Sydney Chi Wai Tang

Background: Dysregulation of mitochondrial homeostasis is associated with kidney tubular injury and subsequent tubulointerstitial fibrosis, contributing to the development of chronic kidney diseases (CKD). Translocator protein (TSPO), located on the outer mitochondrial membrane, is upregulated in kidney tubules after injury; however, its roles in CKD progression remain unknown. Methods: We investigated the impact of TSPO deficiency on mitochondrial dysfunction, kidney inflammation and fibrosis in mouse models of unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (IRI). Tubule-specific TSPO-knockout mice (KspCre ^ERT2 ; TSPO ^lox/lox ) were used. The role of TSPO in metabolic energy metabolism under hypoxic stress was delineated in TSPO-deficient primary renal proximal tubular epithelial cells (RTECs) from mice and in human proximal tubular epithelial cell line (HK-2 cells). The protective effect of TSPO antagonist PK11195 treatment was evaluated in mice with CKD. Results: TSPO expression was increased in the proximal tubules of patients with CKD, and in UUO- and unilateral IRI-induced mice. Tubule-specific deletion of TSPO and treatment with PK11195 mitigated kidney injury, inflammation and fibrosis in UUO or unilateral IRI mice. Bulk RNA-seq analysis further revealed the enrichment of genes in metabolic pathways with increased oxidative phosphorylation (OXPHOS) and reduced glycolysis in kidneys from TSPO knockout mice. In primary RTECs subjected to hypoxic stress, deletion of TSPO preserved mitochondrial function by enhancing mitochondrial biogenesis and membrane potential, improving OXPHOS and reducing glycolysis, thereby increasing ATP production. Finally, TSPO interacted with the first enzyme of the glycolytic pathway, hexokinase 2 (HK2), on mitochondria, and TSPO knockdown triggered HK2 translocation to the cytosol, thereby decreasing its glycolytic capacity and improving mitochondrial homeostasis. Conclusions: TSPO depletion protected mice from kidney injury and tubulointerstitial fibrosis during CKD progression by disrupting HK2-mediated glycolysis and enhancing mitochondrial energy metabolism.

Background and hypothesis: Sparsentan, a non-immunosuppressive, dual endothelin angiotensin receptor antagonist (DEARA), and sodium–glucose cotransporter-2 inhibitors (SGLT2is) reduce proteinuria in patients with immunoglobulin A nephropathy (IgAN). We report the safety and efficacy of sparsentan combined with SGLT2is in patients with IgAN in the SPARTACUS trial and a substudy in the PROTECT open-label extension (OLE). Methods: SPARTACUS (NCT05856760) was a phase 2, open-label trial in which patients had renin–angiotensin system inhibitors (RASi) replaced with sparsentan while continuing stable SGLT2i. In the PROTECT (NCT03762850) OLE substudy, patients receiving sparsentan were randomized 1:1 to add SGLT2i or continue sparsentan alone for 12 weeks; afterward, all could receive 24 weeks of sparsentan + SGLT2i combination therapy. Endpoints in both studies included change in proteinuria and safety. Results: In SPARTACUS, 48 patients were enrolled (mean [SD] age, 48.9 [13.9] y; 58% male); 39 completed treatment. Replacement of RASi with sparsentan while on stable SGLT2i led to rapid urine albumin-to-creatinine ratio reductions sustained through Week 24 (least-squares mean [95% confidence interval, CI], −55.8% [−65.8% to −42.8%]). In the PROTECT OLE substudy, 63 patients enrolled and completed the 12-week randomized treatment (sparsentan + SGLT2i [n = 32] vs. sparsentan alone [n = 31]: mean [SD] age, 51.4 [13.4] y vs. 50.6 [11.1] y; male 81% vs. 68%, respectively); 54 completed 24 weeks of sparsentan + SGLT2i. At Week 12, significant relative reductions occurred in the urine protein-to-creatinine ratio (least-squares mean [95% CI]) with sparsentan + SGLT2i (−11.1% [−26.3% to 7.3%]) vs. sparsentan alone (17.7% [−2.4% to 42.1%]) (ratio [95% CI], 0.75 [0.58 to 0.98]; P < .05). Few treatment-related adverse events were severe or serious or led to discontinuation. Conclusion: In patients with IgAN, replacing RASi with sparsentan while on stable SGLT2i resulted in marked reductions in albuminuria. Adding SGLT2i to stable sparsentan resulted in modest further reductions in proteinuria. Sparsentan combined with SGLT2i was well tolerated, with no unexpected safety signals.

Background: Polypharmacy in chronic kidney disease (CKD) is substantial. Clinicians and patients are often reluctant to add medications to already complex regimens, partly due to concerns about diminishing efficacy and increased adverse effects. We assessed whether the efficacy and safety of canagliflozin are modified by polypharmacy status in patients with type 2 diabetes (DM) and CKD. Methods: We conducted a post-hoc analysis of the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, which evaluated the effects of canagliflozin on outcomes in patients with DM and CKD. Participants were categorized as no polypharmacy (0–4 medicines), polypharmacy (5–9 medicines) or hyperpolypharmacy (≥10 medicines). We assessed the relative effects of canagliflozin on clinical and safety outcomes by polypharmacy status using Cox proportional hazards models. We assessed absolute benefits using Poisson regression. The primary outcome was a composite of doubling of serum creatinine, kidney failure, or death due to cardiovascular or kidney disease. Results: Among 4401 participants, 612 (14%), 2404 (55%) and 1385 (31%) were categorized as no polypharmacy, polypharmacy and hyperpolypharmacy, respectively. Mean number of medications was 8.3 (SD 3.77). The effect of canagliflozin on kidney and cardiovascular outcomes was consistent irrespective of polypharmacy status, with no interaction observed for safety outcomes (all P-interaction >.06). Rates of treatment discontinuation increased with medication burden, but were lower with canagliflozin versus placebo, regardless of polypharmacy status (P-interaction = .16). Incidence of all-cause hospitalization, and heart failure hospitalization or cardiovascular death increased with higher medication burden; thus absolute risk reductions were estimated to be substantially greater in patients with polypharmacy and hyperpolypharmacy. Conclusion: Among patients with DM and CKD, the efficacy and safety of canagliflozin appear consistent regardless of polypharmacy status, with larger estimated absolute reductions in hospitalizations and cardiovascular events in those experiencing polypharmacy or hyperpolypharmacy. These findings suggest that polypharmacy alone should not preclude consideration of sodium glucose cotransporter 2 inhibitor therapy in patients with CKD and DM for whom treatment is otherwise indicated.

Screening for BK polyomavirus (BKPyV) with quantitative polymerase chain reaction (qPCR) or a 2-stage approach with urine cytology followed by qPCR are acc

Monoclonal gammopathies (MG) represent a group of haematological conditions resulting from excessive monoclonal immunoglobulin (MIg) production by abnormal clonal proliferation of plasma cells or B cells. The diseases can range from malignant conditions such as multiple myeloma and B-cell lymphoproliferative disorders to non-malignant monoclonal gammopathy of undetermined significance. The term monoclonal gammopathy of renal significance (MGRS) was introduced to describe kidney damage in the absence of myeloma-defining events or other haematological malignancies. The clones in MGRS are usually small and low-grade but can cause kidney damage due to the nephrotoxic MIg. There is a wide spectrum of kidney injury caused by the MG with MIgs causing nephrotoxicity either via direct deposition onto various parts of the kidney or indirect mechanisms through the autoantibody activity or dysregulation of the complement alternative pathway. The diagnosis of MIg-associated kidney diseases remains challenging due to its complexity and heterogeneity. Prognosis depends on accurate diagnosis of both kidney lesions and the underlying haematological diseases with early initiation of treatment. Clone-directed therapy has now become the cornerstone for the management of this disorder. Various therapeutic agents including proteasome inhibitors, monoclonal antibodies, immunomodulatory drugs, chimeric antigen receptor T-cells and Bruton tyrosine kinase inhibitors have been used to manage patients with MG and kidney diseases. Further clinical research and close collaboration between nephrologists, pathologists and haematologists can help to improve the prognosis of these patients.

Excessive production of complement C5a detected in acute kidney injury (AKI) and during the development of chronic kidney disease (CKD) suggests its possible role in CKD progression, but the underlying mechanism remains unclear. Global, tubule- and myeloid-specific C5aR1 knockout and PMX53-treated mice were subjected to bilateral ischemia reperfusion injury (BIRI). Cultured kidney tubular epithelial cells and bone marrow-derived macrophages were used to analyse the underlying cellular mechanisms. C5aR1 deficiency specifically in kidney tubular cells, but not in myeloid cells, impaired M1 and favored M2 macrophage polarization, resulting in attenuation of proinflammatory responses, oxidative stress and the subsequent tubulointerstitial fibrosis during the progression from AKI to CKD. Deletion of tubular C5aR1 also induced mitochondrial biogenesis with increased mitochondrial DNA copy number and ATP content and reduced cell apoptosis via induction of autophagy in kidney tubules. In vitro, treatment with the C5aR1 antagonist PMX53 attenuated cell apoptosis by enhancing BNIP3-regulated autophagy in C5a- and TNFα-stimulated kidney tubular epithelial cells, which in turn modulated macrophage polarization and inflammatory responses via a paracrine mechanism. Our data reveal a detrimental role of the C5a/C5aR1 axis in AKI-to-CKD transition by triggering macrophage polarization towards a chronic inflammatory phenotype and disrupting mitochondrial homeostasis via the involvement of BNIP3-regulated autophagy in kidney tubular epithelial cells, leading to tubulointerstitial fibrosis and kidney dysfunction. Targeting C5aR1 may provide a promising therapeutic strategy for preventing CKD progression.

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of kidney homeostasis, and their dysregulation has been implicated in a wide range of kidney diseases including acute kidney injury, chronic kidney disease and renal cell carcinoma, as well as in age-related kidney dysfunction. Increasing evidence indicates that lncRNAs have roles in key cellular processes including inflammation, autophagy, cell proliferation, senescence, apoptosis, mitochondrial dysfunction, angiogenesis, epithelial-mesenchymal transition and interstitial fibrosis. LncRNAs interact with RNA, DNA and protein to regulate gene expression via multiple mechanisms, including RNA modifications, scaffold assembly, chromatin remodelling, transcription and post-transcriptional control. Beyond their non-coding functions, some lncRNAs can be translated into bioactive micropeptides that further modulate cellular activity. Given their tissue-specific expression and high stability in body fluids, lncRNAs hold promise as biomarkers for early detection and monitoring of kidney diseases. Furthermore, lncRNA-based therapies offer novel opportunities to halt disease progression in chronic kidney disease and overcome drug resistance in renal cell carcinoma. Improved understanding of lncRNA-mediated disease mechanisms could therefore lead to improvements in the diagnosis and treatment of kidney pathologies.

Background: Evidence on the kidney-protective effects of statins in individuals with normal kidney function is mixed, with some trials suggesting benefits and others raising concerns about acute kidney injury. This study evaluates the impact of statin initiation on kidney function in adults with normal kidney function. Methods: Sequential target trial emulation based on electronic health records in the Hong Kong Hospital Authority were conducted. Patients aged ≥ 18 years old with normal kidney function (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m ² ) who met the indication for statin therapy (i.e. low-density lipoprotein cholesterol ≥ 100 mg/dL without cardiovascular disease or ≥ 70 mg/dL with cardiovascular diseases) in Hong Kong between January 2008 and December 2017 were included. Statin initiators and non-initiators were matched using 1:1 propensity score matching. Hazard ratio (HR) and 10-years absolute risk reduction (ARR) of outcomes, including impaired kidney function (eGFR 2 ), kidney function deterioration (≥30% and ≥50% eGFR decline) and all-cause mortality, were estimated using weighted pooled logistic regression based on intention-to-treat approach. Results: Among 449,595 statin initiators and 449,595 matched non-initiators, statin use was associated with a lower risk of eGFR 2 (HR: 0.92 [0.90, 0.95]; ARR: -0.33% [-0.42%, -0.24%]), eGFR 2 (HR: 0.97 [0.96, 0.98]; ARR: -0.98% [-1.12%, -0.84%]), ≥30% eGFR decline (HR: 0.94 [0.93, 0.95]; ARR: -1.81% [-2.00%, -1.60%]), ≥50% eGFR decline (HR: 0.90 [0.88, 0.91]; ARR: -0.98% [-1.11%, -0.85%]), and all-cause mortality (HR [95% CI]: 0.90 [0.89, 0.91]; ARR [95% CI]: -1.63% [-1.76%, -1.49%]). Conclusions: Statin initiation in adults with normal kidney function was associated with modestly lower all-cause mortality and kidney function impairment, supporting a potential kidney protective benefit of statins without increasing the risks of adverse kidney outcomes.