Monica Suet Ying Ng’s research while affiliated with Royal Brisbane Hospital and other places

Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O 2 ) or hypoxic (1% O 2 ) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia. Hypoxia+IL-1β-treated PTECs had 692 ‘unique’ differentially expressed genes (DEGs) compared to normoxic PTECs, with ‘cell cycle’ the most significantly enriched KEGG pathway based on ‘unique’ down-regulated DEGs (including CCNA2 , CCNB1 and CCNB2 ). Hypoxia+IL-1β-treated PTECs displayed signatures of cellular senescence, with reduced proliferation, G2/M cell cycle arrest, increased p21 expression, elevated senescence-associated β-galactosidase (SA-β-gal) activity and increased production of pro-inflammatory/fibrotic senescence-associated secretory phenotype (SASP) factors compared to normoxic conditions. Treatment of Hypoxia+IL-1β-treated PTECs with either a type I IL-1 receptor (IL-1RI) neutralizing antibody or a senolytic drug combination, quercetin+dasatinib, attenuated senescent cell burden. In vitro findings were validated in human CKD bio-specimens (kidney tissue, urine), with elevated PTEC IL-1RI expression and senescence (SA-β-gal activity) detected in fibrotic kidneys and numbers of senescent (SA-β-gal ⁺ ) urinary PTECs correlating with urinary IL-1β levels and severity of interstitial fibrosis. Our data identify a mechanism whereby hypoxia in combination with IL-1β/IL-1RI signalling trigger PTEC senescence, providing novel therapeutic and diagnostic check-points for restoring tubular regeneration in human CKD.

Kidney aging is the loss of tissue and organ function over time. Cellular senescence is a state of permanent growth arrest and cessation of cell division. Although aging and senescence share some features, the two processes differ. In contrast to aging, senescence occurs when a cell irreversibly exits the cell cycle and assumes a distinct phenotype. This chapter on nephron senescence and mechanisms explores the proposition that senescence in the kidney is more than just normal organ aging but instead encompasses pathobiological pathways that are activated by injury and result in pathologic alterations in kidney tissue and function. We discuss the role of cellular senescence in a variety of kidney diseases and consider the potential therapeutic benefits of targeting senescent cells in diseased and aged kidneys.

Objectives Dysregulation of Epstein–Barr virus (EBV)‐specific cellular immunity has been hypothesised as one of the contributing factors in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis is a major risk factor for overall morbidity in SLE. Immune‐based strategies directed to EBV have been proposed as potential therapeutic strategy for SLE and lupus nephritis. Methods Autologous EBV latent antigen‐specific CD4⁺ and CD8⁺ T cells were expanded in vitro and adoptively transferred to a lupus nephritis patient. Results This adoptive immunotherapy had no immediate adverse effects, and the patient was subsequently treated with the anti‐CD20 antibody, obinutuzumab. The patient showed a reduction in anti‐dsDNA antibodies and improved glomerular filtration rate but remained nephrotic. These observations were coincident with a reduction in anti‐viral and global T‐cell activation. Conclusion To our knowledge, this is the first report of the use of EBV‐specific adoptive immunotherapy to treat a patient with lupus nephritis.

Drug repurposing in glomerular disease can deliver opportunities for steroid-free regimens, enable personalized multi-target options for resistant or relapsing disease and enhance treatment options for understudied populations (for example, children) and in resource-limited settings. Identification of drug-repurposing candidates can be data driven, which utilizes existing data on disease pathobiology, drug features and clinical outcomes, or experimental, which involves high-throughput drug screens. Information from databases of approved drugs, clinical trials and PubMed registries suggests that at least 96 drugs on the market cover 49 targets with immunosuppressive potential that could be candidates for drug repurposing in glomerular disease. Furthermore, evidence to support drug repurposing is available for 191 immune drug target-glomerular disease pairs. Non-immunological drug repurposing includes strategies to reduce haemodynamic overload, podocyte injury and kidney fibrosis. Recommended strategies to expand drug-repurposing capacity in glomerular disease include enriching drug databases with glomeruli-specific information, enhancing the accessibility of primary clinical trial data, biomarker discovery to improve participant selection into clinical trials and improve surrogate outcomes and initiatives to reduce patent, regulatory and organizational hurdles.

Background and hypothesis Advances in organ procurement, surgical techniques, immunosuppression regimens and prophylactic antibiotic therapies have dramatically improved short term kidney transplant graft failure. It is unclear how these interventions have affected longer term graft failure. It is hypothesised that graft failure has improved over the last 20 years. Methods Data on all first kidney transplants from 1995–2014 were extracted from the Australia and New Zealand Dialysis and Transplant Registry with follow-up as of 31 December, 2021. Primary exposure was transplant era, classified into 5-year intervals. Primary outcome was all-cause 5-year graft failure. Secondary outcomes included all-cause 10-year graft failure and cause-specific graft failure. Kaplan Meier curves and multivariable Cox Proportional Hazards Regression models were used to assess trends in all-cause graft failure. Fine-Gray subdistribution hazard models verified that changes in death rates were not biasing the Cox Proportional Hazards Regression models. Cumulative incidence functions were used to assess temporal trends in cause-specific graft failure. Results Across 10 871 kidney transplants, there was a shift towards transplanting more recipients aged over 45 years old, with more comorbidities, longer dialysis vintage, body mass index greater than 30 kg/m2 and greater human leukocyte antigen mismatches. Donor age has increased but no clear shift in donor source was observed. Compared to 1995–1999 (reference), the adjusted hazard ratio for 5-year graft failure was 0.78 (95% CI 0.67–0.91), 0.70 (95% CI 0.59–0.83) and 0.60 (95% CI 0.50–0.73) for 2000–2004, 2005–2009, and 2010–2014, respectively. Ten-year graft failure similarly reduced from 0.83 (95% CI 0.74–0.93) for 2000–04 to 0.78 (95% CI 0.68–0.89) for 2010–14, compared to 1995–99. Conclusion Medium and long term all-cause graft failure has improved steadily since 1995–99. Significant reductions in graft failure due to rejection and vascular causes were observed at 5 years, and due to rejection, vascular causes, death and glomerular disease at 10 years.