Clinical Kidney Journal最新文献

Amino acid metabolism is closely linked with kidney physiology and pathology. In acute kidney injury, chronic kidney disease, diabetic kidney disease, and autosomal dominant polycystic kidney disease, disturbances in the branched-chain amino acids, tryptophan, glutamine, taurine, and sulfur amino acids pathways are consistently observed. Specific metabolites such as D-serine, kynurenine intermediates, and branched-chain keto acids are associated with disease progression. Taurine and indoxyl sulfate have also been proposed as therapeutic targets. At the nephron level, transporters and enzymes controlling amino acid flux influence nitrogen balance, oxidative stress, fibrosis, inflammation, and tubular injury. In chronic kidney disease, impaired amino acid handling contributes to protein-energy wasting, altered muscle metabolism, and systemic complications. In autosomal dominant polycystic kidney disease, cyst fluid metabolomics has revealed alterations in tryptophan and polyamine metabolism. The use of nutritional interventions, microbiome modulation, and selective supplementation as therapeutic strategies is being explored, although clinical trial evidence remains limited. Several key issues remain unresolved, including the need for isotope tracer studies to define renal amino acid kinetics in humans, the rigorous validation of metabolite biomarkers across diverse populations, the integration of diet and microbiome-derived metabolites into mechanistic frameworks, and the systematic evaluation of sex-specific differences. Longitudinal studies are scarce, thus restricting predictive power and therapeutic translation. Further mechanistic clarification may support the development of biomarkers and targeted therapies.

Background: The administration of an adequate dialysis dose is a critical aspect for ensuring the effectiveness of hemodialysis (HD) treatment and improving survival. Kt is a key indicator to evaluate the dose, with two targets: based on sex (Kt-Sx) and body surface area (Kt-BSA).

Methods: This retrospective study (2022-23) was conducted across 15 HD centers analyzed 1829 prevalent patients and 317 842 HD sessions.

Results: It was found that 65.9% met both Kt targets, 21.2% met only Kt-Sx and 12.9% met neither. Failure to meet both of the targets was associated with being male, older age, shorter time on HD, higher comorbidity, low body mass index, use of a catheter, shorter sessions, conventional HD, low flow rates and small membranes. Meeting at least the Kt-Sx target was associated with a 41.6% reduction in 24-month mortality risk, and an even more favorable association was observed when both targets were met, reducing the risk by 61.7%.

Conclusions: These findings highlight the importance of personalizing dialysis considering both sex and BSA, particularly in overweight or obese patients, to improve survival.

Background: Patients with chronic kidney disease (CKD) are frequently hospitalized for heart failure. Sodium-glucose co-transporter 2 (SGLT2)-inhibitors improve cardiorenal outcomes in CKD and heart failure, at least in estimated glomerular filtration rate (eGFR) ranges 20-60 ml/min/1.73 m², possibly through direct cardiac effects. In the cardiac imaging sub-studies of the Renal Lifecycle Trial, we aim to establish the effects of SGLT2-inhibition on cardiac structure and function in patients with advanced CKD, kidney failure and in kidney transplant recipients.

Methods: In the Renal Lifecycle Trial, patients with advanced CKD (eGFR ≤25 ml/min/1.73 m²), those treated with hemodialysis or peritoneal dialysis (PD) or kidney transplant recipients (eGFR ≤45 ml/min/1.73 m²), are randomized to receive either dapagliflozin or placebo. The echocardiography sub-study (acronym: STOP-HF-in-PD) will enroll 100 PD-treated patients, who undergo echocardiography at baseline, and at 6 and 12 months post-randomization. In the cardiac magnetic resonance imaging (MRI) sub-study, 250 Renal Lifecycle Trial participants across all three groups (i.e. advanced CKD, dialysis, kidney transplant recipients), including a subset of STOP-HF-in-PD participants, will undergo cardiac MRI at baseline, and at 12 months post-randomization. The primary endpoint of STOP-HF-in-PD is the difference in left ventricular global longitudinal strain, a measure of cardiac function, after 6-months of dapagliflozin compared to placebo. For the cardiac MRI sub-study, the primary endpoint is the difference of indexed left ventricular mass after 12 months of dapagliflozin compared to placebo.

Conclusions: The Renal Lifecycle Trial cardiac imaging sub-studies will generate novel data on the effects of SGLT2-inhibition on cardiac structure and function in a population with advanced CKD, in whom SGLT2-inhibitor induced cardiovascular protection remains to be established.

Clinical trial registration: The Renal Lifecycle Trial and its sub-studies are registered at ClinicalTrials.gov under registration number NCT05374291.

Mucosal-associated invariant T (MAIT) cells are a distinct subset of innate-like lymphocytes that bridge microbial homeostasis and tissue immunity. These evolutionarily conserved cells are activated via the recognition of microbial metabolites presented by the MR1 molecule and establish stable residency in the kidney, where they profoundly influence local immune-metabolic processes. There is growing interest in the robust regulatory capacities of MAIT cells in renal physiology and pathology. This review systematically delineates their paradoxical roles in kidney diseases. Under specific conditions, they exert protective functions by suppressing inflammation and maintaining tissue homeostasis. Conversely, in distinct microenvironments, they adopt a pro-inflammatory phenotype, exacerbating pathological progression through the release of inflammatory cytokines and cytotoxic effector functions. The gut-kidney axis serves as a critical regulatory hub, wherein dysbiosis-derived signals can significantly amplify the renal impact of MAIT cells. Focusing on clinical translation, we provide an in-depth exploration of innovative strategies targeting MAIT cells, including adoptive cell therapy, receptor-targeting agents, and microbiome reconstruction. These approaches position MAIT cells as promising therapeutic targets for a new generation of immune-mediated kidney diseases.

Tenapanor, a selective inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), was initially developed for the treatment of irritable bowel syndrome with constipation. Subsequent preclinical and clinical studies revealed its ability to reduce gastrointestinal phosphate absorption, leading to effective serum phosphate control with minimal pill burden in patients with kidney failure undergoing dialysis therapy. However, the precise mechanisms underlying NHE3 inhibition, its impact on phosphate handling and the primary site of action within the gastrointestinal tract remain incompletely understood. This review explores the hypothesis that tenapanor-induced NHE3 inhibition elevates the luminal pH via enhanced bicarbonate secretion in the colon, thereby altering phosphate speciation. Phosphate exists in the body as monovalent (H₂PO₄⁻) and divalent (HPO₄²⁻) anions, with the latter predominating under alkaline conditions. Although divalent anions are theoretically more prone to be absorbed from the gut lumen via the paracellular transport route because of the lumen-negative transepithelial potential, on the contrary recent studies have provided evidence that monovalent species are transported more efficiently and that paracellular phosphate permeability is suppressed at high luminal pH. We now propose that the net negative electrostatic environment within the paracellular pore pathway of tight junctions may selectively hinder divalent phosphate transport. This hypothesis aligns with prior findings that tenapanor does not alter the expression of tight junction proteins, suggesting a physicochemical rather than a structural basis for reduced permeability. Further investigations are warranted to determine whether the electrostatic properties of the paracellular pathway contribute to the phosphate-lowering effect of tenapanor.

Background: Sepsis-associated acute kidney injury (S-AKI) represents a critical complication with high mortality rates in intensive care units. Current risk stratification tools lack precision and interpretability for clinical decision-making. This study aimed to develop and validate interpretable machine learning models for predicting hospital mortality in S-AKI patients.

Methods: This retrospective cohort study utilized five international critical care databases: Medical Information Mart for Intensive Care (MIMIC)-IV (n = 12 966), MIMIC-III-CareVue (n = 2209), eICU (n = 8210), Northwestern University Intensive Care Unit (NWICU) (n = 2207) and Salzburg Intensive Care database (SICdb) (n = 1893). Adult patients with S-AKI meeting sepsis-3.0 and acute kidney injury criteria were included. Feature selection used the Boruta algorithm on MIMIC-IV, MIMIC-III and eICU databases. Eleven machine learning algorithms were trained using MIMIC-IV data with external validation on all other datasets. Performance was evaluated using receiver operating characteristic (ROC) curve analysis, calibration plots and decision curve analysis. SHapley Additive exPlanations (SHAP) analysis provided model interpretability.

Results: Among 27 485 S-AKI patients, hospital mortality was 27.5%. Boruta identified 21 consensus features including severity scores [Simplified Acute Physiology Score II (SAPS II), Sequential Organ Failure Assessment (SOFA), OASIS], vital signs and laboratory parameters. Gradient Boosting Machine emerged as optimal with area under the curve (AUC) values of 0.770 (training), 0.731 (internal validation) and 0.732-0.778 across four external validation cohorts. The model demonstrated excellent calibration and minimal overfitting (3.9% AUC difference). Decision curve analysis revealed superior clinical utility across probability thresholds of 4%-82%. SHAP analysis identified SAPS II as the most important predictor, with scores >60 and SOFA >15 associated with substantially increased mortality risk. Complete case analysis confirmed model robustness (AUC 0.766-0.847).

Conclusions: The interpretable machine learning model demonstrated excellent performance and robust generalizability for S-AKI mortality prediction across five international databases. SHAP analysis provided clinically meaningful insights supporting personalized risk stratification and evidence-based clinical decision-making.

Background: Among patients receiving immune checkpoint inhibitor (ICI) therapy, the most common renal immune-related adverse event is interstitial nephritis, which is caused by severe T-cell infiltration and is typically responsive to steroids; although rarer, autoimmune induction in the kidney has also been reported. There is a paucity of data regarding ICI-induced autoimmune disease in the kidney and the challenges associated with continuing ICI therapy. Here, we present a single center case series of ICI-induced glomerulonephritis with data on treatment rechallenge.

Methods: We retrospectively reviewed 241 patients who underwent kidney biopsies at our institution between 2015 and 2024 and identified those who had non-vasculitis-associated glomerulonephritis after ICI therapy. Demographics, renal toxicity, renal response, disease response, and overall survival data were extracted from the patients' medical records. We defined renal response based on creatinine and proteinuria using KDIGO guidelines. We also performed a literature review to identify published cases of ICI-induced glomerulonephritis. Differences between treatment groups were assessed with a two-sided, two-sample t-test and Wilcoxon test or with a chi-square test, as appropriate.

Results: Among 241 kidney biopsies we identified 16 patients with non-vasculitic GN, eight received rituximab with or without corticosteroids, and eight received corticosteroids only, for ICI-induced glomerulonephritis. The median proteinuria grades in the rituximab and corticosteroid groups were 3 and 1, respectively. The median corticosteroid treatment duration in the rituximab group (2.5 weeks) was shorter than that in the corticosteroid group (8 weeks). In the rituximab group, 75% of patients underwent ICI rechallenge and had no proteinuria relapse. Patients who received rituximab had better change in proteinuria response than those who received corticosteroids (P value = .029). Among the 42 patients we identified from the literature review, renal response did not differ significantly between the 10 who received rituximab and the 32 who did not.

Conclusion: Use of Rituximab in treatment of ICI-induced GN is an attractive option to reduce steroids exposure allowing continued ICI treatment for overall improved renal outcome. Clinical trials to evaluate these findings are needed.

Background: Renal thrombotic microangiopathy (TMA) remains a challenge for lupus nephritis (LN) patients. The purpose of this study was to determine the prognostic significance of renal TMA in patients with LN.

Methods: Patients were recruited from the LN database (http://ln.medidata.cn) of the First Affiliated Hospital of Sun Yat-Sen University between 2001 and 2023. To assess the association between renal TMA and kidney recovery outcomes, propensity score matching (PSM), and Cox proportional hazards regression analysis were used.

Results: 5.17% LN patients had kidney biopsies showing TMA. After PSM, patients with renal TMA exhibited lower scores on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Activity Index (AI) scores in renal biopsies. Renal TMA was independently associated with deteriorated renal function recovery compared with non-renal TMA [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.42-0.94, P = .022). This association remained significant after PSM (HR: 0.50; 95% CI: 0.31-0.82, P = .004). Additionally, renal TMA was independently associated with higher risk of renal replacement therapy (RRT) (HR: 6.90; 95% CI: 3.57-13.30, P < .001) in LN patients. The proportion of glomerulosclerosis is a predictive factor for renal function recovery in LN patients with renal TMA (HR: 0.62; 95% CI: 0.40-0.95, P = .027).

Conclusions: Renal TMA is strongly associated with poorer renal function recovery in LN patients. Furthermore, a higher degree of glomerulosclerosis is a significant risk factor for impaired recovery in these patients.