Key PointsA medication was deprescribed for approximately one in five eligible patients with an 80% deprescribing success rate.Few significant clinical changes and no related spontaneously reported adverse events indicated a safe and effective intervention.High levels of agreement with algorithm recommendations among clinicians (>80%) and patients (>70%) demonstrated openness to deprescribing.BackgroundPatients on hemodialysis are at increased risk for polypharmacy-related adverse events (AEs). Deprescribing may optimize medication use and mitigate the harmful effects of polypharmacy, but its application in patients on hemodialysis remains understudied. The overall aim of this study was to implement and evaluate the effectiveness and safety of a deprescribing intervention using a deprescribing toolkit in multiple hemodialysis units across Canada. This preliminary study aims to demonstrate the efficacy and safety of the intervention within one hemodialysis unit in Toronto, Canada.MethodsThis single-center study included patients on hemodialysis for at least three months who were taking at least one of nine study medication classes. Clinicians applied deprescribing algorithms to determine if deprescribing was recommended. Clinicians and patients could decline the algorithm's recommendation. Primary outcomes include the number of patients successfully deprescribed by discontinuing or reducing the dose of their medication over six months and clinically significant AEs. Secondary outcomes include clinician and patient acceptance of algorithm recommendations and clinical monitoring.ResultsNinety-eight patients were taking an average of 13.47 (±4.01) medications, with an average of 2.32 (±1.00) being study medications. The algorithms recommended 40 patients to deprescribe 49 study medications. Clinicians agreed to 39 (80%) recommendations, and patients agreed to 28 of those 39 (72%). Twenty patients successfully deprescribed 23 medications (82%), while five patients failed and restarted five medications (18%) at their baseline dose. Clinical monitoring and spontaneous reporting revealed no AEs considered related to the intervention.ConclusionsApproximately one in five eligible patients successfully deprescribed a medication with minimal clinical detriment. Although the deprescribing algorithms are valuable in guiding clinical decision making, final decisions rest with clinicians, constituting a careful synthesis of potential benefits, risks, and goals of care for each individual patient. Future research will analyze deprescribing outcomes at additional hemodialysis units in Canada.Clinical Trial registry name and registration number:NCT03733262.

Key PointsThere is an unmet critical need currently for a noninvasive approach to accurately diagnose the cause of kidney transplant complications.Cell multispectral autofluorescence signals have demonstrated to be highly biologically informative, reflecting cell and tissue metabolic status.Urinary exfoliated proximal tubule cell multispectral autofluorescence could potentially be used to differentiate between causes of transplant graft dysfunction.BackgroundComplications relating to delayed or deteriorating graft function following kidney transplantation are common. There is no validated method apart from transplant kidney biopsy which can accurately identify between the histopathologic causes of graft dysfunction. Considering an unmet critical need for a noninvasive approach to reliably diagnose kidney transplant complications, this work proposes a novel methodology based on the assessment of exfoliated proximal tubule cells (PTCs) extracted from urine of kidney transplant recipients by using their multispectral autofluorescence features.MethodsThree groups of ten patients who have undergone clinically indicated transplant kidney biopsy and was subsequently diagnosed with either acute tubular necrosis (ATN), graft rejection or non–rejection-associated interstitial fibrosis, and tubular atrophy (IFTA) took part in this study. Exfoliated PTCs from urine collected before transplant biopsy were extracted using a validated immunomagnetic separation method based on anti-CD13 and anti-sodium-glucose co-transport 2 antibodies. Imaging was performed on a custom-made multispectral autofluorescence microscopy and camera system. Multispectral autofluorescence images of PTCs were quantitatively analyzed by using optimized small sets of features to prevent overfitting. Binary classification was performed by a random forest classifier and the AutoGluon machine learning software. The results were validated by five-fold cross-validation.ResultsFor random forest classification, features were selected using entropy-based feature selection, resulting in area under the curve values of 0.92 (ATN versus graft rejection), 0.86 (ATN versus IFTA), and 0.62 (graft rejection versus IFTA) respectively. The AutoGluon classifier optimisation for the same features resulted in area under the curve values of 0.95 (ATN versus graft rejection), 0.92 (ATN versus IFTA), and 0.91 (graft rejection versus IFTA).ConclusionsOur results demonstrate a proof-of-concept that measurement of autofluorescent features from urinary exfoliated PTCs multispectral autofluorescence could differentiate between patient groups with ATN, graft rejection, and IFTA in kidney transplant recipients to an excellent degree of accuracy using AutoGluon classifier optimisation.

Tuberous sclerosis complex (TSC) is a highly variable autosomal dominant disease characterized by dysregulated organ development and growth. Benign tumors, termed hamartomas, may occur across organ systems but typically involve the kidney, brain, skin, heart, and lung. The diagnosis, surveillance, and clinical management of TSC requires a multidisciplinary approach, adopted by dedicated multispecialty centers worldwide. Nephrology involvement predominantly stems from the morbidity and mortality related to the prototypical kidney lesion, angiomyolipomas, whose presence and degree confers risk of CKD, hypertension, retroperitoneal bleeding, and possibly renal cell carcinoma. Surveillance of kidney structural lesions, kidney function, and BP may enable early interventions that limit kidney-related morbidity and mortality, such as mammalian target of rapamycin inhibitor therapy. We review the epidemiology, genetics, and pathogenesis of TSC and how these inform the evaluation, diagnosis, and clinical management of TSC from the vantage point of the treating nephrologist.

Key PointsThe study aims to clarify the effects of bardoxolone methyl using proteomics and metabolomics analyses of plasma and urine from The Phase 2 Study of Bardoxolone Methyl in Patients with CKD and Type 2 Diabetes.This study demonstrated the first evidence in humans that bardoxolone methyl activates an antioxidant response.BackgroundNF erythroid 2-related factor 2 (NRF2) is crucial for defense against oxidative stress. In The Phase 2 Study of Bardoxolone Methyl in Patients with CKD and Type 2 Diabetes, bardoxolone methyl, an NRF2 activator, was shown to increase the GFR in patients with diabetic kidney disease. Although nonclinical reports suggest that bardoxolone methyl acts mainly through NRF2-mediated antioxidant response activation, this has not been proven in clinical settings. This study assessed its effects using plasma and urine from The Phase 2 Study of Bardoxolone Methyl in Patients with CKD and Type 2 Diabetes.MethodsPatients received either bardoxolone methyl or placebo daily for 16 weeks. Urine and plasma samples were collected at baseline, after 16 weeks of dosing, and 4 weeks postdosing and were cryopreserved for an analysis. A total of 45 patients in the bardoxolone methyl group and 52 in the placebo group were subjected to proteomic and metabolic analyses. Proteomic profiling was conducted using the SOMAscan assay, whereas metabolomics analyses were performed by Human Metabolome Technologies, Inc.ResultsPlasma proteomics revealed that two oxidative stress–related pathways have been significantly changed by bardoxolone methyl treatment. Among these two pathways, antioxidative proteins and proteins that enhance the antioxidative process were significantly increased. Some of these increased proteins were known to be NRF2 target proteins. Similarly, urine proteomics revealed that four pathways were changed, and antioxidative proteins that are the target proteins of NRF2 were increased. Furthermore, seven metabolites that potentiate the antioxidative effect were significantly increased in urine.ConclusionsThis study demonstrated the first evidence in humans that bardoxolone methyl activates an antioxidant response.

Prior epigenome-wide association studies (EWAS) of DNA methylation (DNAm) and diabetic kidney disease (DKD) in type 1 diabetes (T1D) focused on advanced disease. We hypothesized DNAm is a biomarker of earlier manifestations of DKD, microalbuminuria (MA) and overt nephropathy (ON), independent of traditional risk factors in T1D. We thus performed separate EWAS of 28-year MA and ON in the Pittsburgh Epidemiology of Diabetes Complications (EDC) T1D cohort. We analyzed baseline whole blood DNAm (total n=405 participants; 683,597 CpGs) and time-to-event in EDC participants free of each respective complication at baseline (n=224 eligible for MA analysis, n=306 eligible for ON analysis). We also identified differentially methylated regions (DMRs), assessed associations between DKD-associated CpGs and established clinical risk factors, and performed in silico functional analyses. In secondary analyses, we performed EWAS of ESKD in participants with existing DKD at baseline (ON or estimated glomerular filtration rate (eGFR) 15-59 ml/min/1.73m2, n=99) for comparison to prior studies. DNAm at cg06568490 (HDAC11) and cg13618568 (CRELD2) was associated with MA incidence (False Discovery Rate [FDR]<0.05). Associations between both CpGs and MA remained similar after risk factor adjustment. We also identified 48 significant DMRs (Šidák value<0.05) for MA. For ON, no individual CpGs had FDR<0.05, but there were 35 significant DMRs. Pathways in Signal Transduction were the most significantly enriched for both endpoints. In EWAS of ESKD, no CpGs were significant in minimally adjusted models, while cg09867934 (ETFDH) was significantly associated with ESKD after adjusting for clinical risk factors (FDR=0.002), but there was little overlap with previously published studies of DNAm and ESKD in T1D. Epigenetic modification of loci including HDAC11, which has been associated with kidney fibrosis, and CRELD2, which is involved in angiogenesis, may contribute to early kidney damage in T1D, thus warranting further study as potential biomarkers of future risk.

Renal sarcoidosis (RS) is a rare but potentially severe manifestation of sarcoidosis, primarily affecting the kidneys through granulomatous interstitial nephritis (GIN) and calcium metabolic disturbances. This study evaluates the clinicopathological features and renal outcomes of biopsy-proven RS, focusing on identifying predictors of renal recovery and disease progression. This retrospective study included 43 biopsy-proven RS at Mayo Clinic (2012-2024). Demographic, clinical, laboratory, and histopathological data were analyzed. Renal recovery within six months was classified as complete, partial, or no recovery based on serum creatinine (sCr) changes. Long-term adverse composite outcomes included the chronic kidney disease (CKD) onset, CKD progression, end-stage kidney disease, dialysis initiation, or death. Logistic regression and Cox proportional hazards regression were used to assess predictors of renal outcomes. Among cohort, 84% exhibited interstitial nephritis, with GIN in 33%. Calcium phosphate deposits were found in 58% of cases. Hypercalciuria (90%) was more common than hypercalcemia (74%). Within six months, 86% achieved recovery (74% complete, 12% partial), while 40% experienced long-term adverse composite outcomes. Higher sCr at biopsy (≥ 2.4 mg/dL) and moderate-to-severe interstitial fibrosis and tubular atrophy (IFTA) were associated with reduced complete recovery and worse long-term outcomes; while pre-existing CKD significantly increased the risk of adverse long-term outcomes. Steroid therapy significantly increased the likelihood of complete recovery and reduced the risk of adverse long-term outcomes. Pre-existing CKD, elevated sCr at biopsy, IFTA, and steroid therapy are key predictors of renal outcomes in RS. Early diagnosis and intervention are crucial to preventing irreversible kidney damage.