Case report of the successful use of semaglutide to achieve target BMI prior to renal transplant in two patients with end-stage-kidney-disease.

The following cases demonstrate a proof of concept for the safe and effective use of the glucagon-like-peptide-1 receptor agonist (GLP-1 RA) semaglutide for weight loss in obese, non-diabetic, end stage kidney disease (ESKD) patients on haemodialysis (HD), who are unable to undergo renal transplantation due to obesity. Obesity is a common barrier to wait-listing for renal transplantation with effective, broadly applicable weight loss strategies lacking. GLP-1 RAs have been shown to be effective adjuncts to achieve weight loss in non-diabetic obese people. However, the major clinical trials excluded patients with ESKD on dialysis. This paper outlines the successful use of semaglutide to achieve a target body mass index (BMI) prior to renal transplant wait-listing in two obese, non-diabetic, HD patients. These patients achieved a 16% and 12.6% weight loss in under 9 months with one now waitlisted and the other transplanted. This strategy has the potential for broader use in this patient cohort to improve wait-list times by overcoming this common barrier to renal transplantation.

Co-design of a question prompt list about pregnancy and childbearing for women with polycystic kidney disease: an exploratory sequential mixed-methods study.

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.

International statistical classification of diseases and related health problems coding underestimates the incidence and prevalence of acute kidney injury and chronic kidney disease in general medical patients.

BACKGROUND: The international classification of diseases (ICD) code is frequently used to identify renal impairment in epidemiological research. However, Australian studies examining accuracy of this administrative data in coding kidney injury are lacking. AIMS: To compare the ICD 10 coding with the kidney disease: improving global outcomes (KDIGO) criteria in diagnosing acute kidney injury (AKI) and/or chronic kidney disease (CKD). METHODS: A retrospective study of 325 patients admitted to general medicine during January 2012 was performed. Sensitivity and specificity of ICD 10 in identifying AKI and CKD were calculated using KDIGO as gold standard. RESULTS: The sensitivities of ICD 10 in identifying AKI and CKD were low for both (59.5% and 54.1%), but the specificities were high (86.2% and 90.2%). Using KDIGO criteria, we identified 72 AKI (22%), 56 CKD (17%), 64 AKI on CKD (19%) and 133 controls (40%). Compared to the control group, patients with AKI and AKI on CKD had longer length of stay (3.2 vs 4.9 days and 3.2 vs 4.8 days, P = 0.20). Renal impairment groups had increased in-hospital mortality rate (5% control, 6% AKI, 10% CKD, 9% AKI on CKD) and re-admission rate within 30 days (13% control, 20% AKI, 25% CKD, 26% AKI on CKD). After adjusting for age, gender and comorbidities, the difference in outcomes was not statistically significant. CONCLUSION: This study shows that ICD 10 fails to identify almost half of the patients with AKI (40.5%) and CKD (45.9%) in our cohort. A total of 60% had evidence of renal impairment as defined by KDIGO.

The Overuse, Underuse, and Misuse of Dialysis in ESKD Patients with Dementia.

The profile of patients on chronic dialysis has shifted. There is a growing group of older patients with comorbid dementia and ESKD, who are at risk of overuse, underuse, and misuse of dialysis. Policy is lacking to help guide treatment decisions in this group. This paper explores clinical considerations specific to patients with comorbid ESKD and dementia. These include: the impact of comorbid dementia on dialysis effectiveness and feasibility; burden of care issues that are specific to patients with dementia; and capacity, autonomy, and consent. A better understanding of these issues may help guide discussions and decision making about treatment. For some older patients with multiple comorbidities including dementia, dialysis does not provide survival or quality of life benefit compared to medical management. These patients also experience additional treatment burden due to a 'dementia unfriendly' environment. However, exceptions may include patients who are younger, more independent, and have fewer comorbidities. Patients with dementia are often inappropriately assumed to lack capacity to participate in treatment decision making, and are at risk of having their preferences overlooked. Many patients with mild-to-moderate dementia remain capable of reporting their preferences and quality of life, and should always be involved in treatment discussions where possible.

Estimated GFR reporting influences recommendations for dialysis initiation.

Automated reporting of estimated GFR (eGFR) with serum creatinine measurement is now common. We surveyed nephrologists in four countries to determine whether eGFR reporting influences nephrologists' recommendations for dialysis initiation. Respondents were randomly allocated to receive a survey of four clinical vignettes that included either serum creatinine concentration only or serum creatinine and the corresponding eGFR. For each scenario, the respondent was asked to rank his or her likelihood of recommending dialysis initiation on a modified 8-point Likert scale, ranging from 1 ("definitely not") to 8 ("definitely would"). Analysis of the 822 eligible responses received showed that the predicted likelihood of recommending dialysis increased by 0.55 points when eGFR was reported (95% confidence interval, 0.33 to 0.76), and this effect was larger for eGFRs >5 ml/min per 1.73 m(2) (P<0.001). Subgroup analyses suggested that physicians who had been in practice ≥13 years were more affected by eGFR reporting (P=0.03). These results indicate that eGFR reporting modestly increases the likelihood that dialysis is recommended, and physicians should be aware of this effect when assessing patients with severe CKD.

An observational outcomes study from 1966-2008, examining pregnancy and neonatal outcomes from dialysed women using data from the ANZDATA Registry.

AIMS: To conduct an observational outcomes study examining pregnancy and neonatal outcomes of dialysed women aged 15-49, from 1966-2008, using data from the ANZDATA Registry. METHODS: Data from the ANZDATA Registry were captured and analysed from 1966-2008. Specific pregnancy outcomes included: live birth (LB), spontaneous abortion, stillbirth (SB) or termination of pregnancy. Delivery and neonatal outcomes, since 2001, were also analysed. RESULTS: There were 23 700 person-years (PY) of observational data during the study period with 49 pregnancies, of which 30 (79%) resulted in a LB, once terminations were excluded. Pregnancy rates: Overall the pregnancy rate was 2.07 per 1000 PY for the study interval. A significant increase in the pregnancy rate was noted for the 1996-2008 time interval (3.3 per 1000 PY, compared with 0.54 and 0.67 in the eras 1976-1985 and 1986-1995, respectively; P = 0.004). Most pregnancies were observed in the 25-29 age group: 20-24, 25-29 and 30-34 (5.31, 5.61 and 3.87 per 1000 PY, respectively). Patients on peritoneal dialysis were less likely to achieve a pregnancy compared with haemodialysis patients (P < 0.02). Live birth rates: The overall LB rate was 1.26 per 1000 PY. The rate for each of the age brackets was as follows: 3.54 for 20-24, 3.61 for 25-29, and 2.39 per 1000 PY for 30-34, compared with 0 in the 15-19 group, and 1.22, 0.2 and 0.16 per 1000 PY among the groups 35-39, 40-44 and 45-49 years, respectively. LB rates were more favourable in the younger age groups. There was no significant era, disease, dialysis modality or race effect on LB rates. Excluding terminations, the LB rate was 79%. Age-effect on pregnancy outcomes: Pregnancy outcome was not affected by age (mean ages shown): spontaneous abortions, 28.7 years (n = 3); LB, 29.3 years (n = 24); SB, 32.4 years (n = 5); terminations 30.6 years (n = 11). Maternal mortality and complications: The preeclampsia rate was 19.4% (6/31). No post-partum maternal deaths were reported. Neonatal outcomes: Since 2001, 21 neonatal outcomes were reported. One baby developed polyhydramnios, one had a congenital malformation and one post-natal death was reported. In total 53.4% were born preterm; 65% had a birthweight <2.5 kg (low birthweight) and 35% <1.5 kg (very low birthweight). Low birthweight correlated with prematurity. CONCLUSION: Seventy-nine per cent of women achieving a pregnancy in our cohort achieved a LB, although 53.4% of babies were born preterm and 65% were of low birthweight (<2.5 kg).

Corticosteroids worsen proteinuria and increase intraglomerular signaling by NF-ĸB in a model of membranous glomerulonephritis.

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-1ß 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 αß 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.

Reduction in renal ACE2 expression in subtotal nephrectomy in rats is ameliorated with ACE inhibition.

Alterations within the RAS (renin-angiotensin system) are pivotal for the development of renal disease. ACE2 (angiotensin-converting enzyme 2) is expressed in the kidney and converts the vasoconstrictor AngII (angiotensin II) into Ang-(1-7), a peptide with vasodilatory and anti-fibrotic actions. Although the expression of ACE2 in the diabetic kidney has been well studied, little is known about its expression in non-diabetic renal disease. In the present study, we assessed ACE2 in rats with acute kidney injury induced by STNx (subtotal nephrectomy). STNx and Control rats received vehicle or ramipril (1 mg. kg (-1) of body weight . day (-1), and renal ACE, ACE2 and mas receptor gene and protein expression were measured 10 days later. STNx rats were characterized by polyuria, proteinuria, hypertension and elevated plasma ACE2 activity (all P<0.01) and plasma Ang-(1-7) (P<0.05) compared with Control rats. There was increased cortical ACE binding and medullary mas receptor expression (P<0.05), but reduced cortical and medullary ACE2 activity in the remnant kidney (P<0.05 and P<0.001 respectively) compared with Control rats. In STNx rats, ramipril reduced blood pressure (P<0.01), polyuria (P<0.05)and plasma ACE2 (P<0.01), increased plasma Ang-(1-7) (P<0.001), and inhibited renal ACE(P<0.001). Ramipril increased both cortical and medullary ACE2 activity (P<0.01), but reduced medullary mas receptor expression (P<0.05). In conclusion, our results show that ACE2 activity is reduced in kidney injury and that ACE inhibition produced beneficial effects in association with increased renal ACE2 activity. As ACE2 both degrades AngII and generates the vasodilator Ang-(1-7), a decrease in renal ACE2 activity, as observed in the present study, has the potential to contribute to the progression of kidney disease.

Pregnancy and maternal outcomes among kidney transplant recipients.

Fertility rates, pregnancy, and maternal outcomes are not well described among women with a functioning kidney transplant. Using data from the Australian and New Zealand Dialysis and Transplant Registry, we analyzed 40 yr of pregnancy-related outcomes for transplant recipients. This analysis included 444 live births reported from 577 pregnancies; the absolute but not relative fertility rate fell during these four decades. Of pregnancies achieved, 97% were beyond the first year after transplantation. The mean age at the time of pregnancy was 29 +/- 5 yr. Compared with previous decades, the mean age during the last decade increased significantly to 32 yr (P < 0.001). The proportion of live births doubled during the last decade, whereas surgical terminations declined (P < 0.001). The fertility rate (or live-birth rate) for this cohort of women was 0.19 (95% confidence interval 0.17 to 0.21) relative to the Australian background population. We also matched 120 parous with 120 nulliparous women by year of transplantation, duration of transplant, age at transplantation +/-5 yr, and predelivery creatinine for parous women or serum creatinine for nulliparous women; a first live birth was not associated with a poorer 20-yr graft or patient survival. Maternal complications included preeclampsia in 27% and gestational diabetes in 1%. Taken together, these data confirm that a live birth in women with a functioning graft does not have an adverse impact on graft and patient survival.

Live kidney donors - assessment and follow up.

BACKGROUND: 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. OBJECTIVE: This overview outlines the clinical pathway and considerations required pre- and post-live kidney donation and highlights some of the uncertainties of donor nephrectomy. DISCUSSION: 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.

Low salt concentrations activate AMP-activated protein kinase in mouse macula densa cells.

The energy-sensing kinase AMP-activated protein kinase (AMPK) is associated with the sodium-potassium-chloride cotransporter NKCC2 in the kidney and phosphorylates it on a regulatory site in vitro. To identify a potential role for AMPK in salt sensing at the macula densa, we have used the murine macula densa cell line MMDD1. In this cell line, AMPK was rapidly activated by isosmolar low-salt conditions. In contrast to the known salt-sensing pathway in the macula densa, AMPK activation occurred in the presence of either low sodium or low chloride and was unaffected by inhibition of NKCC2 with bumetanide. Assays using recombinant AMPK demonstrated activation of an upstream kinase by isosmolar low salt. The specific calcium/calmodulin-dependent kinase kinase inhibitor STO-609 failed to suppress AMPK activation, suggesting that it was not part of the signal pathway. AMPK activation was associated with increased phosphorylation of the specific substrate acetyl-CoA carboxylase (ACC) at Ser(79), as well as increased NKCC2 phosphorylation at Ser(126). AMPK activation due to low salt concentrations was inhibited by an adenovirus construct encoding a kinase dead mutant of AMPK, leading to reduced ACC Ser(79) and NKCC2 Ser(126) phosphorylation. This work demonstrates that AMPK activation in macula densa-like cells occurs via isosmolar changes in sodium or chloride concentration, leading to phosphorylation of ACC and NKCC2. Phosphorylation of these substrates in vivo is predicted to increase intracellular chloride and so reduce the effect of salt restriction on tubuloglomerular feedback and renin secretion.

Dentritic cell derived IL-18 production is inhibited by rapamycin and sanglifehrin A, but not cyclosporine A.

Interleukin-18 (IL-18), a product of dendritic cells (DC), is a pro-inflammatory cytokine involved in the pathogenesis of allograft rejection, vascular disease, arthritis and diabetes. Rapamycin (Rapa) is an immunosuppressant that inhibits T cell mTOR kinase activation. In contrast, Sanglifehrin A (SFA), is a cyclophilin-binding immunosuppressant that does not act on calcineurin phosphatases but appears to inhibit IL-2-dependent T cell proliferation. Rapa and SFA exert some immunosuppressive effects on DC by inhibiting IL-12 production, although their effects on DC have not been investigated as comprehensively as those on T cells. We aimed to determine the impact of these drugs on DC IL-18 synthesis in vivo and in vitro. We found in vivo that LPS-stimulated OX62(+) DC produced significantly more IL-18 mRNA, compared to OX62(+) DC depleted splenocytes (p<0.01) and non-LPS-stimulated OX62(+) DC (p<0.01). OX62(+)CD4(+) and OX62(+)CD4(-) cells produced similar amounts of IL-18 mRNA. Rapa and SFA, but not CsA, significantly inhibited IL-18 production from OX62(+) DC in vitro, in a dose-dependent manner (p<0.05). In vivo IL-18 production was also inhibited by Rapa and SFA in splenic OX62(+) DC (p<0.01). Finally, inhibition of IL-18 production by Rapa and SFA was independent of the FK506 or cyclophilin pathways, respectively. In conclusion, Rapa and SFA, but not CsA, block IL-18 production and this novel Rapa blockade effect on IL-18 may contribute to the ability of Rapa to inhibit chronic allograft nephropathy and restenosis.

Predictors of early dialysis vascular-access failure after thrombolysis.

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.

New approaches to the treatment of dense deposit disease.

The development of clinical treatment protocols usually relies on evidence-based guidelines that focus on randomized, controlled trials. For rare renal diseases, such stringent requirements can represent a significant challenge. Dense deposit disease (DDD; also known as membranoproliferative glomerulonephritis type II) is a prototypical rare disease. It affects only two to three people per million and leads to renal failure within 10 yr in 50% of affected children. On the basis of pathophysiology, this article presents a diagnostic and treatment algorithm for patients with DDD. Diagnostic tests should assess the alternative pathway of complement for abnormalities. Treatment options include aggressive BP control and reduction of proteinuria, and on the basis of pathophysiology, animal data, and human studies, plasma infusion or exchange, rituximab, sulodexide, and eculizumab are additional options. Criteria for treatment success should be prevention of progression as determined by maintenance or improvement in renal function. A secondary criterion should be normalization of activity levels of the alternative complement pathway as measured by C3/C3d ratios and C3NeF levels. Outcomes should be reported to a central repository that is now accessible to all clinicians. As the understanding of DDD increases, novel therapies should be integrated into existing protocols for DDD and evaluated using an open-label Bayesian study design.

Regulation of the renal-specific Na+-K+-2Cl- co-transporter NKCC2 by AMP-activated protein kinase (AMPK).

The renal-specific NKCC2 (Na+-K+-2Cl- co-transporter 2) is regulated by changes in phosphorylation state, however, the phosphorylation sites and kinases responsible have not been fully elucidated. In the present study, we demonstrate that the metabolic sensing kinase AMPK (AMP-activated protein kinase) phosphorylates NKCC2 on Ser126 in vitro. Co-precipitation experiments indicated that there is a physical association between AMPK and the N-terminal cytoplasmic domain of NKCC2. Activation of AMPK in the MMDD1 (mouse macula densa-derived 1) cell line resulted in an increase in Ser126 phosphorylation in situ, suggesting that AMPK may phosphorylate NKCC2 in vivo. The functional significance of Ser126 phosphorylation was examined by mutating the serine residue to an alanine residue resulting in a marked reduction in co-transporter activity when exogenously expressed in Xenopus laevis oocytes under isotonic conditions. Under hypertonic conditions no significant change of activity was observed. Therefore the present study identifies a novel phosphorylation site that maintains NKCC2-mediated transport under isotonic or basal conditions. Moreover, the metabolic-sensing kinase, AMPK, is able to phosphorylate this site, potentially linking the cellular energy state with changes in co-transporter activity.

Activators of the energy sensing kinase AMPK inhibit random cell movement and chemotaxis in U937 cells.

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)1alpha. 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 SDF1alpha 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.

An unexpected cause of macroscopic haematuria.

A 25-year-old man presented with macroscopic haematuria associated with a body mass index of 20 kg/m and a severe coagulopathy consistent with vitamin K deficiency. The diagnosis of a profound malabsorption syndrome secondary to coeliac disease was confirmed by small bowel histology and positive coeliac serology.

New insights into the molecular biology of the glomerular filtration barrier and associated disease.

The glomerular filtration barrier of the kidney can no longer be considered as an inert and adynamic structure, viewed by electron microscopy. Molecular biology, medical genetics and protein chemistry have enabled us to further understand the complex structure and function of this highly specialized barrier of the kidney. Minor aberrations of physiology can lead to fatal disease. Recent advances in the understanding of the physiology of endothelial cells, glomerular epithelial cells and the glomerular basement membrane and its components, and how these relate to disease, will be considered systematically.

Heparanase inhibition reduces proteinuria in a model of accelerated anti-glomerular basement membrane antibody disease.

BACKGROUND: The beta-d-endoglycosidase, heparanase, is emerging as an important contributor to the pathogenesis of proteinuria. The purpose of the present study therefore was to examine the role of heparanase in a model of accelerated anti-glomerular basement disease (anti-GBM). METHODS: Accelerated anti-GBM disease was induced and animals sacrificed at day 10 to establish heparanase expression using immunohistochemistry and western blot analysis. In addition, cortex was isolated from normal and diseased glomeruli to determine if mRNA levels altered with disease. A previously validated anti-heparanase antibody associated with proteinuria reduction, in a model of membranous nephropathy, was administered prior to disease induction to establish its impact on protein excretion in this model. RESULTS: At day 10 of anti-GBM disease, an increase in glomerular heparanase was shown using immunohistochemistry. Sequential staining studies revealed that this increase was associated with glomerular endothelial, epithelial cells and invading ED-1-positive inflammatory cells. RT-PCR revealed an insignificant 1.2-fold induction of mRNA at day 10 of disease. Western blot analysis of kidney cortex confirmed that the active 58-kDa heparanase species was restricted to diseased kidney at day 10. The inactive 65-kDa precursor, however, was found only in cortex derived from normal kidney. Proteinuria at day 10 of disease was significantly reduced, in the absence of altered rat anti-sheep antibody titres, after administration of a validated polyclonal anti-heparanase antibody (P < 0.05). Furthermore, sheep IgG deposition was not altered by administration of the anti-heparanase antibody. CONCLUSION: These data suggest that heparanase contributes to the pathogenesis of proteinuria in a model of anti-GBM disease.