The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases.

In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.

Impact of Prior Abdominal Procedures on Peritoneal Dialysis Catheter Outcomes: Findings From the North American Peritoneal Dialysis Catheter Registry.

RATIONALE & OBJECTIVE: A history of prior abdominal procedures may influence the likelihood of referral for peritoneal dialysis (PD) catheter insertion. To guide clinical decision making in this population, this study examined the association between prior abdominal procedures and outcomes in patients undergoing PD catheter insertion. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults undergoing their first PD catheter insertion between November 1, 2011, and November 1, 2020, at 11 institutions in Canada and the United States participating in the International Society for Peritoneal Dialysis North American Catheter Registry. EXPOSURE: Prior abdominal procedure(s) defined as any procedure that enters the peritoneal cavity. OUTCOMES: The primary outcome was time to the first of (1) abandonment of the PD catheter or (2) interruption/termination of PD. Secondary outcomes were rates of emergency room visits, hospitalizations, and procedures. ANALYTICAL APPROACH: Cumulative incidence curves were used to describe the risk over time, and an adjusted Cox proportional hazards model was used to estimate the association between the exposure and primary outcome. Models for count data were used to estimate the associations between the exposure and secondary outcomes. RESULTS: Of 855 patients who met the inclusion criteria, 31% had a history of a prior abdominal procedure and 20% experienced at least 1 PD catheter-related complication that led to the primary outcome. Prior abdominal procedures were not associated with an increased risk of the primary outcome (adjusted HR, 1.12; 95% CI, 0.68-1.84). Upper-abdominal procedures were associated with a higher adjusted hazard of the primary outcome, but there was no dose-response relationship concerning the number of procedures. There was no association between prior abdominal procedures and other secondary outcomes. LIMITATIONS: Observational study and cohort limited to a sample of patients believed to be potential candidates for PD catheter insertion. CONCLUSION: A history of prior abdominal procedure(s) does not appear to influence catheter outcomes following PD catheter insertion. Such a history should not be a contraindication to PD. PLAIN-LANGUAGE SUMMARY: Peritoneal dialysis (PD) is a life-saving therapy for individuals with kidney failure that can be done at home. PD requires the placement of a tube, or catheter, into the abdomen to allow the exchange of dialysis fluid during treatment. There is concern that individuals who have undergone prior abdominal procedures and are referred for a catheter might have scarring that could affect catheter function. In some institutions, they might not even be offered PD therapy as an option. In this study, we found that a history of prior abdominal procedures did not increase the risk of PD catheter complications and should not dissuade patients from choosing PD or providers from recommending it.

The Association of Intra-Abdominal Adhesions with Peritoneal Dialysis Catheter-Related Complications.

BACKGROUND: This study investigated the association of intra-abdominal adhesions with the risk of peritoneal dialysis (PD) catheter complications. METHODS: Individuals undergoing laparoscopic PD catheter insertion were prospectively enrolled from eight centers in Canada and the United States. Patients were grouped based on the presence of adhesions observed during catheter insertion. The primary outcome was the composite of PD never starting, termination of PD, or the need for an invasive procedure caused by flow restriction or abdominal pain. RESULTS: Seven hundred and fifty-eight individuals were enrolled, of whom 201 (27%) had adhesions during laparoscopic PD catheter insertion. The risk of the primary outcome occurred in 35 (17%) in the adhesion group compared with 58 (10%) in the no adhesion group (adjusted HR, 1.64; 95% confidence interval [CI], 1.05 to 2.55) within 6 months of insertion. Lower abdominal or pelvic adhesions had an adjusted HR of 1.80 (95% CI, 1.09 to 2.98) compared with the no adhesion group. Invasive procedures were required in 26 (13%) and 47 (8%) of the adhesion and no adhesion groups, respectively (unadjusted HR, 1.60: 95% CI, 1.04 to 2.47) within 6 months of insertion. The adjusted odds ratio for adhesions for women was 1.65 (95% CI, 1.12 to 2.41), for body mass index per 5 kg/m 2 was 1.16 (95% CI, 1.003 to 1.34), and for prior abdominal surgery was 8.34 (95% CI, 5.5 to 12.34). Common abnormalities found during invasive procedures included PD catheter tip migration, occlusion of the lumen with fibrin, omental wrapping, adherence to the bowel, and the development of new adhesions. CONCLUSIONS: People with intra-abdominal adhesions undergoing PD catheter insertion were at higher risk for abdominal pain or flow restriction preventing PD from starting, PD termination, or requiring an invasive procedure. However, most patients, with or without adhesions, did not experience complications, and most complications did not lead to the termination of PD therapy.

Industrial Use of Phosphate Food Additives: A Mechanism Linking Ultra-Processed Food Intake to Cardiorenal Disease Risk?

The consumption of ultra-processed food (UPF) keeps rising, and at the same time, an increasing number of epidemiological studies are linking high rates of consumption of UPF with serious health outcomes, such as cardiovascular disease, in the general population. Many potential mechanisms, either in isolation or in combination, can explain the negative effects of UPF. In this review, we have addressed the potential role of inorganic phosphate additives, commonly added to a wide variety of foods, as factors contributing to the negative effects of UPF on cardiorenal disease. Inorganic phosphates are rapidly and efficiently absorbed, and elevated serum phosphate can lead to negative cardiorenal effects, either directly through tissue/vessel calcification or indirectly through the release of mineral-regulating hormones, parathyroid hormone, and fibroblast growth factor-23. An association between serum phosphate and cardiovascular and bone disease among patients with chronic kidney disease is well-accepted by nephrologists. Epidemiological studies have demonstrated an association between serum phosphate and dietary phosphate intake and mortality, even in the general American population. The magnitude of the role of inorganic phosphate additives in these associations remains to be determined, and the initial step should be to determine precise estimates of population exposure to inorganic phosphate additives in the food supply.

Dietary Advanced Glycation End Products: Their Role in the Insulin Resistance of Aging.

Insulin resistance (IR) is commonly observed during aging and is at the root of many of the chronic nontransmissible diseases experienced as people grow older. Many factors may play a role in causing IR, but diet is undoubtedly an important one. Whether it is total caloric intake or specific components of the diet, the factors responsible remain to be confirmed. Of the many dietary influences that may play a role in aging-related decreased insulin sensitivity, advanced glycation end products (AGEs) appear particularly important. Herein, we have reviewed in detail in vitro, animal, and human evidence linking dietary AGEs contributing to the bodily burden of AGEs with the development of IR. We conclude that numerous small clinical trials assessing the effect of dietary AGE intake in combination with strong evidence in many animal studies strongly suggest that reducing dietary AGE intake is associated with improved IR in a variety of disease conditions. Reducing AGE content of common foods by simple changes in culinary techniques is a feasible, safe, and easily applicable intervention in both health and disease. Large-scale clinical trials are still needed to provide broader evidence for the deleterious role of dietary AGEs in chronic disease.

Dietary advanced glycation products and their associations with insulin sensitivity and body weight: A 16-week randomized clinical trial.

Background: Evidence suggests that changes in advanced glycation end-products (AGEs) may influence body weight. Previous studies have focused on cooking methods as the primary way how to reduce the dietary AGEs but little is known about the effects of a change in diet composition. Objective: The aim of this study was to assess the effects of a low-fat plant-based diet on dietary AGEs and test the association with body weight, body composition, and insulin sensitivity. Methods: Participants who were overweight (n = 244) were randomly assigned to an intervention (low-fat plant-based) (n = 122) or control group (n = 122) for 16 weeks. Before and after the intervention period, body composition was measured by dual X-ray absorptiometry. Insulin sensitivity was assessed with the predicted insulin sensitivity index (PREDIM). Three-day diet records were analyzed using the Nutrition Data System for Research software and dietary AGEs were estimated, using a database. Repeated measure ANOVA was used for statistical analysis. Results: Dietary AGEs decreased in the intervention group by 8768 ku/day on average (95% -9611 to -7925; p < 0.001), compared with the control group (-1608; 95% CI -2709 to -506; p = 0.005; treatment effect -7161 ku/day [95% CI -8540 to -5781]; Gxt, p < 0.001). Body weight decreased by 6.4 kg in the intervention group, compared with 0.5 kg in the control group (treatment effect -5.9 kg [95% CI -6.8 to -5.0]; Gxt, p < 0.001), largely due to a reduction in fat mass, notably visceral fat. PREDIM increased in the intervention group (treatment effect +0.9 [95% CI + 0.5 to +1.2]; p < 0.001). Changes in dietary AGEs correlated with changes in body weight (r = +0.41; p < 0.001), fat mass (r = +0.38; p < 0.001), visceral fat (r = +0.23; p < 0.001), and PREDIM (r = -0.28; p < 0.001), and remained significant even after adjustment for changes in energy intake (r = +0.35; p < 0.001 for body weight; r = +0.34; p < 0.001 for fat mass; r = +0.15; p = 0.03 for visceral fat; and r = -0.24; p < 0.001 for PREDIM). Conclusions: Dietary AGEs decreased on a low-fat plant-based diet, and this decrease was associated with changes in body weight, body composition, and insulin sensitivity, independent of energy intake. These findings demonstrate positive effects of qualitative dietary changes on dietary AGEs and cardiometabolic outcomes. Clinical Trial Registry Number: NCT02939638.

Dietary advanced glycation end-products and postmenopausal hot flashes: A post-hoc analysis of a 12-week randomized clinical trial.

OBJECTIVE: Postmenopausal hot flashes are associated with an increased risk of cardiovascular disease and diabetes. Because dietary advanced glycation end-products (AGEs) may act as endocrine disruptors, this study examined the potential association of modifications to the intake of dietary AGEs with the frequency and severity of postmenopausal hot flashes. METHODS: Postmenopausal women (n = 84) reporting ≥2 moderate-to-severe hot flashes daily were randomly assigned to either the intervention group or the control group. The former were asked to follow a low-fat, vegan diet, including cooked soybeans (1/2 cup [86 g]/day) for 12 weeks, and the latter continued their usual diets for 12 weeks. Frequency and severity of hot flashes were recorded with a mobile application. Three-day diet records were analyzed using the Nutrition Data System for Research software and dietary AGEs were estimated, using a database. Seventy-one participants completed the whole study and 63 provided complete hot flash and dietary data for the AGEs analysis (n = 31 in the intervention and n = 24 in the control group). Pearson correlations were used to assess the association between changes in hot flashes and dietary AGEs. RESULTS: Dietary AGEs decreased in the intervention group by 73 %, that is by 5509 ku/day on average (95 % -7009 to -4009; p < 0.001), compared with the control group (+458; 95 % CI -835 to +1751; p = 0.47; treatment effect -5968 ku/day [95 % CI -7945 to -3991]; Gxt, p < 0.001). Severe hot flashes decreased by 92 % (p < 0.001) and moderate-to-severe hot flashes decreased by 88 % in the intervention group (p < 0.001). Changes in dietary AGEs correlated with changes in severe (r = +0.39; p = 0.002) and moderate hot flashes (r = +0.34; p = 0.009) and remained significant after adjustment for changes in energy intake (r = +0.45; p < 0.001; and r = +0.37; p = 0.004, respectively) and changes in body mass index (r = +0.37; p = 0.004; and r = +0.27; p = 0.04, respectively). The reduction in dietary AGEs required to achieve a predicted reduction in hot flashes by 1/day was 6933 ku/day for severe and 4366 ku/day for moderate-to-severe hot flashes. CONCLUSIONS: The reduction in dietary AGEs with a low-fat plant-based diet was associated with a significant reduction in the frequency of severe and moderate-to-severe postmenopausal hot flashes, independent of changes in energy intake and weight loss. Plant-based diets could be used not only to alleviate vasomotor symptoms in postmenopausal women, but also to reduce other health risks associated with AGEs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04587154.

Outcomes of PD for AKI treatment during COVID-19 in New York City: A multicenter study.

BACKGROUND: The high incidence of acute kidney injury (AKI) requiring dialysis associated with COVID-19 led to the use of peritoneal dialysis (PD) for the treatment of AKI. This study aims to compare in-hospital all-cause mortality and kidney recovery between patients with AKI who received acute PD versus extracorporeal dialysis (intermittent haemodialysis and continuous kidney replacement therapy). METHODS: In a retrospective observational study of 259 patients with AKI requiring dialysis during the COVID-19 surge during Spring 2020 in New York City, we compared 30-day all-cause mortality and kidney recovery between 93 patients who received acute PD at any time point and 166 patients who only received extracorporeal dialysis. Kaplan-Meier curves, log-rank test and Cox regression were used to compare survival and logistic regression was used to compare kidney recovery. RESULTS: The mean age was 61 ± 11 years; 31% were women; 96% had confirmed COVID-19 with median follow-up of 21 days. After adjusting for demographics, comorbidities, oxygenation and laboratory values prior to starting dialysis, the use of PD was associated with a lower mortality rate compared to extracorporeal dialysis with a hazard ratio of 0.48 (95% confidence interval: 0.27-0.82, p = 0.008). At discharge or on day 30 of hospitalisation, there was no association between dialysis modality and kidney recovery (p = 0.48). CONCLUSIONS: The use of PD for the treatment of AKI was not associated with worse clinical outcomes when compared to extracorporeal dialysis during the height of the COVID-19 pandemic in New York City. Given the inherent selection biases and residual confounding in our observational study, research with a larger cohort of patients in a more controlled setting is needed to confirm our findings.

Unusual cases of peritonitis: A case series of five patients.

INTRODUCTION: Peritonitis is a complication in patients on peritoneal dialysis that frequently results from touch contamination. Most cases of peritoneal dialysis-related peritonitis are caused by skin organisms. Herein, we are presenting a series of peritonitis cases with unusual organisms in a single home dialysis center at an academic hospital in New York City. METHODS: The records of five patients with an unusual cause of peritonitis were reviewed by a clinician. We have chronologically tabulated the cell count of the dialysate, microbiologic cultures, and antibiotics received by each patient. Additionally, both a table and figure detail the microbiologic organisms that our dialysis unit encountered over the 3-year period concurrent with the infections reported. RESULTS: The first patient presented with refractory polymicrobial peritonitis due to a liver abscess. Another patient presented with diverticulitis and developed enteric peritonitis with various organisms. The following patient had peritonitis in the setting of bowel pathologies and from Rhizobium after exposure to plants. The next patient developed Pasteurella peritonitis from his cat. The final patient developed multiple episodes of peritonitis from organisms including flora native to soil and water. CONCLUSION: These uncommon cases of peritonitis with unusual circumstances bring awareness to various elements that can lead to peritonitis.

Beyond the Urine Anion Gap: In Support of the Direct Measurement of Urinary Ammonium.

Ammonium is a major urinary buffer that is necessary for the normal excretion of the daily acid load. Its urinary rate of excretion (UNH4) may be increased several fold in the presence of extrarenal metabolic acidosis. Therefore, measurement of UNH4 can provide important clues about causes of metabolic acidosis. Because UNH4 is not commonly measured in clinical laboratories, the urinary anion gap (UAG) was proposed as its surrogate about 4 decades ago, and it is still frequently used for that purpose. Several published studies strongly suggest that UAG is not a good index of UNH4 and support the concept that direct measurement of UNH4 is an important parameter to define in clinical nephrology. Low UNH4 levels have recently been found to be associated with a higher risk of metabolic acidosis, loss of kidney function, and death in persons with chronic kidney disease, while surrogates like the UAG do not recapitulate this risk. In order to advance the field it is necessary for the medical community to become more familiar with UNH4 levels in a variety of clinical settings. Herein, we review the literature, searching for available data on UNH4 under normal and various pathological conditions, in an attempt to establish reference values to interpret UNH4 results if and when UNH4 measurements become available as a routine clinical test. In addition, we present original data in 2 large populations that provide further evidence that the UAG is not a good predictor of UNH4. Measurement of urine NH4 holds promise to aid clinicians in the care of patients, and we encourage further research to determine its best diagnostic usage.

Comparing the effect of peritoneal dialysis cycler type on patient-reported satisfaction, support needs and treatments.

BACKGROUND: Most patients on peritoneal dialysis (PD) in the United States choose automated PD via cyclers. Cyclers have evolved considerably over time with older versions (e.g. HomeChoice Pro) replaced by more sophisticated and technologically advanced versions (e.g. Amia). Understanding the effect that different cyclers and their features have on patient treatments and support needs is important.  METHODS: Single center study with retrospective and prospective arms. Retrospective arm: Patients > 18 years old, on Amia or HomeChoice Pro (HC) for ≥ 3 months between 8/1/17 and 1/31/18. Number of office/telephone encounters, PD-related emergency room visits/hospitalizations, PD training days, and dialysis adequacy (Kt/V) were recorded. Prospective arm: Patients > 18 years old, on Amia or HC for ≥ 3 months between 9/1/19 and 2/29/20 were surveyed on their comfort, troubleshooting, satisfaction and reported assistance needed with their cyclers. RESULTS: Retrospective arm: 43 patients on AMIA and 27 patients on HC. Number of PD training days, Kt/Vs achieved, PD-related telephone/office encounters, and PD-related emergency room visits/hospitalizations were all similar. Prospective Arm: 32 patients on AMIA and 6 patients on HC. Higher rate of patient comfort with AMIA, but similar overall patient satisfaction with both cyclers. No difference in terms of patient-reported troubleshooting issues requiring assistance. CONCLUSIONS: Despite the difference in features provided between the 2 cyclers, patient overall satisfaction rates were high irrespective of the PD cycler. The HomeChoice Pro and AMIA cycler patients had a similar number of PD training days, PD-related telephone/office encounters, and PD-related emergency room visits/hospitalizations. TRIAL REGISTRATION: This study was approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board (IRB-17-02704).

Molecular mechanisms and therapeutic targets for diabetic kidney disease.

Diabetic kidney disease has a high global disease burden and substantially increases the risk of kidney failure and cardiovascular events. Despite treatment, there is substantial residual risk of disease progression with existing therapies. Therefore, there is an urgent need to better understand the molecular mechanisms driving diabetic kidney disease to help identify new therapies that slow progression and reduce associated risks. Diabetic kidney disease is initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, and fibrotic processes that contribute to disease progression. This review summarizes existing evidence on the molecular drivers of diabetic kidney disease onset and progression, focusing on inflammatory and fibrotic mediators-factors that are largely unaddressed as primary treatment targets and for which there is increasing evidence supporting key roles in the pathophysiology of diabetic kidney disease. Results from recent clinical trials highlight promising new drug therapies, as well as a role for dietary strategies, in treating diabetic kidney disease.

Higher Dietary Intake of Advanced Glycation End Products Is Associated with Faster Cognitive Decline in Community-Dwelling Older Adults.

OBJECTIVE: Dietary-derived advanced glycation end products (AGEs) vary for different food types and the methods employed during their preparation may contribute to diverse chronic health conditions. The goal of this study was to investigate the associations of dietary AGEs (dAGEs) with cognitive decline in older adults. METHODS: Non-demented older adults (n = 684) underwent annual testing with 19 cognitive tests summarized as a global cognitive score based on five cognitive domains. We modified a previously validated food frequency questionnaire designed to assess dAGE. The modified questionnaire assessed portion size and frequency of consumption of six food groups (meat, poultry, fish, cheese, spreads, and processed foods), as well as the method of their preparation (e.g., grilling, boiling). dAGE was the sum of the scores of the six food groups. Linear mixed-effect models were used to examine the association of baseline dAGE with cognitive decline. All models controlled for age, sex, education, race, and body mass index (BMI). RESULTS: Average follow-up was 3.0 years. Higher baseline dAGEs was associated with a faster rate of global cognitive decline (Estimate = -0.003 (standard error = 0.001, p-value = 0.015). This association was driven by declines in episodic memory (-0.004 (0.002, 0.013)) and perceptual speed (-0.003 (0.001, 0.049)) but not by semantic memory, working memory, and visuospatial domains. These associations were not attenuated by controlling for cardiovascular risk factors and diseases, including diabetes. Levels of dAGE of the specific food groups were not associated with cognitive decline. CONCLUSIONS: Higher levels of dietary AGE levels in older adults are associated with faster cognitive decline. These data lend further support for the importance of diet and that its modification may slow or prevent late-life cognitive impairment. Further clinical studies will be needed and the molecular mechanisms underlying these associations will need to be identified.

Prevalence and Outcomes Associated with Hyperuricemia in Hospitalized Patients with COVID-19.

INTRODUCTION: Coronavirus 2019 (COVID-19) can increase catabolism and result in hyperuricemia. Uric acid (UA) potentially causes kidney damage by alteration of renal autoregulation, inhibition of endothelial cell proliferation, cell apoptosis, activation of the pro-inflammatory cascade, and crystal deposition. Hyperuricemia in patients with COVID-19 may contribute to acute kidney injury (AKI) and poor outcomes. METHODS: We included 834 patients with COVID-19 who were >18 years old and hospitalized for >24 h in the Mount Sinai Health System and had at least 1 measurement of serum UA. We examined the association between the first serum UA level and development of acute kidney injury (AKI, defined by KDIGO criteria), major adverse kidney events (MAKE, defined by a composite of all-cause in-hospital mortality or dialysis or 100% increase in serum creatinine from baseline), as well as markers of inflammation and cardiac injury. RESULTS: Among the 834 patients, the median age was 66 years, 42% were women, and the median first serum UA was 5.9 mg/dL (interquartile range 4.5-8.8). Overall, 60% experienced AKI, 52% experienced MAKE, and 32% died during hospitalization. After adjusting for demographics, comorbidities, and laboratory values, a doubling in serum UA was associated with increased AKI (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.9-4.1), MAKE (OR 2.5, 95% CI 1.7-3.5), and in-hospital mortality (OR 1.7, 95% CI 1.3-2.3). Higher serum UA levels were independently associated with a higher level of procalcitonin (ß, 0.6; SE 0.2) and troponin I (ß, 1.2; SE 0.2) but were not associated with serum ferritin, C-reactive protein, and interleukin-6. CONCLUSION: In patients admitted to the hospital for COVID-19, higher serum UA levels were independently associated with AKI, MAKE, and in-hospital mortality in a dose-dependent manner. In addition, hyperuricemia was associated with higher procalcitonin and troponin I levels.

Restriction of Dietary Advanced Glycation End Products Induces a Differential Plasma Metabolome and Lipidome Profile.

SCOPE: Diets with low content in advanced glycation end products (AGEs) lead to beneficial properties in highly prevalent age-related diseases. To shed light on the mechanisms behind, the changes induced by a low AGE dietary intervention in the circulating metabolome are analyzed. METHODS AND RESULTS: To this end, 20 non-diabetic patients undergoing peritoneal dialysis are randomized to continue their usual diet or to one with a low content of AGEs for 1 month. Then, plasmatic metabolome and lipidomes are analyzed by liquid-chromatography coupled to mass spectrometry. The levels of defined AGE structures are also quantified by ELISA and by mass-spectrometry. The results show that the low AGE diet impinged significant changes in circulating metabolomes (166 molecules) and lipidomes (91 lipids). Metabolic targets of low-AGE intake include sphingolipid, ether-lipids, and glycerophospholipid metabolism. Further, it reproduces some of the plasma characteristics of healthy aging. CONCLUSION: The finding of common pathways induced by low-AGE diets with previous metabolic traits implicated in aging, insulin resistance, and obesity suggest the usefulness of the chosen approach and supports the potential extension of this study to other populations.

Dietary Advanced Glycation End-Products and Mortality after Breast Cancer in the Women's Health Initiative.

BACKGROUND: Advanced glycation end-products (AGE) are formed through nonenzymatic glycation of free amino groups in proteins or lipid. They are associated with inflammation and oxidative stress, and their accumulation in the body is implicated in chronic disease morbidity and mortality. We examined the association between postdiagnosis dietary Nε-carboxymethyl-lysine (CML)-AGE intake and mortality among women diagnosed with breast cancer. METHODS: Postmenopausal women aged 50 to 79 years were enrolled in the Women's Health Initiative (WHI) between 1993 and 1998 and followed up until death or censoring through March 2018. We included 2,023 women diagnosed with first primary invasive breast cancer during follow-up who completed a food frequency questionnaire (FFQ) after diagnosis. Cox proportional hazards (PH) regression models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) of association between tertiles of postdiagnosis CML-AGE intake and mortality risk from all causes, breast cancer, and cardiovascular disease. RESULTS: After a median 15.1 years of follow-up, 630 deaths from all causes were reported (193 were breast cancer-related, and 129 were cardiovascular disease-related). Postdiagnosis CML-AGE intake was associated with all-cause (HRT3vsT1, 1.37; 95% CI, 1.09-1.74), breast cancer (HRT3vsT1, 1.49; 95% CI, 0.98-2.24), and cardiovascular disease (HRT3vsT1, 1.91; 95% CI, 1.09-3.32) mortality. CONCLUSIONS: Higher intake of AGEs was associated with higher risk of major causes of mortality among postmenopausal women diagnosed with breast cancer. IMPACT: Our findings suggest that dietary AGEs may contribute to the risk of mortality after breast cancer diagnosis. Further prospective studies examining dietary AGEs in breast cancer outcomes and intervention studies targeting dietary AGE reduction are needed to confirm our findings.