Nuclear Magnetic Resonance Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls

The results demonstrated that FUS mutations underlie a specific subtype of ALS and enable a careful stratification of newly diagnosed FUS-ALS cases for clinical course and potential therapeutic windows.

source: JASN

Summary

[Posted 11/Nov/2022]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Although NMR-quantified metabolites did not improve discrimination, several urine metabolic profiles were identified that may improve understanding of kidney stone pathogenesis.

BACKGROUND: The urine metabolites and chemistries that contribute to kidney stone formation are not fully understood. This study examined differences between the urine metabolic and chemistries profiles of first-time stone formers and controls.

DETAILS: High-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was performed in 24-hour urine samples from a prospective cohort of 418 first-time symptomatic kidney stone formers and 440 controls. In total, 48 NMR-quantified metabolites in addition to 12 standard urine chemistries were assayed. Analysis of covariance was used to determine the association of stone former status with urine metabolites or chemistries after adjusting for age and sex and correcting for the false discovery rate. Gradient-boosted machine methods with nested cross-validation were applied to predict stone former status. Among the standard urine chemistries, stone formers had lower urine oxalate and potassium and higher urine calcium, phosphate, and creatinine. Among NMR urine metabolites, stone formers had lower hippuric acid, trigonelline, 2-furoylglycine, imidazole, and citrate and higher creatine and alanine. A cross-validated model using urine chemistries, age, and sex yielded a mean AUC of 0.76 (95% CI, 0.73 to 0.79). A cross-validated model using urine chemistries, NMR-quantified metabolites, age, and sex did not meaningfully improve the discrimination (mean AUC, 0.78; 95% CI, 0.75 to 0.81). In this combined model, among the top ten discriminating features, four were urine chemistries and six NMR-quantified metabolites.

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Source: Thongprayoon, C., Vuckovic, I., Vuckovic, L. E., et al. (2022). Nuclear Magnetic Resonance Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls. JASN. 2022, 33(11): 2071-2086. Published: November, 2022. DOI: 10.1681/ASN.2022040416.



Apixaban Dosing Patterns Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation Receiving Dialysis

Among patients with nonvalvular AF undergoing dialysis, warfarin is associated with an increased risk of bleeding compared with apixaban.

source: Am J Kidney Dis

Summary

A Retrospective Cohort Study

[Posted 24/Nov/2022]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Among patients with nonvalvular AF undergoing dialysis, warfarin is associated with an increased risk of bleeding compared with apixaban. The risk of bleeding with below-label apixaban was not detectably less than with label-concordant dosing. Label-concordant apixaban dosing is associated with a mortality benefit compared to warfarin. Label-concordant dosing, rather than reduced-label dosing, may offer the most favorable benefit-risk trade-off for dialysis patients with nonvalvular AF.

BACKGROUND: Comparison of clinical outcomes across anticoagulation regimens using different apixaban dosing or warfarin is not well-defined in patients with nonvalvular atrial fibrillation (AF) who are receiving dialysis. This study compared these outcomes in a US national cohort of patients with kidney failure receiving maintenance dialysis.

DETAILS: Patients receiving dialysis represented in the US Renal Data System database 2013-2018 who had AF and were treated with apixaban or warfarin. Cox proportional hazards models with inverse probability of treatment weighting. Analyses simulating an intention-to-treat (ITT) approach as well as those incorporating censoring at drug switch or discontinuation (CAS) were also implemented. Inverse probability of censoring weighting was used to account for possible informative censoring. Among 17,156 individuals, there was no difference in risk of stroke/systemic embolism among the label-concordant apixaban, below-label apixaban, and warfarin treatment groups. Both label-concordant (HR, 0.67 [95% CI, 0.55-0.81]) and below-label (HR, 0.68 [95% CI, 0.55-0.84]) apixaban dosing were associated with a lower risk of major bleeding compared with warfarin in ITT analyses. Compared with label-concordant apixaban, below-label apixaban was not associated with a lower bleeding risk (HR, 1.02 [95% CI, 0.78-1.34]). In the ITT analysis of mortality, label-concordant apixaban dosing was associated with a lower risk versus warfarin (HR, 0.85 [95% CI, 0.78-0.92]) while there was no significant difference in mortality between below-label dosing of apixaban and warfarin (HR, 0.97 [95% CI, 0.89-1.05]). Overall, results were similar for the CAS analyses.

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Source: Wetmore, J. B., Weinhandl, E. D., Yan, H., et al. (2022). Apixaban Dosing Patterns Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation Receiving Dialysis: A Retrospective Cohort Study. XXXXXXXX. 2022; 80(5): 561-563. Published: November, 2022. DOI: 10.1053/j.ajkd.2022.03.007.



Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death

Among patients with CKD, H-FABP was associated with non-CV death and MACE, even after adjustment for hs-TNT.

source: Am J Kidney Dis

Summary

Findings From the German CKD Cohort Study

[Posted 1/Nov/2022]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: In this large cohort of patients with CKD, H-FABP was associated with non-CV death and MACE, even after adjustment for hs-TNT. Whether measurement of H-FABP improves cardiovascular disease risk prediction in these patients warrants further studies.

BACKGROUND: Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with coronary artery disease independently of high-sensitivity troponin T (hs-TNT). We examined the independent associations of H-FABP with cardiovascular outcomes in patients with chronic kidney disease (CKD).

DETAILS: 4,951 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 or overt proteinuria (urinary albumin-creatinine ratio > 300 mg/g or equivalent). Hazard ratios (HRs) for associations of H-FABP and hs-TNT with outcomes were estimated using Cox regression analyses adjusted for established risk factors. During a maximum follow-up of 6.5 years, 579 non-CV deaths, 190 CV deaths, 522 MACE, and 381 CHF hospitalizations were observed. In Cox regression analyses adjusted for established risk factors, H-FABP was associated with all 4 outcomes, albeit with lower HRs than those found for hs-TNT. After further adjustment for hs-TNT levels, H-FABP was found to be associated with non-CV death (HR, 1.57 [95% CI, 1.14-2.18]) and MACE (HR, 1.40 [95% CI, 1.02-1.92]) but with neither CV death (HR, 1.64 [95% CI, 0.90-2.99]) nor CHF hospitalizations (HR, 1.02 [95% CI, 0.70-1.49]).

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Source: Schneider, M. P., Schmid, M., Nadal, J., et al. (2022). Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death: Findings From the German CKD Cohort Study. Am J Kidney Dis. 2022; 80(4): 483-494. Published: October, 2022. DOI: 10.1053/j.ajkd.2022.01.424.

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Incretin-Based Drugs and the Risk of Acute Liver Injury Among Patients With T2D

DPP-4 inhibitors were associated with an increased risk of acute liver injury compared with SGLT-2 inhibitors in patients with type 2 diabetes. An increased risk of acute liver injury was observed only among female GLP-1 RA users.

source: Diabetes Care

Summary

[Posted 28/Oct/2022]

AUDIENCE: Endocrinology, Ob/Gyn

KEY FINDINGS: In this population-based study, DPP-4 inhibitors were associated with an increased risk of acute liver injury compared with SGLT-2 inhibitors in patients with type 2 diabetes. In contrast, an increased risk of acute liver injury was observed only among female GLP-1 RA users.

BACKGROUND: Purpose of the study is to determine whether the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs), separately, is associated with an increased risk of acute liver injury compared with the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors.

DETAILS: Used the U.K. Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and the Office for National Statistics databases to assemble two new-user, active-comparator cohorts. The first included 106,310 initiators of DPP-4 inhibitors and 27,277 initiators of SGLT-2 inhibitors, while the second included 9,470 initiators of GLP-1 RAs and 26,936 initiators of SGLT-2 inhibitors. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate hazard ratios (HRs) and 95% CIs of acute liver injury. Compared with SGLT-2 inhibitors, DPP-4 inhibitors were associated with a 53% increased risk of acute liver injury (HR 1.53, 95% CI 1.02-2.30). In contrast, GLP-1 RAs were not associated with an overall increased risk of acute liver injury (HR 1.11, 95% CI 0.57-2.16). However, an increased risk was observed among female users of both DPP-4 inhibitors (HR 3.22, 95% CI 1.67-6.21) and GLP-1 RAs (HR 3.23, 95% CI 1.44-7.25).

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Source: Pradhan, R., Yin H., Yu, O. H. Y., et al. (2022). Incretin-Based Drugs and the Risk of Acute Liver Injury Among Patients With Type 2 Diabetes. Diabetes Care . 2022; 45(10): 2289-2298. Published: October, 2022. DOI: 10.2337/dc22-0712.



Fractures and Osteoporosis in Patients With Diabetes With Charcot Foot

Patients with diabetes with a Charcot foot have an increased risk of fractures and osteoporosis compared with patients with diabetes without a Charcot foot.

source: Diabetes Care

Summary

[Posted 26/Sep/2022]

AUDIENCE: Endocrinology, Family Medicine

KEY FINDINGS: Patients with diabetes with a Charcot foot have an increased risk of fractures and osteoporosis compared with patients with diabetes without a Charcot foot.

BACKGROUND: Charcot foot is a serious complication of diabetes, with degeneration of the bones and joints in the foot and ankle. It is unknown whether patients with diabetes with a Charcot foot have an increased risk of osteoporosis and fractures. The aim of this study was to investigate whether patients with diabetes with a Charcot foot have an increased risk of fracture and/or osteoporosis compared with patients with diabetes without Charcot foot.

DETAILS: A Danish register-based, nationwide population-based matched cohort study was conducted. During 1995-2018, identified 1,602 patients with diabetes with Charcot foot and matched them on sex and date of diagnosis of diabetes with 16,296 patients with diabetes without Charcot foot. Used logistic regression to estimate odds ratios (ORs) with 95% CIs for fracture and osteoporosis. Information about exposure, outcome, and comorbidities was retrieved from the Danish National Patient Register. Diabetes patients with Charcot foot had higher risk of fractures compared with those without Charcot foot (i.e., ORs for any fracture, lower-leg fracture, foot fracture, and osteoporotic fracture were 1.8 [95% CI 1.6-2.0], 2.4 [2.0-2.8], 2.9 [2.6-3.3], and 1.3 [1.1-1.4], respectively). Furthermore, patients with diabetes with Charcot foot had higher risk of osteoporosis compared with the patients without Charcot foot, with an OR of 1.3 (95% CI 1.1-1.5).

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Source: Rabe, O. C., Winther-Jensen, M., Allin, K. H., et al. (2022). Fractures and Osteoporosis in Patients With Diabetes With Charcot Foot. Diabetes Care . 2022; 44(9): 2033-2038. Published: September, 2022. DOI: 10.2337/dc21-0369.



Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates

Cabozantinib plus nivolumab showed promising efficacy in most non-clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC.

source: J Clinical Oncology

Summary

[Posted 26/Jul/2022]

AUDIENCE: Oncology, Nephrology

KEY FINDINGS: Cabozantinib plus nivolumab showed promising efficacy in most non–clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non–clear-cell RCC variants warrant further study as predictors of response.

BACKGROUND: Objective of this trial is to assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non–clear-cell renal cell carcinoma (RCC).

DETAILS: Patients had advanced non–clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n= 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n= 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations.

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Source: Lee, C., Voss, M. H., Carlo, M. I., et al. (2022). Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non–Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Journal of Clinical Oncology. 2021; 40(21): 2333-2341. Published: July 20, 2022. DOI: 0.1200/JCO.21.01944.



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