Patients with chronic kidney disease (CKD) are more prone to oxidative stress and chronic inflammation, which may lead to an increase in the synthesis of advanced glycation end products (AGEs). Because AGEs are mostly removed by healthy kidneys, AGE accumulation is a result of both increased production and decreased kidney clearance. On the other hand, AGEs may potentially hasten decreasing kidney function in CKD patients, and are independently related to all-cause mortality. They are one of the non-traditional risk factors that play a significant role in the underlying processes that lead to excessive cardiovascular disease in CKD patients. When AGEs interact with their cell-bound receptor (RAGE), cell dysfunction is initiated by activating nuclear factor kappa-B (NF-κB), increasing the production and release of inflammatory cytokines. Alterations in the AGE-RAGE system have been related to the development of several chronic kidney diseases. Soluble RAGE (sRAGE) is a decoy receptor that suppresses membrane-bound RAGE activation and AGE-RAGE-related toxicity. sRAGE, and more specifically, the AGE/sRAGE ratio, may be promising tools for predicting the prognosis of kidney diseases. In the present review, we discuss the potential role of AGEs and sRAGE as biomarkers in different kidney pathologies. Proteinted AGEs ,5. Intrated AGEs ,8.An increasing body of research indicates that AGEs may have a role in the development of a variety of illnesses. AGEs have a role in the development of diabetic, vascular, and uremic problems ,10,11. ARAGE also exists as a soluble molecule called sRAGE, which is composed of two forms: cleaved RAGE (cRAGE), which results from proteolytic cleavage of membrane-bound RAGE, and endogenous secretory RAGE (esRAGE), a splice variant with the extracellular domains but lacking the intracytoplasmic and transmembrane domains . sRAGE iThe purpose of this review is to provide an overview of the role of AGEs and sRAGE in diverse kidney disorders. In the kidneys, the glomeruli filter the AGEs, which are then reabsorbed by the renal proximal tubules . Their cAGEs may be measured in plasma, urine, or tissues, with skin being the most commonly utilized. The most reliable technology for determining AGE levels is gas chromatography–mass spectrometry (GC-MS) . Gas or Patients with CKD have malnutrition; accelerated biological aging; cardiometabolic, musculoskeletal, and cerebral problems; functional and quality-of-life deficits; and an increased mortality rate. Excessive oxidative stress, chronic inflammation, and uremia may all lead to an increase in AGE formation, which promotes CKD morbidity and death . Serum A2 and 15% with DM at baseline), increased serum CML and sRAGE were independently linked with lower eGFR and seemed to predict reduced eGFR [2), although sRAGE isoforms decreased significantly (p < 0.0001). The AGE/sRAGE ratios rose (p = 0.004), but variations in AGEs and RAGEs isoforms were not associated with changes in eGFR during follow-up. This absence of relationship implies that plasma AGE concentrations were related to the individual pro-oxidant environment rather than kidney function. The increased AGE/sRAGE ratio at follow-up showed a higher risk of AGE-dependent development of both CKD and other co-morbidities. The potential usefulness of the AGE/sRAGE ratio as a prognostic tool should be examined further [In the Women’s Health and Aging Study I, a prospective cross-sectional study of 548 older community-dwelling women (52% with a decreased eGFR of <60 mL/min/1.73 mced eGFR . At 1 ye further .n = 1874) found that kidney-related variables  were linked to increased levels of AGE-CML, sRAGE, and esRAGE. After controlling for basic demographic information and body mass index (BMI), C-reactive protein (CRP), black race, and advanced glycosylation end product-specific receptor (AGER) genetic variations (rs2070600 and rs2071288) were highly related to lower serum sRAGE and esRAGE concentrations. Fructosamine and glycated albumin were moderately linked with AGE-CML, indicating that serum AGE-CML may also represent short-term glycation (2–4 weeks). Hemoglobin A1c (HbA1c) was not linked with serum AGE-CML, sRAGE, or esRAGE after adjusting for baseline demographic variables and BMI. In this community-based group, AGE-CML and sRAGE were linked to renal, inflammatory, and genetic markers rather than DM. However, the authors concluded that these biomarkers lack specificity when tested by ELISA and have limited use in assessing the involvement of these compounds in DM [A cross-sectional analysis of the Atherosclerosis Risk in Communities (ARIC) study  and peritoneal dialysis (PD)), in comparison with healthy individuals ,65. IncrA negative connection was discovered between sRAGE and the AGE/sRAGE ratio. In HD patients, sRAGE is increased due to decreased kidney function, which is a strong determinant of sRAGE levels, and is not significantly modified by dialysis therapy ,64,69,70glyoxalase I gene associates with serum sRAGE levels. The CC variant shows a genetic predisposition to vascular complications in HD patients [The AGE/sRAGE ratio might be used as a general risk biomarker for ESKD . sRAGE wpatients .A rise in sRAGE levels has been linked with a substantial increase in mortality risk in HD and PD patients ,61. The Diabetic nephropathy (DN), or diabetic kidney disease (DKD), is a major microvascular complication of DM and the most common cause of ESKD, characterized by the presence of increased urine albumin excretion, diabetic glomerular lesions, and loss of GFR . DKD risIn animal studies, increasing AGE exposure induced microvascular dysfunction and DKD ,89. High2 and albuminuria). When age, gender, BMI, DM duration, and mean updated HbA1c were all taken into account, a positive relationship between fructose-lysine and CML and albuminuria was discovered. This points to oxidative stress playing a role in the etiology of DKD [Eleven plasma protein-bound AGEs were detected using LC-MS in 466 individuals in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study at three timepoints (TPs): DCCT years 4 (TP1) and 8 TP2), and EDIC years 5/6. (TP3). Methionine sulfoxide (MetSOX) was linked to DKD at TP1  and Veterans Affairs Diabetes Trial (VADT) (n = 447), respectively. After adjusting for baseline and follow-up HbA1c and other risk variables in the ACCORD trial, the AGE score based on serum levels of the five AGE-free adducts was linked with macroalbuminuria, a decline in eGFR, a sustained 30% decrease in eGFR, a sustained 40% decrease in eGFR, and high-risk CKD  < 30 mg/g, or eGFR < 45 mL/min/1.73 m2 with uACR 30–299 mg/g, or eGFR < 60 mL/min/1.73 m2 with uACR ≥ 300 mg/g). A similar relationship between baseline AGE score and eventual renal function impairment in a different T2DM cohort verified the durability of this finding. A predictive model for a sustained 30% decrease in eGFR that included clinical risk factors as well as an AGE score derived from the ACCORD data distinguished between participants who developed this outcome in VADT and those who did not, indicating the potential predictive value of a standard AGE score across T2DM populations. As different pathways from specific precursors lead to individual AGE-free adducts [2), there was a link between a higher AGE score and a higher likelihood of poor renal outcomes. Because they are related with two separate renal outcomes, the deterioration of both proteinuria and creatinine clearance, plasma AGEs have a wide pathophysiologic relationship with acute kidney problems [The Natural History of Diabetic Nephropathy Study  evaluate adducts ,94, the Plasma levels of sRAGE were not substantially different among CKD patients with variable glycemic control status in a study of 150 CKD patients and 64 non-CKD patients. Regardless of glycemic control status, plasma sRAGE levels were higher in diabetic individuals with CKD than in those without CKD. There were no interactions between CKD level and glycemic control status in terms of sRAGE. Despite the benefits of excellent glycemic control, well-controlled DM in CKD did not change the activities of enzymatic antioxidants or sRAGE levels, suggesting that this is not the predominant strategy for dealing with oxidative stress. The presence of CKD may negate the impact of glycemic management on enzymatic antioxidant activity and sRAGE levels . HoweverA prospective cohort study from the Hong Kong diabetic biobank looked at the relationship between SAF and kidney failure in 3725 people with T2DM who did not have ESKD. During a median follow-up of 1.8 (1.1–3.1) years, 411 patients had incident ESKD or had a 30% decrease in eGFR. After controlling for risk variables such as baseline eGFR and uACR, SAF was linked to kidney disease progression and yearly drop in eGFR. Reduced eGFR (12.9%) and increased uACR (25.8%) accounted for 38.7% of the effect of SAF on renal outcome .Atherosclerosis is a chronic disease process involving various biological elements such as myocytes, endothelial cells, lymphocytes, and platelets, as well as adhesion molecules and cytokines . This co2 microglobulin). After adjusting for gender, age, and race, one interquartile range higher log10-transformed sRAGE was associated with the development of CKD (p = 0.02) and ESKD (p < 0.001), but not after adjusting for baseline kidney function. These findings show that circulating levels of sRAGE may be directly influenced by a kidney’s inability to filter endogenous chemicals properly, or that sRAGE directly affects kidney function [In the ARIC Study, which included 151 CKD patients, 152 ESKD patients, and 1218 healthy people, baseline serum sRAGE levels were inversely associated with baseline eGFR, and positively correlated with other kidney filtration markers  had substantially higher quantities of AGEs and sRAGE than patients with abdominal aortic aneurysm and aortoiliac occlusive disease. The increase in AGE levels might be explained by increased oxidative stress and a loss of kidney function. The underlying pathophysiological process may be based on growing protein stiffness caused by protein cross-linking, cytokine, and enhanced adhesion molecule expression . AGEs ha2) and 49 healthy control people [In a study of 12 CKD patients , an inflammation of the kidney that encompasses diverse patterns of kidney disease such as glomerular, tubulointerstitial, and vascular pathology, is a severe complication of systemic lupus erythematosus (SLE) that progresses to ESKD in approximately 10% of patients within 5 years of onset ,108. PenPlasma sRAGE levels were adversely linked with SLE disease activity index in a Chinese cross-sectional investigation of 27 consecutive female patients. esRAGE and sRAGE plasma concentrations were considerably higher in LN patients without a flare than in those who did have a flare . This leAGER polymorphisms have been linked to susceptibility to SLE and LN. When compared to healthy controls, the C allele of AGER-429 T/C, the T allele of AGER-374 T/A, and the G allele of AGER-2184 A/G were considerably more frequent in SLE and LN. During the first two years of therapy, the C allele of AGER-429 T/C, the A allele of AGER-374 T/A, and the G allele of AGER-2184 A/G polymorphism were substantially related to higher proteinuria and lower kidney function in LN. Although AGER polymorphisms may have a causal relationship with illness susceptibility in SLE and disease severity in LN, no genotype-sRAGE connection was detected [detected .Renal amyloidosis is an uncommon and difficult-to-treat protein misfolding condition that causes progressive kidney failure . The funp < 0.001) in a prospective observational study with 35 ICU patients and a control group (n = 231). AGE buildup was not related to illness severity, ICU duration of stay, or death [In the majority of patients admitted to the intensive care unit (ICU), oxidative stress plays a significant role in the course and final fate. AGEs accumulation has only been documented in chronic situations. However, it may also develop abruptly as a result of oxidative stress. Oxidative stress results in the development of reactive carbonyl molecules, which then react with protein to generate AGEs . An acutor death . Higher or death ,121. Theor death . The inior death .Because kidney transplantation is intended to restore eGFR, it is expected to reduce circulating AGE concentrations. Despite this, AGEs remain higher than usual and disproportionally high in relation to eGFR, suggesting that additional variables, such as increased oxidative stress, may impact AGE production in the context of kidney transplant recipients . Kidney A direct association between CML and CEL concentrations and long-term risk of CV mortality was found in a prospective cohort study of 555 stable kidney transplant recipients with a median follow-up of 6.9 years, independent of traditional CV risk factors . These tAGER gene expression in primary human keratinocytes [In a study including 630 kidney transplant patients and 41 healthy kidney donors, the median urinary excretion rates of CML and CEL were lower pre-donation but higher post-donation. With the exception of N-G-carboxyethylarginine (CEA), kidney donation resulted in a reduction in the urine excretion rates of all AGEs. Kidney donation may alter the production of methylglyoxal and glyoxal, which are precursors of CEA and N-G-carboxymethylarginine (CMA), respectively. Lower urinary CML and furosine excretion rates were linked to increased all-cause mortality in kidney transplant recipients. Furthermore, reduced urinary furosine excretion rates were associated with increased CV mortality . Urinaryinocytes .p < 0.0001). However, SAF levels in transplant patients remained significantly higher than in healthy controls (p < 0.0001). As a result, kidney transplantation cannot totally repair dialysis patients’ increased AGE tissue levels. After transplantation, there was a negative connection between SAF levels and creatinine clearance (p < 0.0001). The existing disparities in kidney function are most likely to explain the differences in fluorescence between control participants, dialysis patients, and transplant recipients. Other factors, in addition to kidney function, contribute to the increased AGE amount following donation. After transplantation, there may be a pool of irreversible AGEs or a de novo generation of AGEs as a result of increased oxidative stress caused by immunosuppressive medicines such as cyclosporin or changes in AGE food consumption [After kidney transplantation, AGEs may have a role in the development of CVD and chronic kidney transplant failure ,134. SAFsumption . Furthersumption .p < 0.001) than in healthy controls. Following transplantation, plasma pentosidine levels in the kidney (p < 0.0001) and SPKT (p < 0.005) decreased significantly. In reversing increased plasma pentosidine levels after SPKT, correction of kidney failure is more crucial than the restoration of euglycemia. However, the correction is insufficient, and more than two years after transplantation, plasma levels of pentosidine remained more than thrice higher than in healthy people. Because these individuals seldom have an adequate kidney function, prolonged renal insufficiency may account for the slight but persistent rise in plasma pentosidine concentrations in both kidney and SPKT patients. In the partial correction of pentose-derived glycation of plasma proteins, SPKT has no benefit over kidney transplantation alone [p = 0.022). Several well-known inflammatory/infectious insults, as well as high dosages of new drugs such as immunosuppressors, might explain the first elevation in these markers after SPKT. Major surgery, indwelling catheters, wound episodes, and urinary, abdominal, or systemic infections may all contribute to an early inflammatory state in SPKT patients [In T1DM patients, simultaneous pancreas–kidney transplantation (SPKT) can restore glycemic control and kidney function, reducing AGE accumulation. Prior to transplantation, plasma pentosidine concentrations in kidney and SPKT candidates were 20 to 35 times higher (on alone . A transpatients .AGEs may be among the key contributors to the development of kidney diseases, raising oxidative stress in the body through multiple mechanisms and causing an inflammatory response. These processes have a significant impact on the onset and worsening of kidney dysfunction. The observed connections between sRAGE and kidney pathology, as well as associated consequences, may likely be a result of reduced kidney filtration rather than a complication of hyperglycemia. Further study findings will assist in elucidating the function of AGEs and sRAGE in kidney disorders.sRAGE levels may be affected by numerous molecules in the AGE-RAGE pathway; however, many studies have only examined sRAGE or a combination of sRAGE, CML-AGE, and esRAGE, only capturing a fraction of the AGE-RAGE pathway . The AGEBecause of their stability in body fluids, the validation of AGEs as biomarkers in kidney diseases would not be a problem. Despite the achievements of the current analytical methods for measuring AGEs and sRAGE, there are still questions about their cost, complexity, and the variability of their results. There is a need for more standardized, noninvasive techniques with simpler applications and improved dependability .The traditional treatment of chronic kidney diseases may alter in the future as novel therapeutic drugs to inhibit AGE-RAGE-mediated pathogenic pathways are developed ,136. Ano


This cohort study investigates the association of exposure to ambient fine particulate matter air pollution with kidney transplant outcomes. 2.5) air pollution associated with increased risk of adverse posttransplant outcomes among patients with kidney transplants?Is exposure to increased levels of ambient fine particulate matter  air pollution are associated with increased risks for detrimental health outcomes, but risks for patients with kidney transplants (KTs) remain unknown.Increased levels of ambient fine particulate matter  and mean PM2.5 level in the year before KT  in quartiles, as well as baseline annual mean PM2.5 level (in 10 μg/m3).Exposures included post-KT time-dependent annual mean PM2.5 levels greater than the Environmental Protection Agency recommended level of 12 μg/m3 was estimated.Acute kidney rejection , time to death-censored graft failure, and time to all-cause death. Multivariable logistic regression for kidney rejection and Cox analyses with nonlinear assessment of exposure-response for death-censored graft failure and all-cause death were performed. The national burden of graft failure associated with PM2.5 level was 9.8 (8.3-11.9) μg/m3. Increased baseline PM2.5 level, compared with quartile 1 baseline PM2.5 level, was not associated with higher odds of acute kidney rejection for quartile 2  but was associated with increased odds for quartile 3  and quartile 4 . Nonlinear assessment of exposure-response for graft failure and death showed no evidence for nonlinearity. Increased PM2.5 levels were associated with increased risk of death-censored graft failure  and all-cause death . The national burden of death-censored graft failure associated with PM2.5 above 12 μg/m3 was 57 failures  per year among patients with KTs.Among 112 098 patients with KTs, 70 522 individuals (62.9%) were older than age 50 years at the time of KT, 68 117 (60.8%) were men, and the median (IQR) follow-up was 6.0 (3.9-8.9) years. There were 37 265 Black patients (33.2%), 17 047 Hispanic patients (15.2%), 48 581 White patients [43.3%]), and 9205 patients (8.2%) of other race or ethnicity. The median (IQR) baseline PM2.5 level was an independent risk factor associated with acute rejection, graft failure, and death among patients with KTs. These findings suggest that efforts toward decreasing levels of PM2.5 concentration may be associated with improved outcomes after KT.This cohort study found that PM The etiology of kidney disease may be mediated by an increase in systemic inflammation and oxidative stress associated with air pollutants.15 It also has been found that particulate matter inhaled through the respiratory tract and cleared by the kidney may be associated with direct damage to renal tissue.16 Furthermore, air pollutants and PM2.5 are associated with insulin resistance,18 attenuated flow-mediated arterial dilation,19 and systemic hypertension,22 which are important factors that may be associated with kidney function.In the field of kidney disease, epidemiological studies from 2016 to 20202.5 levels and health outcomes, few studies have examined the association between PM2.5 levels and the outcomes of solid organ transplantation. Among patients with lung transplants, Bhinder et al23 found that increased PM2.5 levels were associated with an increased risk of chronic lung allograft dysfunction and overall mortality. Similar findings have been observed among individuals with heart transplants.24 Among individuals with kidney transplant (KT), studies26 found that exposure to air pollutants was associated with an increased risk of cardiovascular mortality, but associations of PM2.5 levels with other important transplant outcomes have not been examined to date, to our knowledge. With the identified knowledge gap in the association of PM2.5 levels with KT outcomes, this study aimed to determine whether PM2.5 concentration is an independent risk factor associated with kidney rejection, graft failure, or overall mortality among patients with KTs.Despite the existing evidence for an association between PMSTROBE) reporting guideline for cohort studies.Exemptions for study approval and informed consent were obtained for this cohort study from the Washington University in St. Louis School of Medicine Institutional Review Board because the study was secondary analyses of deidentified data. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology . Transplant outcomes were followed up until March 2021. Detailed descriptions of OPTN data were described elsewhere.31 ADI summarizes factors for the theoretical domains of income, education, employment, and housing quality.32 Data on population density were obtained from the US Bureau of Census 2010 Zip Code Tabulation Area to tract Relationship File.33 Data on remaining contextual characteristics were obtained from 2011 to 2015 American Community Survey 5-year estimates accessed through ArcGIS Living Atlas of the World.34We obtained recipient characteristics, including age, sex, race and ethnicity , body mass index , insurance status, and zip code of residence at the time of KT, as well as clinical data on panel reactive antibodies (PRA), diabetes, chronic obstructive pulmonary disease, etiology of kidney disease, and duration of dialysis closest to transplant. Race and ethnicity were among the many recipient and donor characteristics  that we used to adjust for recipient and donor characteristics. We also collected donor characteristics, including age, sex, race and ethnicity, BMI, kidney donor profile index, donor type, and history of hypertension, as well as transplant factors, including donor-recipient cytomegalovirus seropairing, level of human leukocyte antigen (HLA) mismatch, and cold ischemia time. Patient zip codes of residence were mapped to zip code–level data to obtain contextual characteristics, including area deprivation index (ADI), population density , median income, high school graduation and unemployment rates, and proportion of residents below the federal poverty line. Data on ADI were obtained from the University of Wisconsin School of Medicine and Public Health’s Neighborhood Atlas.2.5 concentration in micrograms per cubic meter in the recipient residential zip code area to reflect changing levels of PM2.5 over time after KT. Data on annual mean PM2.5 concentration (1 × 1 km) in the contiguous United States were obtained from aerosol optical depth retrievals from the NASA Moderate Resolution Imaging Spectroradiometer, Multi-Angle Imaging Spectroradiometer, and Sea-Viewing Wide Field-of-View Sensor calibrated using geographically weighted regression.36 The years of availability were 2001 to 2018. The overlap of 1 × 1–km resolution PM2.5 grids and zip code area produced surface area–weighted PM2.5 levels for each zip code.11The exposure was post-KT time-dependent annual mean PM2.5 level, defined as the annual mean PM2.5 level in the year before KT for a patient’s residential zip code area, was also considered as baseline PM2.5 level in 10 μg/m3 increments and baseline PM2.5 level categorized in quartiles.Baseline PMThe outcomes included acute kidney rejection reported at 1 year after KT (yes or no), death-censored graft failure , and all-cause death , with all data from the OPTN. The latter 2 transplant outcomes were followed up until March 2021 unless otherwise specified.The cohort included patients who underwent KT from 2004 to 2016. We excluded patients aged younger than 18 years at KT, patients receiving kidneys from living donors, patients with a previous KT, and patients with missing data on zip codes or continuous covariate variables.2.5 level quartiles in percentages for categorical variables and in medians (IQRs) for continuous variables. To compare between baseline PM2.5 level quartiles, χ2 tests were performed for categorical variables and Kruskal-Wallis tests were performed for continuous variables. Survival curves for time-to-event transplant outcomes  stratified by baseline PM2.5 level quartiles were adjusted for recipients' age, sex, race and ethnicity, dialysis status and duration, and ADI.Recipient characteristics, donor characteristics, transplant factors, and contextual factors were stratified by baseline PM2.5 concentration with time-to-event transplant outcomes were analyzed by multivariable Cox models. Robust sandwich variance estimators for Cox models were used.38 Follow-up was censored at the end of 2018 because data on annual mean PM2.5 concentration were available only up to 2018. The covariates in these multivariable models were selected from all recipient demographics, donor characteristics, transplant factors, contextual factors  was analyzed using multivariable logistic regression.The associations of post-KT PM2.5 level quartiles,39 and the statistical significance of spline terms was assessed for nonlinearity of spline terms. When there was no evidence of deviation from linearity, patients residing in areas with the lowest 1%  and the highest 1%  baseline PM2.5 levels were excluded from the analytic cohort, and multivariable-adjusted hazard ratios using the aforementioned Cox models were estimated using 3.7 μg/m3 as the reference level. These multivariable-adjusted hazard ratios (HRs) were plotted against the baseline PM2.5 level from 3.7 μg/m3 to 16.9 μg/m3 with the background of the histogram distribution of baseline PM2.5 level for the included analytic cohort.11To plot the exposure-response function for death-censored graft failure and all-cause death, cubic spline analyses were first performed in multivariable Cox models with knots placed at baseline PM2.5 levels greater than the Environmental Protection Agency (EPA) recommended PM2.5 concentration of 12 μg/m3 was plotted using the population attributable fraction (PAF) multiplied by incidence of graft failure per 100 000 patients with KTs per year from 2004 to 2016. PAF was the proportional reduction of the condition in the KT population that would occur if exposure to PM2.5 was decreased to 12 μg/m3. PAF was computed using piecewise constant hazard models for graft failure incidence.41Geographic distribution of the estimated national burden of graft failure associated with PM2.5 concentration was computed using ArcGIS Pro software version 2.7.0 (Esri). Data were analyzed from April 2020 through July 2021.All tests were 2-sided, and results were considered statistically significant at α = .05 or when 95% CIs did not cross 1 for odds ratios and hazard ratios. All statistical analyses were performed using SAS statistical software version 9.4 (SAS Institute) and R statistical software version 4.0.2 . Zip code–level PM11 Cities were defined as core-based (including metropolitan and micropolitan) statistical areas, which were obtained from the US Census Bureau33 and linked to patient residential zip codes. Additionally, for the acute kidney rejection outcome, multivariable logistic regression was performed adjusting for city clustering.To account for variations in city characteristics that could confound the association, sensitivity analyses for all 3 outcomes were conducted using multilevel models and adapting city-adjusted and within-city models. These models were detailed elsewhere.Among 214 317 patients who received KTs from 2004 to 2016 in the United States , while 37 265 patients (33.2%) were Black, 17 047 patients (15.2%) were Hispanic, and 9205 patients (8.2%) were of other race or ethnicity. Most patients had obesity or overweight BMI and were on dialysis more than 24 months before KT. Most patients received kidneys from donors who were aged 18 to 50 years (69 483 patients [62.0%]), men (67 284 patients [60.0%]), and White , while 15 550 patients had donors who were Black (14.0%), 15 189 patients had donors who were Hispanic (14.0%), and 3851 patients had donors who were of other race or ethnicity (3.4%). Most patients received kidneys from donors with a BMI from 18.5 to 24.9 (38 504 patients [34.4%]) or 25.0 to 29.9 (34 735 patients [30.99%]). Among transplant factors, most patients had a level of HLA mismatch of 3 to 6 hours and 12 to 24 hours of cold ischemia time. The median (IQR) ADI of patient residential zip code areas was 53.7 (31.1-72.3), and the median (IQR) population density was 0.00076 (0.00013-0.00186) individuals per square meter.2.5 level was 9.8 (8.3-11.9) μg/m3. Baseline PM2.5 concentration ranged from 1.2 μg/m3 to less than 8.3 μg/m3 among 28 025 patients in the first quartile, from 8.3 μg/m3 to less than 9.8 μg/m3 among 28 024 patients in the second quartile, from 9.8μg/m3 to less than 11.9 μg/m3 among 28 025 patients in the third quartile, and from 11.9 μg/m3to less than 22.4 μg/m3 among 28 024 patients in the fourth quartile. All recipient demographics, donor characteristics, transplant factors, and contextual factors were statistically significantly different across PM2.5 level quartiles except for sex for recipients and donors. Factors that decreased with PM2.5 level quartiles included proportion of recipients aged older than 50 years  and the proportion who were White  (The median (IQR) baseline PM < .001) .2.5 levels by quartile were associated with increases in acute kidney rejection , death-censored graft failure , and all-cause death   . The adjuartiles A-B demon2.5 level   and all-cause death . Using continuous baseline PM2.5 exposure .Risks for adverse KT outcomes increased with levels of post-KT time-dependent PM14-1.28) B left. Uexposure B, right,2.5 was reduced to the EPA recommended level of 12 μg/m3 was 3.99% (95% CI 3.32%-4.65%). The national burden of graft failure associated with increased levels of PM2.5 over 12 μg/m3 was estimated to be 57 failures  among 8623 patients with KTs per year from 2004 to 2016. The map illustrating the geographic distribution of the burden of graft failure (per 100 000 patients with KTs) associated with increased levels of PM2.5 over 12 μg/m3 is presented in 2.5 level, increased baseline PM2.5 level quartiles were associated with increased risk of acute kidney rejection, graft failure, and all-cause death (eTable in the The PAF for graft failure if exposure to PM2.5 concentration during post-KT follow-up or in the year before KT (by quartile or quantity), our study consistently found that PM2.5 concentration was an independent risk factor associated with acute rejection, death-censored graft failure, and all-cause mortality among recipients of KTs. These results were robust when different statistical models (with or without adjustment for city variations) were used. We also found linear exposure response associations between baseline PM2.5 concentration and risks for death-censored graft failure and all-cause death. These findings suggest that consistent exposure to fine particulate matter air pollution is associated with increased risk of worse transplant outcomes among recipients of KTs, including kidney rejection, kidney graft failure, and all-cause death.This cohort study is one of the first studies, to our knowledge, to assess the association of ambient fine particulate matter air pollution with outcomes among recipients of KTs. Using annual mean PM2.5 over 12 μg/m3 suggests that the highest burden was concentrated in areas with high population density and a high degree of air pollution, such as the Southwest and East North Central regions. The map showing areas with increased burden is consistent with that in Goodkind et al,42 in which the authors illustrated the estimated monetary marginal damages at every emission source location on a map.42The geographic distribution of the burden of graft failure associated with increased levels of PM2.5 concentration was associated with increased risk of kidney graft failure. This finding is consistent with those in previous reports finding increased risks for CKD and ESRD among individuals with native kidneys.43 Additionally, using multiple definitions of exposures, Bowe et al11 found an association between exposure to PM2.5 and risk for incident CKD and ESRD in a cohort of US veterans. In an earlier study, Mehta et al13 found that 1-year exposure to increased PM2.5 concentration was associated with an annual decrease in kidney function. Globally, it was estimated that PM2.5 concentration is associated with 3.3 million cases of incident CKD and 122.4 million cases of prevalent CKD.43 However, our finding is not supported by the finding in a Feng et al,44 which found that risk of death-censored graft failure was increased with increased PM2.5 concentrations, although this change was not statistically significant. This deviation could be associated with a shorter follow-up time .One highlight of this study is the finding that increased PM47 We found a 13% increase in odds of rejection within the first year of KT among recipients residing in areas with the fourth quartile of baseline PM2.5 levels, compared with the first quartile. This finding is consistent with that in Feng et al44 and suggests an alloimmune etiology as a possible pathway for rejection that may be associated with increased risk of graft loss. The exact mechanism of increased risk of rejection with PM2.5 has not yet been elucidated. We hypothesize that this could be associated with increased systemic inflammation and activation of the innate and adaptive immune systems. This hypothesis is based on a growing body of literature suggesting that the organic compounds, free radicals, and transition metals contained in PM2.5 are associated with increased oxidative stress, as well as the gene and protein expression of proinflammatory mediators, such as tumor necrosis growth factor α, monocyte chemoattractant protein 1, macrophage inflammatory protein 2, interleukin 6, interleukin 1β, and interleukin 8.48 Studies have also found that PM2.5 is associated with increased expression of adhesion molecules like vascular cellular adhesion molecule 1 and the adhesion of monocyte cells to endothelial cells.50 In lung transplant, aryl hydrocarbon receptor is considered as a pathway to changing naive T cells to inflammatory T helper 17 cells and promoting chronic inflammation and chronic rejection.51Kidney graft rejection is a major risk factor associated with graft loss.3 increase in PM2.5 level, similar to the finding of Feng et al (15% increase per 10 ug/m3 increase in PM2.5 level).44 Prior studies among recipients of KTs have found increased risk of cardiovascular mortality from exposure to air pollutants.26 The increased mortality risk has also been reported among individuals with heart transplants: 26% to 43% increases in mortality risk per 10 ug/m3 increase in time-dependent PM2.5 concentration.24 In patients with lung transplants, the increase in mortality risk was not statistically significant, as reported by Bhinder and colleagues,52 possibly associated with the exposure definition  and a smaller sample size . As for mortality among patients with CKD, it was estimated at 211 019 deaths associated with CKD associated with PM2.5 exposure globally.43 However, similar to the situation in the general nontransplant population, it is likely that most of these deaths are associated with detrimental cardiovascular outcomes of PM2.5 exposure.53Our study found a 21% increase in mortality risk among individuals with KTs for every 10 ug/m2.5 levels with acute rejection, graft failure, and death in a large national cohort of individuals with KTs. Second, our analyses benefited from merges of multiple databases to comprehensively account for potential confounding, including patient, donor, and transplant factors, as well as contextual characteristics . Third, multiple exposure definitions were used to ensure the robustness of study findings. Fourth, the robustness of the findings was strengthened by sensitivity analyses adjusting for city variations. We note that PM2.5 concentration generally decreased over time. As a consequence, using time-dependent exposure is particularly important to capture the association of decreasing PM2.5 levels over time with transplant outcomes. Furthermore, this trend was associated with changes in included recipient and donor characteristics, transplant factors, and contextual factors, as well as transplant outcomes when recipients were grouped by baseline PM2.5 level quartiles, as presented in the This study has several strengths. First, to our knowledge, it is one of the first studies on the association of PM2.5 concentration was available up to 2018 at the time of the study, limiting follow-up time. Nonetheless, we were able to include a follow-up of 2 to 15 years. Third, the most up-to-date residential zip codes for recipients of KTs were recorded at the time of KT. Time-dependent analyses may be biased if the patients moved to another zip code area after KT. However, this bias may be decreased if patients who moved after KT were not systematically more likely to move to areas with higher or lower levels of PM2.5 compared with their area of residence at KT. Fourth, composition and toxic content of PM2.5 may change over time and by geography; consequently, use of PM2.5 level alone may underestimate risk.54 Fifth, indoor air pollution was not accounted for in this study. Sixth, although we controlled for as many covariates as possible and adjusted for city variations, residual confounding may remain, which could bias the estimated association.Nonetheless, this study has several limitations that should be noted. First, like most retrospective studies, the results rely on the accuracy of the recorded data from multiple databases. Second, although time-dependent analyses allowed for capturing the exposure after KT, the most updated annual mean PM2.5 were independently associated with increased risk of acute rejection, graft loss, and death. Our findings suggest that efforts toward cleaner air may be associated with decreased burden of adverse outcomes after KT. In clinical practice, suggesting that recipients of KTs reside in areas with lower levels of PM2.5 concentration may be associated with improved transplant outcomes.To our knowledge, this is one of the first studies in a national cohort of recipients of KTs that found that increased levels of PM


The results showed that the UHPLC-MS/MS method is capable of investigating IgG profiles, and monitoring IgG and glycosylation patterns is worthy of further clinical application for kidney disease.Immunoglobulin G (IgG) N-glycosylation was discovered to have an association with inflammation status, which has the potential to be a novel biomarker for kidney diseases. In this study, we applied an ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method to plasma and urine samples from 57 individuals with different levels of kidney function. Natural abundances of total IgG, IgG1, IgG2, and IgG3 subclasses in plasma showed positive correlations to the estimated glomerular filtration rates (eGFRs). Eighteen IgG glycopeptides also showed positive correlations. In contrast, higher IgG amounts were found in urine samples from participants with lower eGFR values. After normalizing IgG glycopeptides from plasma to their respective protein amounts, H4N4F1S1-IgG1 ( The global burden of chronic kidney disease (CKD) is substantial in terms of both economic and disease impacts ,2. CKD cA proportion of CKD patients develop end-stage renal disease (ESRD) and require long-term renal replacement therapy; however, it remains difficult to predict patients who will progress to ESRD. Some groups have tried to determine specific markers to predict kidney function progression by proteomics investigation . Sets ofHuman IgGs are classified into four subclasses, and the glycosylation profiles of their fragment crystallizable region  are associated with proinflammatory and anti-inflammatory statuses. Different glycosylation patterns of the IgG subclasses affect their stability and affinity to IgG receptors or complements. Many studies have used mass spectrometry (MS)-based analytical methods to monitor IgG profiles for biomarker discovery and disease diagnosis ,16. For Natural human IgG standards, including IgG1, IgG2, IgG3, and IgG4, were purchased from Abcam . The internal standard used in this study was the SILu™MAB K1 Stable-Isotope-Labeled Universal Monoclonal Antibody, purchased from Sigma-Aldrich . Iodoacetamide (IAA), ammonium bicarbonate, and formic acid were also purchased from Sigma-Aldrich. Dithiothreitol (DTT) was purchased from Merck . Protein G Mag Sepharose Xtra beads were obtained from GE . Chicken serum, used as a blank matrix, was purchased from Thermo Scientific . Phosphate-buffered saline  was purchased from VWR International . Lyophilized trypsin was purchased from Promega . MS-grade acetonitrile (ACN) was purchased from J.T. Baker .Sample preparation and analytical conditions were previously developed and validated by our team . Briefly® Core-Shell C18  column was used in this study for analyte separation. Dynamic multiple reaction monitoring (MRM) was applied to target peptides representing total IgG, four IgG subclasses, and 26 IgG glycopeptides. Information on the target analytes is summarized in The Waters ACQUITY UPLC system (quaternary pumps) coupled with an Xevo TQ-XS triple quadruple mass spectrometry system  was used for sample analysis. A KinetexIn this study, we analyzed IgG and IgG glycopeptides in plasma and urine samples from 57 participants with CKD, and healthy controls. Participants were enrolled in Taipei Medical University Hospital, and the study was approved by the ethics committee (N201704064). Informed consent forms were provided, and signed forms were received from all participants. Whole blood (10 mL) was collected, and the plasma fraction was obtained by centrifuging the blood at 3000 relative centrifugal force (RCF) for 15 min. A urine sample was also collected, and sodium azide was added to a final concentration of 10 mM as preservative. All plasma and urine samples were stored in a −80 °C freezer before use.TM Creatinine Assay, KGE005, LOT#: P289536 . Ten microliters of urine were diluted with buffer solution 20 times for sample incubation. After adding alkaline picrate solution for a 30 min incubation time, the signals were determined with a microplate spetrophotometer (490 nm).Plasma concentrations of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined by using ELISA kits: Human IL-6 ELISA Kit, RAB0306-1KT, LOT#: 0428I140; Human Tumor Necrosis Factor alpha ELISA Kit, RAB0476-1LT, Lot#: 0422I193 . Brifly, calibration curves were prepared by using protein standards with suitable serial dilutions. Fifty microliters of plasma were diluted with buffer solution two times for sample incubation. After adding antibodies and reporter reagent for a specified incubation time, the signals were determined with a microplate spetrophotometer (450 nm). The optical density (OD) values were used to calculate the analyte concentrations. Urine creatinine concentrations were also determined by using a commercially available ELISA kit: ParameterAll raw UHPLC-MS/MS data were processed by MassLynx . The peak area and peak area ratio (responses) of all signals were integrated and calculated by the software, and exported to Excel files for further analysis. Natural abundance (Response) indicated in this study was the peak area of the analyte divided by the peak area of the internal standard. The normalized area indicated in the study was the natural abundance of the analytes divided by the abundance of their respective proteins. Correlations between IgG profiles and the estimated glomerular filtration rate (eGFR) were calculated by GraphPad Prism . Statistical analysis of glycopeptides and cytokines between two or four groups defined in this study were conducted by Mann-Whitney test and Kruskal Wallis test, respectively (GraphPad Prism).2. In To investigate the relationships between IgG profiles and kidney function, 22 female and 35 male participants were recruited for this study. The ages ranged 27~77 years old, and the eGFR values ranged 15~171 mL/min/mr) of the calibration curves for total IgG, IgG subclasses, and the 26 glycopeptides ranged from 0.947~0.999. The accuracies of the QC samples at four concentrations ranged from 83.4%~103.5% for total IgG and the IgG subclasses. Total ion current chromatograms from two individuals with high and low eGFR values are shown in UHPLC-MS/MS is one type of analytical platform, with the advantages of high sensitivity and selectivity, with which it is possible to determine multiple analytes in one injection. It has been widely applied to biological and clinical samples for small molecule and biomolecule analyses. IgG and glycopeptides have recently been monitored and correlated with many disease statuses as biological signatures for diagnosis or progression ,20. In tr values ranged from 0.36~0.42. All p values were <0.05. Only human IgG4 did not show a correlation with kidney function indicators  were further normalized with the urine creatinine concentration to account for the variation of the urine flow rate. The creatinine normalized urine IgG subclasses were used for statistical analysis. In 2. There were still no significant differences between the two groups  in patients with type 2 diabetes mellitus . Howeverr = 0.37, p = 0.0047). Another glycopeptide, H5N4F1S1-IgG1, with sialic acid, also showed a moderate correlation, but with a relatively higher p value. Compared to human IgA isotype, IgG is less sialylated, and sialylation of the IgG Fc region decreases their affinities to the Fcγ receptor, which was pointed out to be anti-inflammatory. Our finding corresponds to the results from Drs. Bassios and Menni et al., in which a decrease in sialylation was found in patients with CKD [Since different glycosylation levels of the IgG Fc region have been reported to have proinflammatory or anti-inflammatory effects, studies of N-glycosylation of IgG have been used in clinical applications, including kidney transplants, kidney function in type 2 diabetes, and moderate kidney dysfunction ,22,23. Iwith CKD . The decwith CKD . AlthougAge and gender are two important factors which also affect IgG N-glycosylation profiles. In our study, the ages of participants showed no significant differences among the four eGFR groups, but more males had lower eGFR values. Therefore, we checked the literature to see if monosialylation (H4N4F1S1-IgG1 and H5N4F1S1-IgG1) was gender-related. A study published by Dr. Gornik et al. found that there were no significant difference of sialylation of IgG in boys and girls (<18 years) . A studyThere are still limitations of the study. We assumed that renal damage plays a primary role in modulating IgG plasma levels based on the results of reduction in plasma IgG and the concomitant increase in urinary IgG at lower eGFR levels. However, the pathological histories for the current population are heterogeneous which made detailed classification difficult. It is hard for us to correlate discovered IgG profiles to different types of renal damages at the current stage. The correlations of sialylated IgG peptides to the pathogenesis and the progression of renal damage also require further investigation.Kidney function is affected by many biological factors and diseases. Novel biosignatures for predicting and monitoring kidney functions need to be discovered. Inflammation is known to be involved in the progression of nephropathies, and IgG glycosylation has shown correlations with different kidney diseases. In this study, we applied a validated UHPLC-MS/MS method to determine IgG glycosylation profiles from individuals with different eGFR values. The natural abundances of total IgG, IgG1, IgG2, IgG3, and 18 IgG N-glycopeptides showed lower levels in patients with lower eGFR values. After normalizing the responses of glycopeptides to their respective proteins, two glycopeptides with sialic acid, H4N4F1S1-IgG1 and H5N4F1S1-IgG1, showed positive correlations with eGFR values, which were statistically significant and marginally significant, respectively. The results corresponded to previous findings that lower blood levels of IgG and less sialylation occur in patients with kidney diseases. The detailed pathological mechanism between IgG and kidney function is worthy of further investigation.


Objectives: Experimental data indicate that activating mutations in the mTOR  pathway may lead to abnormal arterial wall structure. Vascular anomalies like arterial stenoses are reported in pediatric patients with tuberous sclerosis complex (TSC). In addition, large renal lesions (angiomyolipoma—AML and cysts) are risk factors for arterial hypertension in adult patients with TSC. This study aimed to assess blood pressure, including central blood pressure and arterial damage (early vascular aging—EVA) in children with TSC.Materials and Methods: In a group of 33 pediatric patients with TSC , we evaluated peripheral and central office blood pressure, 24-h ambulatory blood pressure, and arterial damage: aortic pulse wave velocity (aPWV) [m/s], [Z-score], augmentation index (AIx75HR [%]), common carotid artery intima-media thickness (cIMT) [mm], [Z-score], stiffness of common carotid artery (E-tracking), renal lesions in magnetic resonance and ultrasonography, and selected biochemical parameters. The control group consisted of 33 healthy children .Results: In TSC group 7 (21.2%) children had arterial hypertension, 27 (81.8%) children had renal angiomyolipomas, 26 (78.8%)—renal cysts, and 4 (12.1%) patients were treated with mTOR inhibitors (2 patients with everolimus and 2 patients with sirolimus) at the moment of evaluation. Children with TSC had higher central systolic blood pressure (AoSBP) , cIMT , cIMT Z-score , aPWV  and aPWV Z-score  compared to healthy children, without differences in AIx75HR  and stiffness of common carotid artery. In children with TSC AoSBP correlated positively with serum cystatin C concentration  and with maximum diameter of renal cyst ; mean arterial pressure (MAP) 24 h Z-score correlated with serum cystatin C concentration ; and aPWV Z-score with daily urinary albumin loss [mg/24 h] .Conclusions: Children with tuberous sclerosis complex are at risk of elevated central blood pressure and early vascular aging. In children with TSC, blood pressure and arterial stiffness are related to renal involvement. TSC1 (chromosome 9q34) or TSC2 (chromosome 16p13) are found in 85–90% of the TSC patients; remaining individuals were found to have mutations in non-coding regions of the genes or to show genetic mosaicism (de novo mutation); approximately 30% of cases are inherited from one of the affected parents  signaling pathway, i.e., hamartin and tuberin, respectively. Constant activation of the mTOR pathway leads to uncontrolled cell proliferation and formation of hamartomas, benign neoplasms, and rarely, malignant neoplasms in virtually all parts of the body. Thus, the spectrum of TSC-associated disorders includes skin lesions , retinal lesions (87% of patients), central nervous system abnormalities (70–90% of patients), heart , lungs (angiomyolipoma and lymphangioleiomyomatosis present mainly in women) and, finally, diversified renal lesions  is an autosomal dominant disorder found in 1:5,800–1:12,500 births. At present, TSC is diagnosed on the basis of recently updated 2021 International Tuberous Sclerosis Complex Consensus Group (ITSCCG) genetic and clinical criteria  in these patients. The spectrum of renal abnormalities involves angiomyolipomas (AML)—present in 55–90% of patients with kidney lesions, renal cysts, glomerulocystic disease, oncocytoma, and renal cell carcinoma (RCC) , 5. AngiExperimental data indicate that activating mutations in the mTOR pathway may lead to degenerative phenotype and uncontrolled proliferation of vascular smooth muscle cells (SMC) and abnormal structure of arterial wall , 8. ArteThis single-center cross-sectional study included patients with TSC treated in 2018–2021 in one tertiary center of pediatric nephrology. The criterion for inclusion in the study was confirmed TSC following ITSCCG recommendations . The excThe authors obtained approval from the local Bioethical Committee before initiating the research . All procedures involving human participants were in accordance with the highest ethical standards of the institutional research committee and were performed according to the Declaration of Helsinki on the treatment of human subjects and its later amendments. Informed consent was obtained from all participants' representatives and participants (≥16 years) before enrolling in the study.2]. Anthropometric parameters were compared with the standards for the Polish population and presented in the form of a Z-score  was calculated in all patients [mL/min/1.73 m formula . Impairerding to ], and hyng to   in line with ESH recommendations. They were analyzed using pediatric normative values  , 24. Acc-scores) . Systoli-scores) . The blo-scores) .Z-score —common carotid artery intima-media thickness (cIMT) [mm], Z-score , and com in B-mode. Renal length [mm], echogenicity and corticomedullary differentiation, and the presence of renal parenchymal changes, including typical TSC lesions: angiomyolipoma (AML) and cysts were evaluated. The longest dimension of the largest lesion [mm] was assessed for AML and cysts. In patients diagnosed with arterial hypertension duplex Doppler ultrasonography was performed to exclude renal artery stenosis. In 24/33 (72.7%) patients, magnetic resonance imaging (MRI) of the abdomen was performed with a MAGNETOM Skyra 3T 3-tesla scanner  in T2-weighted, DWI, and T1-weighted sequences before and after intravenous administration of the contrast agent—Gadovist (gadobutrol) . Renal length [mm], renal cortical signal and differentiation, and presence of renal parenchymal lesions  with the assessment of the largest dimension of the largest lesion [mm] were evaluated. Fat-poor AMLs were recognized according to the Polish Society of Nephrology recommendations . In caset-test for independent groups and non-normally distributed data using the Mann–Whitney U test. The relationship between the two groups of variables was analyzed using Pearson correlation or Spearman rank correlation (depending on the distribution). Percentages in both groups were compared using the chi-square test. A p-value < 0.05 was considered statistically significant.The results were statistically analyzed using TIBCO Statistica 13.3 software . The normality of variables was studied using the Shapiro–Wilk test. The numerical data obtained were presented as mean and standard deviation (SD)  or median and interquartile range  . Normally distributed data were compared with Student Clinical and biochemical parameters in the studied children were presented in Z-score. In the group of TSC patients, elevated (≥95th percentile) office systolic or diastolic blood pressure was revealed in 10 (30.3%) patients, including two patients with previously recognized arterial hypertension. Elevated blood pressure in ABPM was revealed in 4 (12.1%) patients—all of them were considered as normotensives before the study. Among these four patients, one 13-year-old girl also had elevated office blood pressure. Additionally, ABPM revealed masked hypertension in three patients. All three patients with previously recognized and treated arterial hypertension had normal ABPM results at the moment of the study. The analysis of blood pressure in TSC children was depicted in The comparison of blood pressure in children with TSC and healthy children was depicted in p = 0.003) and thicker common carotid artery intima-media thickness  than healthy individuals. There were no differences between the groups regarding augmentation index, subendocardial viability ratio, local carotid arterial dimension, or stiffness parameters. Central systolic blood pressure, aortic pulse wave velocity, and common carotid intima-media thickness in both groups were presented in Parameters of arterial damage in both groups were presented in p = 0.011, aPWV Z-score: −0.18 ± 1.18 vs. −0.96 ± 0.87, p = 0.006) and thicker common carotid artery intima media thickness . The groups still did not differed in age  and sex .When we excluded 7 children with arterial hypertension from the study group, we found that remaining 26 children with TSC were still characterized by significantly faster aortic pulse wave velocity . Aortic systolic blood pressure and mean arterial pressure during 24 h Z-score correlated with serum cystatin C concentration .In TSC patients, aortic systolic blood pressure and peripheral office diastolic blood pressure p = 0.660; aPWV Z-score:−0.07 ± 1.12 vs.−0.21 ± 1,21, p = 0.752) or common carotid artery intima media thickness . We found a positive correlation between aPWV Z-score and daily urinary albumin loss  and trend toward a positive correlation between aPWV Z-score and maximal AML diameter .Boys with TSC did not differ from girls in terms of aortic pulse wave velocity  , arterial compliance (AC) correlated with systolic blood pressure load during 24 h  and with MAP 24 h Z-score  and local pulse wave velocity (PWVbeta) also correlated with MAP 24 h Z-score .As for parameters of local carotid artery stiffness in patients with TSC, pressure strain elasticity modulus (Ep) correlated with mean arterial pressure during 24 h This is the first study to analyze central blood pressure and the phenomenon of early vascular aging in pediatric patients with tuberous sclerosis complex. We have compared our results with perfectly sex- and age-matched healthy peers. Our analysis revealed that TSC patients were characterized by significantly higher central systolic blood pressure, aortic pulse wave velocity, and common carotid artery intima-media thickness. We have found that blood pressure correlated with serum cystatin C and renal cyst diameter in this group of patients. There was also positive relation between pulse wave velocity and the extent of renal involvement. Parameters of local artery stiffness correlated with ambulatory blood pressure.Our analysis has involved 33 children with already diagnosed TSC hospitalized in one tertiary center of pediatric nephrology. Our center has developed a program of nephrological care for pediatric TSC patients in 2017 based on ITSCCG and the Polish Society of Nephrology recommendations , 29. TheTSC2 and PKD1 genes are characterized by a very severe phenotype with large cysts from early childhood. Many of these patients develop a rapid progression to end-stage renal disease already in the second or third decade of life  than in other pediatric patients groups—renal involvement is estimated to occur in approximately 38.5−55% of preschool children and 75–80% of schoolchildren , 31, 32. of life , 32. In  authors . It has In the analyzed group of patients with TSC, hypertension was present in 21.2% of patients, which is higher than the average prevalence of hypertension in the population of healthy children (3–5%)  and is aArterial damage is one of the first alterations observed in pediatric populations with increased cardiovascular risk, such as chronic kidney disease (CKD) , primaryOur study is the first to reveal signs of EVA in pediatric patients with TSC. The primary cause of EVA in this group of patients is yet to be solved. Nevertheless, there is some possible explanation for this result. Firstly, vascular senescence in this population could be the effect of blood pressure rise as blood pressure is the primary determinant of cIMT and aPWV in the general pediatric population , 43. MorTsc2 deficiency leads to SMC proliferation and de-differentiation in vitro and in vivo, which can be reversed with rapamycin treatment  in the treatment of virtually all symptoms of the disease, including central nervous system lesions , renal Ahenotype . Inhibithenotype . There ihenotype  or PH , and treatment with mTOR inhibitors. As arterial hypertension was recognized previously in only 3 patients, we could not analyze the influence of duration of hypertension on arterial damage in TSC patients.Some limitations to our research need to be listed. Firstly, the study's cross-sectional nature precludes drawing final conclusions on the relation between blood pressure, arterial damage, and clinical parameters in the studied TSC patients . Secondly, the study population was small and heterogeneous in terms of age, presence of arterial hypertension, the extent of renal involvement, genetic background . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin and the participants (≥16 years).PS, AMW, and MS drafted and revised the manuscript. PS, SJ, MB, and MP-T contributed to the conception and design of the work. PS, AMW, MS, MB, AJ-K, and PB contributed to the acquisition of data. PS, AMW, MS, SJ, MB, AJ-K, PB, and MP-T contributed to the analysis or interpretation of the data. SJ and MP-T critically revised the manuscript. All authors gave their final approval and agreed to be accountable for all aspects of this work ensuring its integrity and accuracy.This research was funded from the statutory funds of the Department of Pediatrics and Nephrology, Medical University of Warsaw.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To test the value of preoperative and postoperative cystatin C (CysC) as a predictor on kidney function after partial (PN) or radical nephrectomy (RN) in renal cell carcinoma (RCC) patients with normal preoperative renal function.2 underwent surgical RCC treatment with either PN or RN. Logistic and linear regression models tested for the effect of CysC as a predictor of new-onset chronic kidney disease in follow-up (eGFR < 60 ml/min/1.73m2). Moreover, postoperative CysC and creatinine values were compared for kidney function estimation.From 01/2011 to 12/2014, 195 consecutive RCC patients with a preoperative estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73m2 were 55.9 and 30.2%. In multivariable logistic regression models, preoperative CysC [odds ratio (OR): 18.3] and RN (OR: 13.5) were independent predictors for a reduced eGFR < 60 ml/min/1.73m2 in follow-up (both p < 0.01), while creatinine was not. In multivariable linear regression models, a difference of the preoperative CysC level of 0.1 mg/dl estimated an eGFR decline in follow-up of about 5.8 ml/min/1.73m2. Finally, we observed a plateau of postoperative creatinine values in the range of 1.2–1.3 mg/dl, when graphically depicted vs. postoperative CysC values (‘creatinine blind area’).Of 195 patients, 129 (66.2%) underwent PN. In postoperative and in follow-up setting , rates of eGFR < 60 ml/min/1.73mPreoperative CysC predicts renal function impairment following RCC surgery. Furthermore, CysC might be superior to creatinine for renal function monitoring in the early postoperative setting. In localized renal cell carcinoma (RCC), surgical treatment with either nephron-sparing partial nephrectomy (PN) or radial nephrectomy (RN) is associated with excellent oncological outcomes –3. HowevMoreover, multiple studies showed a better accuracy of cystatin C (CysC), relative to serum creatinine, to estimate kidney function through eGFR in surgically and non-surgically treated patients –15. SeveWe addressed this knowledge gap and hypothesized that CysC may play a crucial role in outcome measurements of kidney function after surgical treatment with RN or PN for RCC patients. Moreover, we postulated that CysC may be less influenced by patient’s age than creatinine.2 (n = 54), non-RCC postoperative histology (n = 17), surgical treatment for kidney trauma (n = 1) and death during follow-up (n = 9). These selection criteria resulted in 195 eligible surgically treated patients.The current study was performed in accordance with the Declaration of Helsinki and approved by the local ethic committee of the University Hamburg-Eppendorf (number PV4219). All consecutive patients who underwent surgical treatment with either PN or PN for RCC between 01/2011 and 12/2014 at the Department of Urology, University Medical Center Hamburg-Eppendorf, Germany, were retrospectively identified. Exclusion criteria consisted of patients with preoperative impairment of kidney function, defined as eGFR < 60 ml/min/1.73From patient’s data files patient’s baseline characteristics according to blood, urine and tumor values/characteristics were collected. All RCC patients were surgically treated with either open, laparoscopic or robotic RN or PN. Preoperative and postoperative unsuspicious CysC values were defined as ≤ 0.96 mg/l, as previously described .2 = 186  ×  (S-Creatinine − 1.154)  ×  (age − 0.203) × 1.212 (if African American race/ethnicity) × 0.742  [Provided data regarding eGFR, were calculated in accordance with the four variable MDRD Study Equation: GFR in ml/min/1.73ale sex) , 23. Proale sex) .2, in accordance with current definitions [Primary endpoint of the study was the assessment of postoperative (day 1) and follow-up kidney function with regard to preoperative and postoperative CysC blood levels. Kidney function impairment in follow-up was defined as an eGFR < 60 ml/min/1.73initions . Patientt test and Kruskal–Wallis tests assessed differences among groups as appropriate.Descriptive statistics included frequencies and proportions for categorical and medians and interquartile ranges (IQR) for continuous variables. The Chi-square, the Uni- and multivariable logistic, as well as linear regression models were fitted to assess the value of CysC as a predictor of kidney function in follow-up after PN or RN. Significant variables in univariable logistic regression models, were included in multivariable models. Moreover, loess-plots were used to depict the correlation between first-day postoperative creatinine and postoperative CysC in surgically treated RCC patients. Subsequently, same tabulations were made for different age cut-offs and in postoperative AKI patients.p < 0.05 [All statistical analyses were performed using the R statistical package system 3.4.3 , with a two-sided significance level set at p < 0.05 .2 (IQR 76–103) and 0.8 mg/l (IQR 0.7–0.9). In the entire cohort, rates of postoperative and follow-up eGFR < 60 ml/min/1.73m2 were respectively 55.9 and 30.2%. In particular, at follow-up, 75.9% of patients had CKD G3a (eGFR 45–59 ml/min/1.73m2/ and 24.1% of had CKD G3b (eGFR 30–44 ml/min/1.73m2).Of all eligible 195 patients , exhibited higher rates of preoperative diabetes  than patients with normal postoperative CysC. Additionally, patients with postoperative elevated CysC more frequently underwent RN (48.6 vs. 16.7%) and exhibited larger tumor sizes (4.6 vs. 3.4 cm).Further stratification according to postoperative elevated or normal CysC level was made Table . Here, 1n = 95) participated in the follow-up. At baseline, median eGFR was 88 vs. 67 ml/min/1.73m2 at follow-up (p = 0.2). In univariable logistic regression models (Table p < 0.001) were associated with an eGFR < 60 ml/min/1.73m2. Moreover, tumor size , postoperative AKI  and RN  were associated with an eGFR < 60 ml/min/1.73m2 at follow-up .Median follow-up duration was 14 months IQR 10–20) and of all patients, 46.2% (0 and of 2 at follow-up (both p ≤ 0.01). Conversely, postoperative CysC was not associated with an eGFR < 60 ml/min/1.73m2 at follow-up (p = 0.3). Additionally, when preoperative creatinine was used and adjusted for the same covariates, creatinine did not achieve independent predictor status for an eGFR < 60 ml/min/1.73m2 at follow-up (p = 0.2).In multivariable logistic regression models, preoperative CysC  and RN  were independent predictors for a reduced eGFR < 60 ml/min/1.73mp < 0.01) was also independently influencing the patients’ eGFR at follow-up. This means that a preoperative increase of the CysC level of 0.1 mg/dl was associated with an eGFR decline of 5.8 ml/min/1.73m2 at follow-up.We further validated these observations in multivariable linear regression models Table . Here, pTo further investigate the performance of postoperative CysC in surgically treated patients, we plotted postoperative CysC values vs. creatinine values in all examined patients Fig. A. Here, Several studies suggested CysC as a better marker for kidney function estimations than creatinine, based on CysC’s molecular structure and its physiology regarding filtration and reabsorption , 27. HowFirst, we found that patients with postoperative elevated CysC after RCC surgery were older (61 vs. 59 years), underwent more frequently RN (48.6 vs. 16.7%) and presented larger tumor sizes (4.6 vs 3.4 cm), than patients with normal postoperative CysC level. Moreover, expectedly, patients with elevated postoperative CysC had a lower preoperative eGFR, and higher creatinine and CysC values, than patients with normal postoperative CysC. Additionally, patients with postoperative elevated CysC level more frequently exhibited diabetes (20 vs. 6%). These observations are not surprising, since they validate preoperative selection criteria for patients who are candidates for either PN or RN, as already observed in previous studies . Here esHowever, it is also particularly important that approximately 30% of all patients with elevated postoperative CysC were not classified as AKI, according to traditional criteria . TherefoSecond, we also made important observation regarding cystatin C as a predictor for kidney function impairment at follow-up. Specifically, we observed in multivariable logistic regression models that preoperative cystatin C was an independent predictor of kidney function impairment in follow-up. Conversely, postoperative cystatin C level was not found to be such a predictor after adjusting for the above-mentioned risk factors of age, surgical approach and diabetes among others. Consequently, it is possible that a postoperative increase in the CysC level (measured on the first postoperative day) only reflects a physiological reaction on the performed surgery and is measured too early to predict valid long-term kidney function estimates. Conversely, the preoperative CysC level may better reflect the cumulative overall lifestyle and comorbidity-related kidney function and its potential to be of high risk for post-surgical impairment. These assumptions are also emphasized by the observations by Alesawi et al., where already five minutes after unclamping the kidney vessels an increase of the CysC level was observed .2 in the follow-up. To the best of our knowledge, we are the first to observe this important relationship of CysC in a surgically treated cohort of RCC patients. In consequence, our data cannot be directly compared to previous studies. However, in a previous study investigating the effect of CysC in a donor nephrectomy cohort for living-donor kidney transplantation, similar observations have been also reported. Here, cystatin C concentration was also independently associated with the occurrence of CKD in follow-up [Moreover, our observations were further validated in linear regression models, where an increase of the preoperative CysC blood level of 0.1 mg/l was independently associated with an eGFR reduction of − 5.8 ml/min/1.73mollow-up . NonetheThird, we also made important observation regarding postoperative CysC level as a marker for kidney function impairment. Specifically, we observed that regardless of rising postoperative CysC level in the range of approximately 0.9–1.0 mg/l, the postoperative creatinine level remained at a plateau of 1.3 mg/dl. However, for postoperative CysC below 0.9 mg/l and above 1.0 mg/l a linear correlation between postoperative cystatin C and creatinine was observed. The same observations were further made in subgroup analyses of AKI patients and different age groups. These observations are particularly noteworthy, since in a postoperative setting kidney function impairment might not be detected in the range around 1.3 mg/dl creatinine value. In consequence, CysC might be a better marker for postoperative kidney function measurement. Moreover, a previous study by Roberts et al. showed that kidney function may be overestimated in older patients, when creatinine-based estimates are used . HoweverOur study has several limitations and needs to be interpreted in its retrospective, single-institution design. Some of our observations and findings may be limited by sample size, especially in subgroup analyses addressing elderly patients. Moreover, we relied on the MDRD formula for eGFR estimates, which may underestimate its values, relative to other formulas. Also, patients’ medication may have impacted eGFR estimates. Finally, only approximately the half of all the surgical treated patients of the current study participated in the follow-up, which may bias follow-up results and predictions. Follow-up was not obtained at standardized time points after RCC surgery. In consequence, all of the above findings need to be ideally further validated in RCC cohorts with bigger sample sizes.Taken together, our results suggest that baseline patient characteristics such as age, as well as the comorbidity profile  and the surgical approach identify patients with high risk of postoperative elevated CysC level and consecutive renal function impairment. Moreover, elevated CysC detected approximately 30% of patients with reduced kidney function, which may not have been identified through traditional creatinine-based AKI definitions. Second, we also observed that the preoperative CysC level was a predictor for long-term kidney function impairment and CKD prediction, while postoperative CysC level was not. However, the postoperative CysC level seems to be more sufficient to uncover early postoperative kidney function impairment than creatine values, especially in a creatinine range around 1.3 mg/dl.


Diabetic nephropathy (DN) is one of the most common microvascular complications in type 1 diabetes Mellitus (T1D). Urinary markers of renal damage or oxidative stress may signal early stages of DN. The association of these markers with blood pressure (BP) patterns and glycemic variability (GV) in children is yet to be explored.Subjects between the ages of 10 and 21 years with T1D were enrolled. Continuous glucose monitoring (CGM) and ambulatory blood pressure monitoring (ABPM) were performed on each subject. Urine samples were collected and analyzed for albumin, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) and pentosidine.The study included 21 subjects  with median age of 16.8 . Median HbA1C was 8.4 . While microalbuminuria was negative in all but one case (4.8%), urinary NGAL/Cr and pentosidine/Cr ratios were significantly elevated (P<0.001) in diabetic patients despite having normal microalbuminuria, and they correlated significantly with level of microalbumin/Cr . Using ABPM, none had hypertension, however, poor nocturnal systolic BP dipping was found in 48% of cases (95% CI: 28-68%). Urinary NGAL/Cr negatively correlated with nocturnal SBP dipping . Urine NGAL/Cr also showed a significant negative correlation with HbA1c measurements, mean blood glucose, and high blood glucose index . Median urinary NGAL/Cr and pentosidine/Cr ratios were higher in the high GV group but were not significantly different.This pilot study explores the role of ABPM and urinary markers of tubular health and oxidative stress in early detection of diabetic nephropathy. GV may play a role in the process of this diabetic complication. Diabetic nephropathy (DN) is one of the most frequent microvascular complications of diabetes mellitus, affecting 25 to 40% of patients with type 1 diabetes (T1D) . HyperteTraditionally, measurement of microalbuminuria  has been used in the clinical setting to screen for diabetic nephropathy. However, evidence suggests that renal pathological changes such as nephromegaly and glomerular basement membrane thickening develop soon after diabetes diagnosis and much earlier than microalbuminuria can be detected –9. SeverIn-vitro studies have demonstrated that glycemic excursions are more deleterious to human endothelial cells than sustained hyperglycemia , in the pathogenesis of diabetic kidney disease is well established , the rolglycemia . GV has glycemia , 21. Usiglycemia . Howeverglycemia . The speThe current study was designed to evaluate the use of NGAL and Pentosidine as urinary markers of DN in children with T1D and their relationship with ABPM patterns. Secondarily, we studied the association of glycemic variability measures as well as measures of glycemic control (HbA1c) with the levels of urinary markers of nephropathy.This is a cross-sectional study. Subjects between the ages of 10 and 21 years with T1D for more than 1 year were recruited from the Diabetes and Nephrology pediatric outpatient clinics. Given the known effects of puberty on both glycemic control and microvascular complications, the age range of cases was chosen to avoid prepubertal population. Patients were excluded if they had type 2 or monogenic diabetes, obesity (BMI ≥95th percentile or ≥30 kg/m2 for patient ≥ 18 years of age), secondary hypertension unrelated to diabetes, chronic kidney disease from another etiology, chronic inflammatory diseases, acute infection, or a history of malignancy. Consents and assents were obtained from all participates. Controls (n=10) were enrolled from Nephrology- Urology clinics.The study entailed a single visit for each case. Weight (kg), height (cm) and manual blood pressure in the seated position were obtained. Pubertal staging was assessed by a pediatric endocrinologist or a pediatric endocrinology fellow. Random urine samples were collected at the time of the visit. ABPM was performed for 24 hours and CGM for 3 to 7 days. Electronic medical records were reviewed for the most recent HbA1c (within 1 month of enrollment) and for lipid panel. Records were also reviewed for a recent serum Creatinine (Cr) value to estimate the renal function; most cases did not have a Cr value within one year of enrollment and thus was not included in the analysis. During the monitoring period, cases continued their usual diabetes care as recommended by their pediatric endocrinologist.For the controls, they only provided a urine sample and did not get ABPM or CGM.®. Waltham, MAThermoFisher Scientific). For analysis of the urine creatinine, the urine samples were first deproteinized using 10 kD spin columns . Enzymatic colorimetric assay was used for analysis of creatinine on the deproteinized sample . Urine NGAL  and pentosidine  were analyzed by ELISA. All urine markers were represented as ratios to urine creatinine to adjust for hydration status.All participants were asked to provide a first morning sample, but most samples were midday samples. After collection, urine samples  were centrifuged and the supernatant aliquoted and stored at -80°C for later analysis. Urine albumin was analyzed by ELISA (24 hour ABPM readings were obtained with an automatic oscillometric method device (Spacelab monitor) to all cases. The ABPM monitor was set for measurements at 20 minute intervals during the day and 30 minute intervals during the night. All cases were asked to record their bedtime and wake-up time while wearing the monitor and were not on blood pressure medications. Systolic and diastolic BP during daytime, nighttime and average BP were compared to the reference value based on sex and height (www.libreview.com), and raw data were extracted for analysis. Measures of glycemic variability (©University of Oxford 2010+). The primary measure of glycemic variability used in this study was the coefficient of variation . Sensors were placed on the upper arm for all cases and continued for 3-7 days. CGM readings were downloaded using the secure company website , version 3.6.3, and Graphpad Prism 7.Descriptive statistics are summarized as median (interquartile range [IQR]) or as frequency (percent). The Wilcoxon rank sum test was used for comparing continuous variables and Fisher’s exact test was used to test for categorical relationship within ABPM groups and GV groups. Spearman’s correlation was used for summarizing the relationship between continuous clinical variables. Scatterplots were used to examine the relationship between logarithmically-transformed urinary markers and their independent variables. Two-tailed The study enrolled 21 cases. Manual BP measurements were normal for all study cases. ABPM findings are outlined in p = 0.008 and r= 0.787, p <0.001, respectively; Although there was only one case had abnormal urine microalbumin/creatinine ratio (36 mcg/g), urine NGAL/Cr and pentosidine/Cr were significantly elevated compared to the controls  >36%, a cutoff proposed by . Twelve HbA1c, mean blood glucose, and HBGI correlated negatively with uNGAL/Cr but not with the other urine markers  Figure 2Diabetic nephropathy is a multifactorial, insidious disease process and represents a major complication for individuals with T1D. This study in a pediatric T1D cohort aims to explore the characteristics of BP profile and glucose variability and their correlation with urinary markers of glomerular and tubular damage as well as markers of oxidative stress. We found that subjects with T1D have high urinary NGAL/Cr (marker of tubular injury) and pentosidine/Cr (marker of oxidative stress) than controls, when microalbuminuria was negative. We also found a high prevalence of abnormal blood pressure dipping in our cohort, which is consistent with the results of other studies, including normotensive and normoalbuminuric pediatric T1D patients , 29. AbnOxidative stress is another prominent contributor to the pathophysiology of DN. Urinary pentosidine is a major component of advanced glycation end (AGEs) products resulting from tissue exposure to hyperglycemia causing oxidative stress. It has been shown to be elevated in children with T1D starting at disease onset. Pentosidine levels are higher in children with microalbuminuria compared to those with normal urine albumin excretion (UAE) and correlate with traditional measures of glycemic control (HbA1c) , 35. OurSince its discovery, HbA1c has been used as the primary measure of metabolic control in people with diabetes, representing the mean average glucose over the preceding 2-3 month period. Apart from that “average”, not a lot is known about how the frequency and/or amplitude of day-to-day and hour-to-hour blood glucose fluctuations might affect complications. Glycemic variability is recognized as a potential risk factor for diabetes complications. The increasing availability of glucose data from CGM systems provides the potential to understand the role of blood glucose excursions in relationship to diabetes comorbidities. In addition, recent advances in insulin pump technologies (Hybrid closed-loop systems) target the reduction of such variability and improve overall diabetes control. Interestingly in our cohort, the higher glycemic variability (higher CV) group tended to have lower HbA1c and would be viewed in “better” glycemic control using this traditional measure of metabolic control. This observation makes our finding of a negative correlation between uNGAL and HbA1C, HBGI, and mean blood glucose levels highly provocative and points towards a potential greater contribution of glycemic excursions in the pathophysiology of nephropathy than the exposure to significant but stable hyperglycemia. Further clarification of relationships between measures of GV and markers of DN as well as blood pressure patterns might be possible with a larger cohort.Our study had limitations, such as the small number of cases and the lack of long term follow up. However, this study was designed as a pilot in order to explore the feasibility of larger, prospective and multicenter studies looking into the development of DN and mitigation of its risk factors.In summary, diabetic nephropathy is a multifactorial complication that starts early after diagnosis and eventually has a large impact on patient’s quality of life and prognosis. Our study highlights the high prevalence of abnormal BP pattern as well as identifies early urinary biomarkers of renal injury before the development of microalbuminuria. Our results suggest that higher blood glucose values are not necessarily associated with higher markers of tubular injury, raising the question of whether glycemic variability rather than mean blood glucose has a stronger impact on development of DN. Future research is needed to identify the disease process earlier to allow for intensified intervention and new therapeutic targets.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by University at Buffalo/Oishei Children’s Hospital of Buffalo, and Nationwide Children’s Hospital. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The first draft of the manuscript was written by LeM and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.Study was funded by the fellow’s division funding at University at Buffalo, NY and the Research Institute, Nationwide Children’s Hospital, Columbus, OH, USA.Author LuM has received research grants from Novo Nordisk, Astrazeneca, Sanofi Aventis, and from Juvenile Diabetes Research Foundation.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.