Temporal validation of the Australian estimated post-transplant survival score.

AIMS: The Australian estimated post-transplant survival (EPTS-AU) prediction score was developed by re-fitting the United States of America EPTS, without diabetes, to the Australian and New Zealand kidney transplant population over 2002-2013. The EPTS-AU score incorporates age, previous transplantation and time on dialysis. Diabetes was excluded from the score, as this was not previously recorded in the Australian allocation system. In May 2021, the EPTS-AU prediction score was incorporated into the Australian kidney allocation algorithm to optimize utility for recipients (maximized benefit). We aimed to temporally validate the EPTS-AU prediction score to ensure it can be used for this purpose. METHODS: Using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, we included adult recipients of deceased donor kidney-only transplants between 2014 and 2021. We constructed Cox models for patient survival. We assessed validation using measures of model fit (Akaike information criterion and misspecification), discrimination (Harrell's C statistic and Kaplan-Meier curves), and calibration (observed vs. predicted survival). RESULTS: Six thousand four hundred and two recipients were included in the analysis. The EPTS-AU had moderate discrimination with a C statistic of 0.69 (95% CI 0.67, 0.71), and clear delineation between Kaplan-Meier's survival curves of EPTS-AU. The EPTS was well calibrated with the predicted survivals equating with the observed survival outcomes for all prognostic groups. CONCLUSIONS: The EPTS-AU performs reasonably well in choosing between recipients (discrimination) and to predict a recipient's survival (calibration). Reassuringly, the score is functioning as intended to predict post-transplant survival for recipients as part of the national allocation algorithm.

Confirmed microsporidial graft infection in a HIV-negative renal transplant recipient: A case report and review of the literature.

Microsporidia are intracellular organisms most commonly known to cause opportunistic infection in patients with human immunodeficiency virus (HIV). There have been several case reports of infection in solid organ and bone marrow transplant recipients. Here, we report a case of a non-HIV-infected renal transplant patient with microsporidiosis of the renal tract associated with acute graft dysfunction. We also review the literature of 12 previously reported cases of microsporidiosis in patients with renal transplants who had described graft involvement. We review the pattern of illness as well as the common renal biopsy features when microsporidial infection is associated with renal graft infection.

Laboratory identification of donor-derived coxsackievirus b3 transmission.

Unexpected donor-to-recipient infectious disease transmission is an important, albeit rare, complication of solid organ transplantation. Greater work and understanding about the epidemiology of these donor-derived transmissions is continually required to further mitigate this risk. Herein we present the first reported case of proven donor-derived transmission of coxsackievirus serogroup-3, an enterovirus, following solid organ transplant. Swift and effective communication between the organ donation agency, treating physicians, laboratory testing and notification ensured a coordinated approach. The resulting clinical syndromes in the organ recipients were mild. This case highlights the requirement for ongoing surveillance over a broad range of infecting pathogens that may present as a donor-derived infection.

International travel in the immunocompromised patient: a cross-sectional survey of travel advice in 254 consecutive patients.

AIMS: Our primary aim was to determine the rate of overseas travel in immunocompromised individuals attending appropriate clinics at an Australian tertiary care hospital. We also aimed to characterise health-seeking behaviour prior to travel and investigated sources of pre-travel advice, compared travel patterns and activities between three specific immunosuppressed groups, and examined pre-immunosuppression patient serology. METHODS: We implemented a cross-sectional survey of patients between February and August 2012. This survey was implemented among three outpatient populations at Monash Medical Centre, an Australian tertiary care hospital. RESULTS: We recruited 254 immunosuppressed adults from three patient populations: human immunodeficiency virus-positive individuals, renal transplant patients and rheumatology patients requiring immunosuppressive therapy. No clinical intervention was performed. In the 10 years preceding the survey, 153 (60.2%) participants reported international travel. Of these, 105 (68.6%) were immunosuppressed at the time of travel. These patients were 47.6% male and 60% Australian born. Forty per cent were visiting friends and relatives as part of their travel. Fifty-four per cent of those immunocompromised at the time of travel were going to high-risk destinations. Pathology files indicated that serological screening was frequently not performed prior to immunosuppression in the renal transplant and rheumatology groups. CONCLUSIONS: Immunocompromised patients often travel to high-risk destinations with limited or inadequate pre-travel preparations. Doctors caring for the immunocompromised should be aware of travel risks, suitable vaccination protocols and when to refer to specialist travel clinics.

BK Virus Associated Nephropathy, a Cause of Early Renal Allograft Dysfunction: A Single Centre Study.

BACKGROUND: BK virus associated nephropathy (BKVN) is an important cause of early graft dysfunction in renal transplant recipients. The present study was carried out to determine the burden of BKVN in a single renal transplant centre in Australia. METHOD: A retrospective analysis of de novo renal transplant recipients from 2010 to 2013 was performed to identify biopsy proven BKVN. Estimated glomerular filtration rate (eGFR) was compared at baseline, at BKVN diagnosis and 3 and 12 months postdiagnosis. RESULT: Of the 317 de novo renal transplants recipients in the study period, 20 (6.3%) developed BKVN. The mean age was 54.8 ± 13.1 years and 13 (65%) were male. The mean time from transplant to BKVN was 8.7 ± 6.7 months with 17 (85%) diagnosed within 12 months. Four recipients each were diagnosed BKVN on 3 and 12 month surveillance biopsy. Six (30%) had normal eGFR at diagnosis. Mean eGFR at diagnosis was 38.8 ± 19.2 ml/min/1.73 m2, which was significantly lower (p < 0.01) than that at baseline (50.3 ± 16.4 ml/min/1.73 m2). eGFR improved numerically at 3 and 12 months post-diagnosis, however the difference was not significant. One patient had graft failure, 19 months after diagnosis. CONCLUSION: BKVN generally occurs in first post-transplant year and is an important cause of early graft dysfunction. Surveillance biopsy helps in detecting subclinical BKVN.

A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients.

This was a systematic review of randomized controlled trials comparing delayed conversion of mammalian target of rapamycin inhibitors (mTORi) for calcineurin inhibitors (CNIs) versus CNI continuation in kidney transplantation. Databases (2000-2012) and conference abstracts (2009-2012) were searched giving a total of 29 trials. Outcomes analyzed included GFR, graft loss, rejection and adverse events and were expressed as weighted mean differences (WMDs) or as risk ratios (RRs). Patients converted to mTORi up to 1 year posttransplant in intention-to-treat analysis had higher GFR compared with those remaining on CNI (WMD 0.28 mL/min/1.73 m(2) , 95% confidence interval [CI] 0.21-0.36; I(2) = 68%, p < 0.001). Stratifying trials by time posttransplant or type of mTORi did not change the overall heterogeneity. For on-treatment population, mTORi was associated with higher GFR (14.21 mL/min/1.73 m(2) , 10.34-18.08; I(2) = 0%, p = 0.970) 2-5 years posttransplant. The risk of rejection at 1 year was higher in mTORi trials (RR 1.72, 1.34-2.22; I(2) = 12%, p = 0.330). Discontinuation secondary to adverse events was more common in patients on mTORi, whereas the incidence of skin cancers and cytomegalovirus infection was lower in patients on mTORi. Conversion from CNI to mTORi is associated with short-term improvements in GFR in a number of studies but longer-term follow-up data of graft and patient survival are required.

Measurement of Humoral Immune Competence and the Risk of Sinopulmonary Infection in a Cohort of Kidney Transplant Recipients.

PURPOSE: The aim of this study was to determine if measurement of B cell protective immunity was associated with susceptibility to sinopulmonary infection in kidney transplant recipients. METHODS AND MATERIALS: A prospective cohort of 168 patients with stable graft function (median 4.1 years) underwent assessment of B-lymphocyte antigen CD19 (CD19+) cell number, immunoglobulin G concentration, and seroresponses to influenza vaccination upon study entry. Patients received a single dose of a trivalent, seasonal influenza vaccine. RESULTS: After 2 years follow-up, 31 patients (18%) developed sinopulmonary infection. CD19+ cell number was strongly associated with future sinopulmonary infection. A higher proportion of patients with CD19+ cell counts below the fifth percentile for controls developed sinopulmonary infections than those above the fifth percentile, 30% (23 of 77 patients) compared with 9% (7 of 79 patients; P = .001). There was a trend toward a higher proportion of patients with reduced immunoglobulin G concentrations developing infections than in the normal range for controls, 29% (14 of 48 patients) compared with 15% (16 of 108 patients; P = .060). Influenza vaccination seroresponses were poor in patients and controls such that they could not be used to identify a subgroup of patients at high risk for the development of severe pulmonary infection. CONCLUSIONS: Monitoring B-cell numbers represents a simple, inexpensive means of stratifying transplant recipients' risk of sinopulmonary infection.

Implementation and learning of laproscopic donor nephrectomy by a non-transplant general surgeon with advanced laparoscopic skills.

INTRODUCTION: Traditionally performed by vascular surgeons or urologists, laparoscopic nephrectomy for live kidney donor transplantation has emerged as a new effective and safe technique. This study examines the implementation of this technique at our centre, as performed by a single general surgeon with expertise in advanced laparoscopic surgery. METHODS: Patient records for 78 live donor transplants performed between February 2002 and September 2008 were divided into two groups (with 39 patients each) analyzed. A variety of outcome variables were compared. The same individual surgeon performed all laparoscopic donor nephrectomy (LDN) procedures. RESULTS: A significant advantage was noted for LDN with respect to hospital stay (LDN 5.1 ± 1.1 days vs open donor nephrectomy [ODN] 6.4 ± 2.6 days, P=0.01) while ODN had a significant advantage with respect to operative time (LDN 241.1 ± 55.7 min vs ODN 152.0 ± 27.7 min, P<0.01). Within the LDN group, we noted a significant shortening in the operation time with each case as experience increased (see graph; P<0.01). The total postoperative complication rate was similar in both groups (LDN: 31% vs ODN: 44%, P=0.25). There was a trend towards more respiratory complications in ODN (ODN 11/39 [28%] vs LDN 5/39 [13%], P=0.09). CONCLUSION: While implementing a new procedure may result in longer operative times initially, these improve with time, and our data demonstrates no compromise in patient safety or outcomes. The LDN procedure proved to be a desirable alternative to ODN, with shorter hospital stay and improved operator skills with each case, and without significant compromise in allograft recovery.

Vascular endothelial growth factor is a survival factor for renal tubular epithelial cells.

Vascular endothelial growth factor (VEGF) acts primarily as an endothelial cell mitogen via the "endothelial cell-specific" receptors VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR). Only a few nonendothelial cells have been shown to possess functional VEGF receptors. We therefore examined the rat renal tubular epithelial cell line NRK52-E. NRK52-E expressed VEGFR-1 and VEGFR-2 mRNA and protein by RT-PCR, Northern blotting, Western blotting, immunofluorescence, and ligand binding. Serum-starved NRK52-E incubated with VEGF showed a significant increase in [(3)H]thymidine incorporation compared with control (2.3-fold at 1-10 ng/ml, P < 0. 05; 3.3-fold at 50-100 ng/ml, P < 0.01). VEGF also protected NRK52-E from hydrogen peroxide-induced apoptosis and necrosis compared with control (annexin-V-FITC-positive cells, 39 vs. 54%; viable cells, 50. 5 vs. 39.7%). Immunohistochemical staining using a variety of antibodies showed expression of both VEGF receptors in normal rat renal tubules in vivo. Because VEGF induced a proliferative and an antiapoptotic response in renal tubular epithelial cells, these data suggest that VEGF may act as a survival factor for renal tubular epithelium in vivo.

Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemia-reperfusion injury.

BACKGROUND: Vascular endothelial growth factor (VEGF) mRNA and protein expression are increased by hypoxia in a variety of cell types and organs. In the kidney, however, chronic hypoxia does not up-regulate VEGF mRNA. This suggests that VEGF may be regulated by unique mechanisms in the kidney. METHODS: Unilateral ischemia was induced in rats by vascular cross-clamping (40 min) followed by reperfusion (0, 20, 40, and 80 min). The distribution of VEGF protein was determined by immunohistochemical staining and Western blotting. mRNA was detected by Northern blotting and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining for VEGF was verified using two VEGF antibodies. To further substantiate the immunohistochemical findings, laser scanning confocal fluorescence microscopy was used to demonstrate the distribution of VEGF protein in rat renal tubular epithelial cells (NRK52-E) subjected to hypoxia (40 min) and re-oxygenation (0, 5, 20, 40 and 80 min). RESULTS: Normal kidneys showed diffuse immunohistochemical staining for VEGF in all tubules of the renal cortex and medulla. Following ischemia, staining demonstrated a prominent shift of cytoplasmic VEGF to the basolateral aspect of tubular cells with both VEGF antibodies. The distribution of cytoplasmic VEGF returned to normal following 40 and 80 minutes of reperfusion. Western blots of cytoplasmic samples from ischemic kidneys reperfused for 0 and 20 minutes showed decreased levels of VEGF164 compared with normal (P < 0.01). VEGF164 and VEGF188 levels in the membrane fraction showed no change. Northern blots and semiquantitative RT-PCR showed no significant up-regulation of VEGF mRNA or change in the splice pattern. NRK52-E cells subjected to hypoxia and re-oxygenation for 0 and 5 minutes showed increased staining for VEGF compared with normal, with prominent VEGF staining at the periphery of the cell, similar to the appearance in ischemic kidneys. VEGF staining became more diffuse with further re-oxygenation. CONCLUSION: Although synthesis of VEGF mRNA and protein is not increased during ischemia reperfusion injury, pre-existing VEGF in the tubular cell cytoplasm redistributes to the basolateral aspect of the cells. These data suggest that the kidney may have evolved unique patterns of VEGF regulation to cope with acute hypoxia.

Heparin-binding epidermal growth factor-like growth factor in experimental models of membranous and minimal change nephropathy.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a recently described member of the epidermal growth factor (EGF) family. It binds to heparan sulfate proteoglycans via a cationic domain and is a potent mitogen for epithelial cells, fibroblasts and vascular smooth muscle cells. In the present study we have attempted to identify changes in quantity and distribution of HB-EGF in two models of acute glomerular epithelial cell injury, using Western blotting, immunohistochemistry and in situ hybridization. Prior to disease induction, Western blots showed some expression of HB-EGF protein within glomeruli. Within the first three days in the acute puromycin aminonucleoside (PAN) and passive Heymann nephritis (PHN) models, immunohistochemistry and in situ hybridization demonstrated an up-regulation of HB-EGF mRNA and protein in glomerular epithelial cells (GEC). In both cases, increased protein and mRNA was found prior to the onset of proteinuria and continued until day 21 post-induction, the last time point studied. Early in the course of the models, HB-EGF was localized to the cytoplasm of glomerular epithelial cells. At day 21, however, HB-EGF protein was distributed in a nodular pattern within GEC and along the glomerular basement membrane (GBM) in both models, suggesting that the secreted form might bind to the membrane. The increase in HB-EGF protein within glomeruli was confirmed by Western blots of glomerular membrane protein which, however, demonstrated a single 29 kDa species, consistent with the transmembrane form. These data are not consistent with binding of the secreted form of HB-EGF to the GBM. The transmembrane form of HB-EGF is able to signal in a juxtracrine fashion, so increased expression of HB-EGF mRNA and protein by GEC might contribute to the genesis of proteinuria through the initiation of abortive GEC mitogenesis.

Increased expression of heparanase in puromycin aminonucleoside nephrosis.

BACKGROUND: The beta-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. METHODS: 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. RESULTS: 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. CONCLUSION: The previously mentioned data confirm that the novel beta-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.

Heparin-binding epidermal growth factor-like growth factor is expressed in the adhesive lesions of experimental focal glomerular sclerosis.

BACKGROUND: In this study, we attempted to determine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) was up-regulated in two chronic models of proteinuria. METHODS: Chronic passive Heymann nephritis (PHN) and puromycin aminonucleoside (PAN) models were induced in Sprague-Dawley rats. HB-EGF expression was studied by Northern blotting, in situ hybridization, and immunohistochemistry. RESULTS: The chronic PAN model was associated with the development of glomerular lesions of focal glomerular sclerosis (FGS), severe interstitial fibrosis, and renal failure. Lesions of FGS were seen in approximately 80% of glomeruli at all time points, with a slight increase in the number of glomeruli showing extensive adhesion between 40 and 90 days. Northern blots of whole kidney tissue showed a 3- to 5.8-fold increased expression of HB-EGF mRNA in the chronic PAN group. Increased mRNA and protein were localized by in situ hybridization and immunohistochemistry to tubules, glomerular epithelial cells (GECs), and cells of Bowman's capsule. HB-EGF mRNA and protein were strongly expressed by epithelial cells involved in the formation of the lesions of FGS. By contrast, in chronic PHN, there was a small increase in HB-EGF, and the extensive lesions of FGS did not develop despite continued, heavy proteinuria. CONCLUSIONS: These data suggest that HB-EGF may contribute to formation of the lesions of FGS, perhaps through stimulation of abortive mitogenesis in GECs or an adhesive interaction between transmembrane HB-EGF and the exposed glomerular basement membrane.