Sex Differences in Age-Related Loss of Kidney Function

Melsom, Toralf; Norvik, Jon Viljar; Enoksen, Inger Therese; Stefansson, Vidar Tor Nyborg; Mathisen, Ulla Dorte; Fuskevåg, Ole-Martin; Jenssen, Trond; Solbu, Marit Dahl; Eriksen, Bjørn Odvar

doi:10.1681/asn.2022030323

Cited by 56 publications

(44 citation statements)

References 56 publications

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“…In contrast, female gender was associated with lower SHAP values and decreased risks of developing ESRD. A previous study also found that renal function decline in women was slower compared to men among middle-aged and elderly individuals [51].…”

Section: Discussionmentioning

confidence: 81%

Prediction of the risk of developing end-stage renal diseases in newly diagnosed type 2 diabetes mellitus using artificial intelligence algorithms

Tsai

Lee

et al. 2023

BioData Mining

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Objectives Type 2 diabetes mellitus (T2DM) imposes a great burden on healthcare systems, and these patients experience higher long-term risks for developing end-stage renal disease (ESRD). Managing diabetic nephropathy becomes more challenging when kidney function starts declining. Therefore, developing predictive models for the risk of developing ESRD in newly diagnosed T2DM patients may be helpful in clinical settings. Methods We established machine learning models constructed from a subset of clinical features collected from 53,477 newly diagnosed T2DM patients from January 2008 to December 2018 and then selected the best model. The cohort was divided, with 70% and 30% of patients randomly assigned to the training and testing sets, respectively. Results The discriminative ability of our machine learning models, including logistic regression, extra tree classifier, random forest, gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and light gradient boosting machine were evaluated across the cohort. XGBoost yielded the highest area under the receiver operating characteristic curve (AUC) of 0.953, followed by extra tree and GBDT, with AUC values of 0.952 and 0.938 on the testing dataset. The SHapley Additive explanation summary plot in the XGBoost model illustrated that the top five important features included baseline serum creatinine, mean serum creatine within 1 year before the diagnosis of T2DM, high-sensitivity C-reactive protein, spot urine protein-to-creatinine ratio and female gender. Conclusions Because our machine learning prediction models were based on routinely collected clinical features, they can be used as risk assessment tools for developing ESRD. By identifying high-risk patients, intervention strategies may be provided at an early stage.

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Section: Discussionmentioning

confidence: 81%

Prediction of the risk of developing end-stage renal diseases in newly diagnosed type 2 diabetes mellitus using artificial intelligence algorithms

Tsai

Lee

et al. 2023

BioData Mining

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“…It has been known for 30 years that in experimental models, the male gender enhances the age-related decline in renal function ( Bolignano et al, 2014 ). In a recently published study on sex differences in the loss of kidney function, it was reported that in the general population without major chronic diseases or risk factors for CKD, women exhibited a slower mean GFR decline rate than did men ( Melsom et al, 2022 ). Considering the different genotypes, age-associated renal damage in the glomeruli and tubules increases significantly in male RAGE-KO animals, which is significant when compared with wild-type male mice and also with female RAGE-KO.…”

Section: Resultsmentioning

confidence: 99%

RAGE is a critical factor of sex-based differences in age-induced kidney damage

Bajwa

Luebbe

et al. 2023

Front. Physiol.

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Introduction: Advanced glycation end products (AGEs) are a heterogeneous group of molecules with potential pathophysiological effects on the kidneys. Fibrosis together with the accumulation of AGEs has been investigated for its contribution to age-related decline in renal function. AGEs mediate their effects in large parts through their interactions with the receptor for AGEs (RAGE). RAGE is a transmembrane protein that belongs to the immunoglobulin superfamily and has the ability to interact with multiple pro-inflammatory/pro-oxidative ligands. The role of RAGE in aging kidneys has not been fully characterized, especially for sex-based differences.Methods: Therefore, we analyzed constitutive RAGE knockout (KO) mice in an age- and sex-dependent manner. Paraffin-embedded kidney sections were used for histological analysis and protein expression of fibrosis and damage markers. RNA expression analysis from the kidney cortex was done by qPCR for AGE receptors, kidney damage, and early inflammation/fibrosis factors. FACS analysis was used for immune cell profiling of the kidneys.Results: Histological analysis revealed enhanced infiltration of immune cells (positive for B220) in aged (>70 weeks old) KO mice in both sexes. FACS analysis revealed a similar pattern of enhanced B-1a cells in aged KO mice. There was an age-based increase in pro-fibrotic and pro-inflammatory markers (IL-6, TNF, TGF-β1, and SNAIL1) in KO male mice that presumably contributed to renal fibrosis and renal damage (glomerular and tubular). In fact, in KO mice, there was an age-dependent increase in renal damage (assessed by NGAL and KIM1) that was accompanied by increased fibrosis (assessed by CTGF). This effect was more pronounced in male KO mice than in the female KO mice. In contrast to the KO animals, no significant increase in damage markers was detectable in wild-type animals at the age examined (>70 weeks old). Moreover, there is an age-based increase in AGEs and scavenger receptor MSR-A2 in the kidneys.Discussion: Our data suggest that the loss of the clearance receptor RAGE in male animals further accelerates age-dependent renal damage; this could be in part due to an increase in AGEs load during aging and the absence of protective female hormones. By contrast, in females, RAGE expression seems to play only a minor role when compared to tissue pathology.

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“…Crude incidence rates of adverse outcomes were generally higher among men aged 18-39 years, while adjusted hazard ratios for each outcome were generally higher among women. Previous epidemiological studies, including analyses of data from the Chronic Renal Insufficiency Cohort in the US54 and the Renal Iohexol Clearance Survey in northern Europe,55 reported higher baseline prevalence of chronic kidney disease among women. However, men were more likely to progress to end-stage kidney disease or die from any cause, suggesting a slower rate of eGFR decline in women than men.…”

Section: Discussionmentioning

confidence: 96%

Associations between modest reductions in kidney function and adverse outcomes in young adults: retrospective, population based cohort study

Hussain

Grubic

Akbari

et al. 2023

BMJ

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Objective To study age specific associations of modest reductions in estimated glomerular filtration rate (eGFR) with adverse outcomes. Design Retrospective, population based cohort study. Setting Linked healthcare administrative datasets in Ontario, Canada. Participants Adult residents (18-65 years) with at least one outpatient eGFR value (categorized in 10 unit increments from 50 mL/min/1.73m 2 to >120 mL/min/1.73m 2 ), with no history of kidney disease. Main outcome measures eGFRs and hazard ratios of composite adverse outcome (all cause mortality, any cardiovascular event, and kidney failure) stratified by age (18-39 years, 40-49 years, and 50-65 years), and relative to age specific eGFR referents (100-110 mL/min/1.73m 2 ) for ages 18-39 years, 90-100 for 40-49 years, 80-90 for 50-65 years). Results From 1 January 2008 to 31 March 2021, among 8 703 871 adults (mean age 41.3 (standard deviation 13.6) years; mean index eGFR 104.2 mL/min/1.73m 2 (standard deviation 16.1); median follow-up 9.2 years (interquartile range 5.7-11.4)), modestly reduced eGFR measurements specific to age were recorded in 18.0% of those aged 18-39, 18.8% in those aged 40-49, and 17.0% in those aged 50-65. In comparison with age specific referents, adverse outcomes were consistently higher by hazard ratio and incidence for ages 18-39 compared with older groups across all eGFR categories. For modest reductions (eGFR 70-80 mL/min/1.73m 2 ), the hazard ratio for ages 18-39 years was 1.42 (95% confidence interval 1.35 to 1.49), 4.39 per 1000 person years; for ages 40-49 years was 1.13 (1.10 to 1.16), 9.61 per 1000 person years; and for ages 50-65 years was 1.08 (1.07 to 1.09), 23.4 per 1000 person years. Results persisted for each individual outcome and in many sensitivity analyses. Conclusions Modest eGFR reductions were consistently associated with higher rates of adverse outcomes. Higher relative hazards were most prominent and occurred as early as eGFR <80 mL/min/1.73m 2 in younger adults, compared with older groups. These findings suggest a role for more frequent monitoring of kidney function in younger adults to identify individuals at risk to prevent chronic kidney disease and its complications.

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Sex Differences in Age-Related Loss of Kidney Function

Cited by 56 publications

References 56 publications

Prediction of the risk of developing end-stage renal diseases in newly diagnosed type 2 diabetes mellitus using artificial intelligence algorithms

Prediction of the risk of developing end-stage renal diseases in newly diagnosed type 2 diabetes mellitus using artificial intelligence algorithms

RAGE is a critical factor of sex-based differences in age-induced kidney damage

Associations between modest reductions in kidney function and adverse outcomes in young adults: retrospective, population based cohort study

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