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Background Although women with polycystic kidney disease (PKD) generally have healthy pregnancies and babies, pregnancy is associated with a greater risk of maternal complications and requires planning and management of their condition. Given these possible complications, routine communication about childbearing between women with PKD and their treating team is important. A question prompt list (QPL), a structured list of questions used by patients during consultations with healthcare providers, may be beneficial in assisting women with PKD to discuss their childbearing concerns with, and seek related information from, their treating team. The aims of this study were to co‐design a QPL about pregnancy and childbearing for women with PKD, and evaluate its comprehensibility, salience, and acceptability. Methods An exploratory sequential mixed‐methods study of women of reproductive age with PKD living in Australia, using an experience‐based co‐design approach with two phases. Women were recruited from a metropolitan public health service and via social media and invited to complete an anonymous online survey about the development of the PKD QPL (phase one) and participate in an online discussion group about its refinement (phase two). Results Sixteen women completed the development survey and seven participated in the evaluation discussion group. Participants reported that women with PKD would value and use a QPL to prompt discussions with and seek further information about pregnancy and childbearing from their healthcare providers. Women identified four main topics for the QPL: ‘thinking about having a baby’, ‘pregnancy’, ‘my medications’ and ‘after my baby is born’. Within each section a series of questions was developed. Based on the findings, a QPL about pregnancy and childbearing for women with PKD was co-designed. Conclusions Women with PKD often find it difficult to access information and have discussions with their health care providers about pregnancy and childbearing. The PKD QPL co-designed in this study was perceived to be an acceptable tool which will, from the perspectives of participants, assist women with PKD to access information more easily about pregnancy, childbearing and PKD; ask more targeted questions of their treating team; and make informed childbearing decisions.

Increased expression of heparanase in puromycin aminonucleoside nephrosis. The β-D-endoglycosidase heparanase has been proposed as an important contributor to loss of glomerular charge in proteinuria. Expression of heparanase was, therefore, determined in acute puromycin aminonucleoside (PAN) nephrosis. A rabbit polyclonal antibody was produced against a 17-amino acid peptide derived from the predicted amino acid sequence of heparanase. The antibody was validated by Western blot. Immunohistochemical staining and Western blotting were used to localize heparanase protein in normal kidneys and kidneys from rats with PAN nephrosis. Northern blot analysis was used to determine mRNA expression. Immunohistochemical staining showed that heparanase protein was localized to tubular cells in the distal convoluted tubules, thick ascending limb of the loop of Henle, and transitional cell epithelium in normal kidney. Minimal expression was noted in normal glomeruli. Western blot analysis of protein from isolated normal glomeruli showed minimal expression of the 65 kD proheparanase protein. A marked increase in the staining for heparanase was found at day 5 of the PAN nephrosis model, at approximately the time of onset of proteinuria, and at day 14. Expression was predominantly seen in podocytes. At day 5, only the 65 kD proheparanase species was identified, but at day 14, mature 58 kD heparanase also was present. Northern blot analysis of sieved glomeruli at day 14 confirmed an increase in heparanase mRNA. The human podocyte cell line 56/10A1 also produced both proheparanase and mature heparanase, suggesting that podocytes can activate heparanase without other cell types. The previously mentioned data confirm that the novel β-D-endoglycosidase heparanase is up-regulated and activated in glomeruli from rats with proteinuria. Heparanase may be involved, therefore, in the loss of glomerular charge seen in proteinuria. Moreover, the presence of heparanase in normal tubules suggests that it may also be involved in cell migration or turnover.

Live kidney donation has increased steadily over the past decade, both in Australia and internationally. In some centres more than 50% of patients receiving a kidney transplant do so from a living related or unrelated donor. Live nondirected or altruistic donation has become more popular, as have paired exchange programs. General practitioners may be involved in pre-donation counselling and the assessment and follow up of otherwise healthy kidney donors. This overview outlines the clinical pathway and considerations required pre- and post-live kidney donation and highlights some of the uncertainties of donor nephrectomy. Live donation requires comprehensive physical, psychological and immunological assessment of the donor-recipient pair. Assessment requires an integrated approach that incorporates the skills of a number of clinicians and allied health practitioners. General practitioners have a crucial role in the counselling, assessment and follow up of live kidney donors.

Background: Vascular-access patency is critical for effective and uninterrupted haemodialysis. Limited literature exists evaluating if a surgical or repeated radiological approach is superior for reocclusion following failure of radiological recanalization. Few consistent early predictors of failure have been identified after radiological intervention for thrombosed vascular access. Methods: 138 patients with thrombosed arteriovenous fistulas or prosthetic grafts treated by radiological intervention, over 10 years, were retrospectively investigated. Reocclusion was treated by either repeated thrombolysis or surgery. Radiological patency rates, after first and second episodes of access thrombosis at 12 months after intervention were analysed. Surgical and radiological patency rates for second access thrombosis were compared. The Cox and logistic regression models were used to identify potential factors associated with reocclusion. Results: In patients who experienced reocclusion within 1 month after radiological intervention, the 3-month repeated radiological patency rate (n = 13) was 38.5%, compared to a 60% surgical patency rate (n = 10), but this did not reach statistical significance. Radiological patency rates after first access thrombosis at 3 and 12 months were 56.6 and 39.5%, respectively. In contrast, radiological patency rates after a second access thrombosis were 51.1 and 24.4%, respectively; a statistical difference in success was not achieved. Native arteriovenous fistulas were 3.23 times as likely to remain patent over 12 months following a first radiological intervention (p < 0.02) and less likely to experience a second reocclusion event (p < 0.01). Anticoagulation was associated with a lower risk of second reocclusion, whilst a history of venous thrombosis was associated with a greater risk (p < 0.02). Conclusion: Surgery achieves superior patency rates compared to repeated radiological interventions and should be considered if reocclusion occurs within a month following radiological thrombolysis.

AMP‐activated protein kinase (AMPK) is a key energy sensor, known to regulate energy metabolism in diverse cell types. Hypoxia is encountered frequently in the microenvironments of inflammatory lesions and is a critical regulator of function in inflammatory cells. Energy deficiency is one of the consequences of hypoxia, but its potential role in modulating leucocyte function has received little attention. Using micropore chemotaxis assays to assess migratory responses of the monocyte‐like cell line U937, it was found that the AMPK activators AICAR and phenformin rapidly reduced random migration (chemokinesis) as well as chemotaxis due to stromal cell‐derived factor (SDF)1α. There was an approximate 50% reduction in both chemokinesis and chemotaxis following 30 min preincubation with both AICAR and phenformin (P < 0.01), and this continued with up to 24 h preincubation. The binding of SDF1α to its receptor CXCR4 was unaltered, suggesting AMPK was acting on downstream intracellular signalling pathways important in cell migration. As AMPK and statins are known to inhibit HMG CoA reductase, and both reduce cell migration, the effect of mevastatin on U937 cells was compared with AMPK activators. Mevastatin inhibited cell migration but required 24 h preincubation. As expected, the inhibitory effect of mevastatin was associated with altered subcellular localization of the Rho GTPases, RhoA and cdc42, indicating decreased prenylation of these molecules. Although the effect of AMPK activation was partially reversed by mevalonate, this was not associated with altered subcellular localization of Rho GTPases. The data suggest that activation of AMPK has a general effect on cell movement in U937 cells, and this is not due to inhibition of HMG CoA reductase. These are the first data to show an effect of AMPK on cell movement, and suggest a fundamental role for energy deficiency in regulating cellular behaviour.

AMP-activated protein kinase (AMPK) is a key energy sensor, known to regulate energy metabolism in diverse cell types. Hypoxia is encountered frequently in the microenvironments of inflammatory lesions and is a critical regulator of function in inflammatory cells. Energy deficiency is one of the consequences of hypoxia, but its potential role in modulating leucocyte function has received little attention. Using micropore chemotaxis assays to assess migratory responses of the monocyte-like cell line U937, it was found that the AMPK activators AICAR and phenformin rapidly reduced random migration (chemokinesis) as well as chemotaxis due to stromal cell-derived factor (SDF)1 alpha . There was an approximate 50% reduction in both chemokinesis and chemotaxis following 30 min preincubation with both AICAR and phenformin (P < 0.01), and this continued with up to 24 h preincubation. The binding of SDF1 alpha to its receptor CXCR4 was unaltered, suggesting AMPK was acting on downstream intracellular signalling pathways important in cell migration. As AMPK and statins are known to inhibit HMG CoA reductase, and both reduce cell migration, the effect of mevastatin on U937 cells was compared with AMPK activators. Mevastatin inhibited cell migration but required 24 h preincubation. As expected, the inhibitory effect of mevastatin was associated with altered subcellular localization of the Rho GTPases, RhoA and cdc42, indicating decreased prenylation of these molecules. Although the effect of AMPK activation was partially reversed by mevalonate, this was not associated with altered subcellular localization of Rho GTPases. The data suggest that activation of AMPK has a general effect on cell movement in U937 cells, and this is not due to inhibition of HMG CoA reductase. These are the first data to show an effect of AMPK on cell movement, and suggest a fundamental role for energy deficiency in regulating cellular behaviour.

Background/Aims: Passive Heymann nephritis (PHN) is a model of human membranous glomerulonephritis characterized by heavy proteinuria. We have recently demonstrated activation of NF-κB by podocytes in this model. In this study, therefore, we have determined whether dexamethasone (DEX) and pyrrolidine dithiocarbamate (PDTC), therapies that inhibit NF-κB, influence proteinuria. Methods: Twenty-one days after induction of PHN, rats were divided into three groups: group 1 received saline, group 2 received DEX for 7 days, and group 3 received PDTC for 7 days. The effects of these drugs on activation of NF-κB and proteinuria were then determined. Results: DEX administration was associated with a very significant increase in proteinuria, whereas PDTC produced a slight decrease. Within the glomerulus, both agents were associated with increased levels of IL-1β mRNA and protein, compared with untreated rats, and there was increased nuclear localization of p50 in both of the treated groups. Neither agent, therefore, inhibited NF-κB activation within the glomerulus. Both agents produced a decrease in the systemic anti-sheep Ig immune response, and there was reduced interstitial αβ T-cell infiltration compared with controls. Conclusion: These data suggest that agents predicted to inhibit NF-κB might have opposing effects in membranous glomerulonephritis. The use of steroids to treat membranous glomerulonephritis, therefore, might produce unpredictable results, depending on whether suppression of the systemic immune response or inflammatory events within the kidney is more important in a particular patient. Copyright © 2010 S. Karger AG, Basel [PUBLICATION ABSTRACT]

Background: The high level of expression of vascular endothelial growth factor (VEGF) in normal podocyte foot processes suggests that VEGF has an important role in maintaining normal glomerular function. While altered VEGF expression occurs in many glomerular diseases, a direct role for VEGF in the pathogenesis of proteinuria has not been demonstrated. Methods: Expression of VEGF and its receptors (VEGFR-1 and VEGFR-2) was examined in passive Heymann nephritis (PHN) and puromycin aminonucleoside nephrosis (PAN), by immunohistochemistry, in situ hybridization, Northern and Western blotting. Inhibition of VEGF in the PAN model was performed by administration of a blocking antibody. Results: In both models, glomeruli showed upregulation of VEGF and VEGF receptors compared to control animals. VEGF mRNA was increased most significantly (5-fold) at day 5 after induction of PHN, prior to the onset of proteinuria, with persistent upregulation (3-fold) at day 21. Increased VEGF mRNA was also seen in PAN, but it was less marked. In situ hybridization and immunohistochemistry localized VEGF predominantly to podocytes. Increased expression of VEGFR-1 and VEGFR-2 protein was seen in glomerular endothelial cells of PHN and PAN rats by immunohistochemistry, as was VEGFR-2 mRNA by in situ hybridization. Upregulation of VEGFR-1 by endothelial cells was more striking in the PAN model than PHN. Administration of a blocking antibody to rats with PAN did not affect proteinuria, creatinine clearance or sodium excretion. Conclusion: The expression of VEGF and its receptors is significantly increased in the PHN and PAN rat models of proteinuria suggesting a role for VEGF in the disease process. VEGF may have an important role in promoting glomerular repair in a variety of glomerular diseases. Copyright (C) 2004 S. Karger AG, Basel