bright/dark substances having been selected for their edibility/inedibility, respectively). The predicted absence of a size-brightness congruity effect, along with other aspects of the results, supports the proposed conceptual basis for correspondences and speaks against accounts in which modality-specific perceptuomotor representations are entirely responsible for correspondence-induced congruity effects

Organophosphate Pesticide Exposure and Neurodevelopment in Young Mexican-American Children

BACKGROUND: Organophosphate (OP) pesticides are widely used in agriculture and homes. Animal studies suggest that even moderate doses are neurodevelopmental toxicants, but there are few studies in humans. OBJECTIVES: We investigated the relationship of prenatal and child OP urinary metabolite levels with children’s neurodevelopment. METHODS: Participating children were from a longitudinal birth cohort of primarily Latino farm-worker families in California. We measured six nonspecific dialkylphosphate (DAP) metabolites in maternal and child urine as well as metabolites specific to malathion (MDA) and chlorpyrifos (TCPy) in maternal urine. We examined their association with children’s performance at 6 (n = 396), 12 (n = 395), and 24 (n = 372) months of age on the Bayley Scales of Infant Development [Mental Development (MDI) and Psychomotor Development (PDI) Indices] and mother’s report on the Child Behavior Checklist (CBCL) (n = 356). RESULTS: Generally, pregnancy DAP levels were negatively associated with MDI, but child measures were positively associated. At 24 months of age, these associations reached statistical significance [per 10-fold increase in prenatal DAPs: β = −3.5 points; 95% confidence interval (CI), −6.6 to −0.5; child DAPs: β = 2.4 points; 95% CI, 0.5 to 4.2]. Neither prenatal nor child DAPs were associated with PDI or CBCL attention problems, but both prenatal and postnatal DAPs were associated with risk of pervasive developmental disorder [per 10-fold increase in prenatal DAPs: odds ratio (OR) = 2.3, p = 0.05; child DAPs OR = 1.7, p = 0.04]. MDA and TCPy were not associated with any outcome. CONCLUSIONS: We report adverse associations of prenatal DAPs with mental development and pervasive developmental problems at 24 months of age. Results should be interpreted with caution given the observed positive relationship with postnatal DAPs