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Background: In this 30-year national review, we describe trends in DD transplantation for paediatric recipients, assess the impact of paediatric allocation bonuses and identify outstanding areas of need for this population. Method(s): A retrospective review of all DD kidney only transplants to paediatric recipients (<18 years old) in Australia between 1989 and 2018 was conducted using deidentified extracts from the ANZDATA. Result(s): Of the 1011 kidney only transplants performed in paediatric recipients during the study period, 426 (42%) were from deceased donors. Paediatric candidates on the DD waiting list had consistently higher rates of transplantation and shorter time from dialysis initiation to transplantation compared with adult candidates (median 372 vs 832 days in 2018, for example). Donor characteristics remained more favourable for paediatric recipients, despite a decline in the overall quality of the donor pool. The mean number of HLA antigen mismatches for paediatric recipients of DD transplants increased each decade (2.86 [1989-1998], 3.85 [1999-2008], 4.01 [2009-2018]). Both patient and graft survival have improved for paediatric DD transplant recipients in the most recent era (5-year graft and patient survival 85% vs 65% and 99% vs 94%, respectively, for 2009-2018 vs 1999-2008). Conclusion(s): The current DD kidney allocation system in Australia provides rapid access to high-quality organs for paediatric recipients, and early graft loss has decreased significantly in recent years; however, additional targeted interventions to address HLA matching may improve long-term outcomes in this population.Copyright © 2021 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.Copyright © 2018 Asian Pacific Society of Nephrology

AIMS/HYPOTHESIS: The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. METHODS: Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT -> WT) or RAGE-deficient (RG) mice (RG -> WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks. RESULTS: Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-beta were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG -> WT mice also contained fewer infiltrating CD68(+) macrophages that were activated. Diabetic RG -> WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT -> WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG -> WT compared with diabetic WT -> WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. CONCLUSIONS/INTERPRETATION: These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.

Aim: To determine whether deletion of RAGE from bone-marrow derived cells influences the pathogenesis of experimental diabetic nephropathy. Background(s): Advanced glycation end-products (AGEs) and their receptor (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in immunity and is expressed on macrophages which promote injury in diabetic kidneys. Method(s): Groups of irradiated 8 week old wild type (WT) mice (n = 8) were reconstituted with bone marrow from either WT mice (WT->WT) or RAGE (RG) deficient mice (RG->WT). After 8 weeks of bone marrow reconstitution, diabetes was induced by multiple low doses of streptozotocin and diabetic mice were followed for a further 24 weeks. Result(s): At week 24, diabetic mice with WT bone marrow (WT->WT) had increased urinary albumin excretion, podocyte loss, glomerular hyperfiltration, tubular injury and interstitial fibrosis, which were reduced (all P < 0.05) in diabetic mice with RAGE deficiency in their bone marrow (RG->WT). However, glomerulosclerosis was similar in both diabetic groups. The tubulointerstitium of diabetic RG->WTmice contained fewer total (CD68+) and activated (CD169+) macrophages than diabetic WT->WT mice in association with lower renal cortical levels of chemokines (CCL2, MIF) and IL-6 (all P < 0.05). Renal cortical RAGE ligands S100A8/9 and AGEs, but not HMGB-1, were also decreased in diabetic RG->WT compared with diabetic WT->WT mice (all P < 0.05). In addition, bone marrow derived macrophages from WT mice, but not RAGE deficient mice, were activated in vitro by AGEs resulting in secretion of factors that induced increased collagen IV production in cultured proximal tubular cells (P < 0.05). Conclusion(s): RAGE expression on bone marrow derived immune cells contributes to the development of diabetic nephropathy by promoting macrophage infiltration, podocyte loss and tubulointerstitial damage.

Aims/hypothesis: The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. Methods: Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT -> WT) or RAGE-deficient (RG) mice (RG -> WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks. Results: Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-beta were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG -> WT mice also contained fewer infiltrating CD68+ macrophages that were activated. Diabetic RG -> WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT -> WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG -> WT compared with diabetic WT -> WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. Conclusions/interpretation: These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.Copyright

Treatment of children with steroid-dependent nephrotic syndrome (SDNS) continues to be a challenge when relapses recur after treatment with cyclophosphamide and side effects or non-compliance make steroids and cyclosporin unsatisfactory. We treated 12 patients with intravenous vincristine for SDNS in a regime of 1-1.5 mg/m2 weekly for 4 weeks then monthly for 4 months. Four of the 5 patients in relapse when commencing vincristine remitted within 2 doses. Comparing relapse frequency in the 12 months before and after vincristine, there was a reduction from 4 to 1.5 (p=0.004) relapses per year. Median sustained remission was 5 months, but 1 frequently relapsing patient remains in remission 4 years after vincristine. Vincristine was also successfully used in 1 or 2 doses at weekly intervals for subsequent relapses in 5 patients. Side effects were minimal in most cases. Abdominal pain occurred in 2 patients who commenced vincristine at 1.5 mg/m2, but resolved when continued at 1 mg/m2. We felt vincristine had a role in a subset of children with challenging SDNS administered as 1 mg/m2 weekly for 4 weeks then 1.5 mg/m2 monthly for 4 months. Vincristine allowed steroid- and cyclosporin-sparing, contributed to long-term remission in some patients, and was especially valuable in children with poor compliance with oral medication. Many patients expressed a preference for a few doses of vincristine rather than a standard course of oral prednisolone or cyclosporin. © IPNA 2005.

Th1 effector CD4+ cells contribute to the pathogenesis of proliferative and crescentic glomerulonephritis, but whether effector Th17 cells also contribute is unknown. We compared the involvement of Th1 and Th17 cells in a mouse model of antigen-specific glomerulonephritis in which effector CD4+ cells are the only components of adaptive immunity that induce injury. We planted the antigen ovalbumin on the glomerular basement membrane of Rag1-/- mice using an ovalbumin-conjugated non-nephritogenic IgG1 monoclonal antibody against alpha3(IV) collagen. Subsequent injection of either Th1- or Th17-polarized ovalbumin-specific CD4+ effector cells induced proliferative glomerulonephritis. Mice injected with Th1 cells developed progressive albuminuria over 21 d, histologic injury including 5.5 +/- 0.9% crescent formation/segmental necrosis, elevated urinary nitrate, and increased renal NOS2, CCL2, and CCL5 mRNA. Mice injected with Th17 cells developed albuminuria by 3 d; compared with Th1-injected mice, their glomeruli contained more neutrophils and greater expression of renal CXCL1 mRNA. In conclusion, Th1 and Th17 effector cells can induce glomerular injury. Understanding how these two subsets mediate proliferative forms of glomerulonephritis may lead to targeted therapies. Copyright © 2009 by the American Society of Nephrology.

Unilateral ureteral obstruction (UUO) is a well-characterized murine model of renal inflammation leading to fibrosis. Renal dendritic cells (DCs) constitute a significant portion of kidney leukocytes and may participate in local inflammation and have critical roles in antigen presentation. The heterogeneity in renal DC populations and surface marker overlap with monocytes/macrophages has made studying renal DCs difficult. These studies used CD11c-promoter driven reporter/depletion mice to study DCs in vivo. Studying early local inflammatory events (day 3 of UUO), in vivo multiphoton imaging of the intact kidney of CD11c reporter mice revealed more dendrite extensions and increased activity of renal DCs in real time. Phenotypic analysis suggested resident DC maturation in obstructed kidneys with increased CD11b and less F4/80 expressed. CD11bhi Gr-1+ inflammatory DCs were also present in obstructed kidneys. T-cell receptor transgenic mice revealed enhanced antigen-presenting capacity of renal DCs after UUO, with increased antigen-specific T-cell proliferation in vivo and ex vivo. However, conditional DC ablation at days 0, 2, or 4 did not attenuate fibrosis or apoptosis 7 days after UUO, and depletion at 7 days did not alter outcomes at day 14. Therefore, after UUO, renal DCs exhibit inflammatory morphological and functional characteristics and are more effective antigen-presenting cells, but they do not directly contribute to tubulointerstitial damage and fibrosis. © 2012 American Society for Investigative Pathology.

A 12 year old boy presented with severe hypertension and was diagnosed with renal artery stenosis requiring balloon angioplasty. Takayasu's arteritis was subsequently diagnosed, but he also developed acute panuveitis, an entity not previously reported in a child with this condition.