Age-related Decline In Renal Function Research Articles

Sexual dimorphism in renal metabolism, hemodynamics and diseases

Age-related decline of renal function is faster in males than in age-matched females, manifesting in increased susceptibility to both chronic and acute kidney diseases among males. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments, where most reabsorption of water and salt happens, with a high energetic demand. Recent work suggests that male PTs undergo excessive oxidative stress to meet the high energetic demand, while female PTs exhibit an anti-oxidation state. However, it remains elusive how the observed molecular differences relate to sex disparities in renal physiology and pathophysiology. Glomerular filtration rate (GFR) is tightly regulated by tubuloglomerular feedback (TGF) within renal tubules to optimize ultrafiltration of plasma and reabsorption of essential molecules. Importantly, GFR shows a sustained oscillatory pattern over time in rodents, and loss of GFR oscillations is associated with cessation of reabsorption activities and with the occurrence of ischemia-reperfusion injuries in the kidney, as well as with systemic hypertension. To study the relationship between intracellular metabolic events and renal physiology, we developed a mathematical model of TGF linking metabolic regulation within PT cells to fluid handling and salt reabsorption in the nephron, using renal blood flow and intra-vital imaging data. Analysis of this model revealed that dynamical properties of the system differ between male and female kidneys, resulting in male kidneys being more prone to stress-induced damage, thus building towards an explanation for sexual dimorphism in renal aging and diseases. With this mechanistic model, our work also provides insight into how pharmacological interventions can be employed to confer renoprotection. The authors received no funding for this study. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Alterations in Acid-Base Effects on Insulin Signaling.

Insulin tightly regulates glucose levels within a narrow range through its action on muscle, adipose tissue and the liver. The activation of insulin receptors activates multiple intracellular pathways with different functions. Another tightly regulated complex system in the body is acid-base balance. Metabolic acidosis, defined as a blood pH < 7.35 and serum bicarbonate < 22 mmol/L, has clear pathophysiologic consequences including an effect on insulin action. With the ongoing intake of typical acid-producing Western diets and the age-related decline in renal function, there is an increase in acid levels within the range considered to be normal. This modest increase in acidosis is referred to as "acid stress" and it may have some pathophysiological consequences. In this article, we discuss the effects of acid stress on insulin actions in different tissues.

#5461 KIDNEY TUBULE POLYPLOIDIZATION DURING PHYSIOLOGIC AGEING IN MICE

Abstract Background and Aims The aged population is constantly increasing, and kidney-aging is a risk factor for both acute kidney injury (AKI) and chronic kidney disease (CKD). Accordingly, CKD is a major global health problem with an increasing prevalence in older population. Therefore, there is an urgent need to understand the age-related mechanisms underpinning CKD development during ageing. Recent findings contributed to clarify the cellular and molecular mechanisms underlying CKD development and progression, posing tubular cells (TC) at the center of this process. In this regard, we have demonstrated that polyploidization of TC promotes fibrosis, CKD development and its progression in the long run. Here, we aimed to investigate TC polyploidization during physiologic ageing in mice. Method To investigate TC polyploidization during ageing, we took advantage of inducible Pax8/FUCCI2aR mice. In these mice, FUCCI2aR reporter is expressed by all TC after doxycycline hyclate induction. Mice were sacrificed and analyzed at 2, 5, 11 and 20 months of age. By combining DNA content with detection of FUCCI2aR fluorescent proteins, FACS analysis shows diploid (2C), tetraploid (4C) and octaploid or greater (≥8C) TC. Single cell RNA-sequencing (scRNA-seq) analysis was performed on mouse kidneys at 2 and 20 months of age to dissect the transcriptomic profile of polyploid TC and interrogate putative altered signaling pathways. Renal function parameters were assessed at 2, 5, 11 and 20 months before sacrifice. Kidneys were analyzed for senescence and interstitial fibrosis at 2, 5, 11 and 20 months of age. Results Genetic and single-cell transcriptomic approaches in mice were used to investigate TC polyploidization during ageing. Pax8/FUCCI2aR mice showed a progressive increase of polyploid TC during ageing starting from 5 months of age. ScRNA-seq analysis on kidneys of mice at 2 and 20 months of age revealed that polyploid TC were characterized by polyploidy regulators, p21 expression, accumulation of DNA damage and by acquiring senescent/fibrotic markers, demonstrating that polyploid TC rather than diploid TC accumulate DNA damage and acquire a senescent/pro-fibrotic state during physiologic ageing in vivo. In accordance with the increase of polyploid TC, mice developed interstitial fibrosis, showed a marked senescent phenotype and an age-related decline of renal function starting from 5 months of age. Collectively, these results suggest TC polyploidization is a potential trigger for CKD development and progression during physiologic kidney ageing in mice. Conclusion This study demonstrates the increase of TC polyploidization, which is associated with a progressive fibrosis, senescence and CKD development during physiologic kidney ageing in mice.

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

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 (>70weeks 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 (>70weeks 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.

Elastin Insufficiency Accelerates Age‐Related Impairment of Renal Hemodynamics

Gradual loss of functional elastin fibers during aging leads to increased arterial stiffening and decreased compliance. Elastin insufficiency in mice and humans has been shown to be associated with arteriopathy and the development of hypertension. However, it is unclear whether elastin insufficiency in the resistance vasculature, as occurs in the renal vascular bed, contributes to age‐related decline in renal function. We hypothesized that elastin insufficiency exacerbates age‐related impairment of renal hemodynamics by accelerating functional and structural changes of the renal microvasculature. We assessed renal hemodynamics in anesthetized young (4‐6‐month‐old) and old (14–16‐month‐old) female wild‐type (WT) and elastin heterozygous (Eln+/‐) mice. Renal autoregulation was assessed by a stepwise increase in renal perfusion pressure (RPP) by simultaneously occluding the superior mesenteric and celiac arteries. Autonomic activity was clamped by continuous infusion of a cocktail containing vasoactive hormones. Baseline systolic blood pressure (SBP; 91.1±4.2 vs 90.1±3.1mmHg) and renal vascular resistance (RVR; 13.1±2.4 vs 10.0±1.5 mmHg/μL/min/g left kidney weight) were elevated in old versus young WT mice. Renal blood flow (RBF; 7.3±1.7 vs 9.8±1.4 μL/min/g left kidney weight), renal plasma flow (RPF; 5±1.2 vs 6±1mL/min/g left kidney weight) and glomerular filtration rate (GFR), all trended lower in old WT mice compared to young WT mice. However, in Eln+/‐mice, SBP was lower in old mice (78.2±9.4 vs 104.6±4.9mmHg), while RVR (13.5± 2.6 vs 14.4±1.1), RBF (6.7±1.2 vs 7.5±0.6), RPF (4.2±0.7 vs 4.5±0.3) and GFR were all similar between young and old mice. Increasing RPP caused a robust RVR and RPF response in young vs old WT mice. In contrast, the maximal changes in RBF (5.8±0.6 vs 5.5±1 μL/min/g left kidney weight), RVR (23.8±2.5 vs 21.8±7.0 mmHg/μL/min/g left kidney weight) were less robust and similar between young and old Eln+/‐mice. Autoregulatory index average values were closer to 0 in young and old Eln+/‐and old WT miceindicating greater impairment of renal autoregulation compared to young WT mice. Correlation analysis between pulse pressure and RBF showed that a high pulse pressure was more positively correlated to high RBF in young and old Eln+/‐mice as well as old WT mice. Together, our data demonstrate that elastin insufficiency accelerates age‐related impairment of renal hemodynamics and autoregulation likely mediated by functional and structural remodeling of the renal microvasculature.

Age-related Decline in Renal Function is Attenuated in Master Athletes

This study analyzed the kidney function and biomarkers of health in lifelong-trained sprinters and endurance runners, and compared them to untrained aged-matched and young controls. Sixty-two men (21-66 yr.) were recruited and allocated as master athletes from sprints (n=25), master athletes from endurance events (n=8), untrained middle-aged (n=14) and young controls (n=15). Participants underwent anamnesis, anthropometric measures and blood sampling for biochemical analyses of klotho, FGF23 and estimated glomerular filtration rate. Master sprinters presented better kidney function in relation to endurance athletes and their untrained peers (P<0.0001). A number of biochemical variables were observed that negatively (i. e., GDF-15, TGF-Beta, IL-18) or positively (i. e., klotho/FGF23 ratio and sestrin-2) correlated with eGFR. Sestrin-2 presented the strongest association with eGFR (r=0.5, P=0.03). Results also revealed that lifelong-trained individuals presented the highest probability of having better values for cystatin C and thus an estimated glomerular filtration rate that was 37-49% higher than untrained peers. Master sprinters presented better kidney function in relation to endurance athletes and middle-aged untrained peers. Sestrin-2 may play a role in exercise-induced kidney function protection.

Renal lipid accumulation, oxidative stress and uric acid handling in a rodent model of obesity and metabolic syndrome

Hyperuricemia is more prevalent among people with obesity and metabolic syndrome, and is associated with adverse clinical outcomes. We hypothesized that increased renal reabsorption of uric acid (UA) in obesity...

Effect of age on the severity of chronic lithium poisoning

Objectives: Severe lithium toxicity is commonly observed in older people. We aimed to determine the extent to which age is associated with increased severity of chronic lithium poisoning and of which a range of possible factors might explain the associations.Method: We did a retrospective review of patients aged ≥15 years old with serum lithium concentrations ≥1.3 mmol/L from three hospitals. Clinical details, treatment and outcomes were recorded. eGFR, creatinine and lithium clearance were calculated. The severity of lithium toxicity was graded into five categories (Amdisen score). ANOVA was used to quantify the association between age and severity. Spearman correlation coefficient was used to explore relationships between age and different factors expected to alter severity. Ordinal regression analysis was used to determine the interdependence of age and these factors and age on severity of lithium toxicity.Results: From 2008–2018, there were 242 patients with a median age of 56.5 years (IQR: 41–69). There were 156 females (64%). There was a statistically significant association between Amdisen severity scores and age (p = .0004). The median calculated eGFR was 65 mL/min/1.73 m2 (IQR: 41–91) with a corresponding estimated lithium clearance of 18 mL/min (IQR: 13.8–22.8). There was no correlation of age with initial serum lithium concentration (p = .76). There was a strong correlation between age and estimated lithium clearance (r = –0.72, 95% CI: –0.78 to –0.66, p < .001), lithium daily dose (r = –0.65, 95% CI: –0.72 to –0.57, p < .0001) and lithium concentration/dose (r = 0.62, 95% CI: 0.53–0.69, p < .0001). There was a weak correlation between age and infection (r = 0.18, 95% CI: 0.04–0.31, p = .009) and drug interactions (r = 0.25, 95% CI: 0.11–0.37, p = .0003). Ordinal regression indicated the independent predictors for severity of lithium toxicity were lithium concentration (p < .0001) and lithium clearance (p = .03) adjusted for age and dose.Conclusions: Despite lower lithium doses, older patients had more severe toxicity. Increased severity of lithium toxicity in the elderly is largely explainable by decreased lithium clearance from multiple factors such as age-related decline in renal function, drug interactions and infection.

Progression of Diabetic Kidney Disease in the Absence of Albuminuria.

It has been almost 30 years since the first studies were published that challenged the concept that progression of albuminuria was an obligatory predictor of renal function loss in diabetes (1,2). Despite this and until recently, diabetic kidney disease (DKD) has been conceptualized as a condition where there is linear progression from normo- to micro- to macroalbuminuria, with this last step heralding glomerular filtration rate (GFR) loss (3,4). However, there is now a growing body of evidence to suggest that many patients with type 1 diabetes or type 2 diabetes can follow a nonalbuminuric pathway to renal function loss, even after accounting for the use of renoprotective agents (4–8). The significance of nonalbuminuric DKD’s contribution to decline in GFR and progression to end-stage kidney disease (ESKD) still remains to be fully defined. Some studies have suggested an indolent course of renal function decline for normoalbuminuric versus albuminuric DKD. Rates of GFR decline in these studies for normoalbuminuric DKD are reported to be similar to those observed in the general population of people without diabetes and similar to the expected age-related decline in GFR of approximately 1 mL/min/1.73 m2 per year (9,10). A study published in this issue of Diabetes Care (11) suggests that while the presence of albuminuria influences the rate of GFR decline in both type 1 and type 2 diabetes, with macroalbuminuric participants having the greatest decline in estimated (e)GFR, those with normoalbuminuria still display rates of renal function loss above the expected age-related decline in renal function. Furthermore, the …

Chromatin changes trigger laminin genes dysregulation in aging kidneys.

Dysregulation of gene expression is a hallmark of aging. We examined epigenetic mechanisms that mediate aberrant expression of laminin genes in aging rat kidneys. In old animals, no alterations were found in the levels of abundant laminin mRNAs, whereas Lama3, b3, and c2 transcripts were increased compared to young animals. Lamc2 showed the strongest changes at the mRNA and protein levels. Lamc2 upregulation was transcriptional, as indicated by the elevated RNA polymerase II density at the gene. Furthermore, aging is associated with the loss of H3K27m3 and 5mC silencing modifications at the Lamc2 gene. Western blot analysis revealed no changes in cellular levels of H3K27m3 and cognate enzyme Ezh2 in old kidneys. Thus, the decrease in H3K27m3 at Lamc2 resulted from the re-distribution of this mark among genomic sites. Studies in kidney cells in vitro showed that reducing H3K27m3 density with Ezh2 inhibitor had no effect on Lamc2 expression, suggesting that this modification plays little role in gene upregulation in aging kidney. In contrast, treatment with DNA methylation inhibitor 2'-deoxy-5-azacytidine was sufficient to upregulate Lamc2 gene. We suggest that the loss of 5mC at silenced laminin genes drives their de-repression during aging, contributing to the age-related decline in renal function.

Association between the age-related decline in renal function and lumbar spine bone mineral density in healthy Chinese postmenopausal women.

The relationship between the decline of renal function and bone mineral density (BMD) in healthy populations is not well-researched. The aim of this study was to investigate the association between the age-related decline in renal function and lumbar spine BMD (LBMD) in a community-based cross-sectional study of 390 healthy postmenopausal women (mean age 62.97 ± 8.79 years) from Shenyang, China. Dual-energy x-ray absorptiometry was used to measure LBMD. Estimated glomerular filtration rate (eGFR) was calculated using a modified Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for Asians and the CKD-EPI serum creatinine-cystatin c equation. Pearson's correlation analysis and binary logistic regression were used to evaluate associations. The eGFR-ASIA and eGFR-Scys were positively correlated with LBMD (r = 0.120 and r = 0.108, respectively). After adjustments for numerous potential confounders, the odds ratio for participants with LBMD decline in eGFR-ASIA quartile 3 group and 4 group were 2.45 (95% confidence interval [CI] 1.12-5.38, P < 0.05) and 3.89 (95% CI 1.55-9.76, P < 0.01), respectively, with P = 0.003 for the trend in eGFR-ASIA compared with the lowest quartile 1 group of eGFR-ASIA, where the odds ratio of eGFR-Scys for the quartile of 3 and 4 groups were 2.47 (95% CI 1.09-5.62, P < 0.05) and 2.63 (95% CI 1.10-6.29, P < 0.05), respectively, with P = 0.016 for the trend in eGFR-Scys compared with the lowest quartile 1 group of eGFR-Scys. The renal function decline was independently associated with decreased LBMD, and it was possible that the age-related decline in kidney function was an independent risk factor for decreased LBMD in healthy Chinese postmenopausal women.

Abstract P137: Intrauterine Growth Restriction Programs a Greater Age-related Decline in Renal Function Associated With Increased Susceptibility to Chronic Renal Injury

Epidemiological studies indicate that low birth weight ( LBW ) is associated with a reduction in nephron number, hyperfiltration, hypertension, and accelerated loss of renal function. Yet, the mechanisms involved are not understood. Our laboratory uses a rodent model of LBW that results in hypertension but no change in glomerular filtration rate ( GFR ) in male intrauterine growth restricted ( IUGR ) offspring in early adulthood. The aim of this study was to test the hypothesis that IUGR programs a greater decline in GFR with aging and that it enhances susceptibility to a chronic renal insult. Male rats underwent sham ( S ) or uni-nephrectomy ( UNI-X ) with measurement of GFR two months post-surgery at 6 (young adult) and 14 months, or one month post-surgery at 19 months of age. GFR (mL/min/100 g body weight), determined by transcutaneous FITC-sinistrin clearance, was significantly decreased with age in IUGR S and IUGR UNI-X (** P &lt;0.001 and * P &lt;0.05 vs 6-month-old counterparts, respectively; Table). Although not significant, IUGR S had a higher mean GFR than Control S in young adulthood suggesting baseline hyperfiltration as a potential contributor to the greater age-related decline in GFR in IUGR offspring. In IUGR UNI-X at 19 months: GFR was significantly reduced ( † P&lt;0.05 vs IUGR S), urinary NGAL was increased (59872 vs 11620 ng/day in IUGR S; P&lt;0.05), and renal TNF-α and TGF-β mRNA expression were elevated (9- and 3-fold greater than both Control UNI-X and IUGR S; P&lt;0.05). Thus, these data indicate that IUGR programs a greater age-related decline in GFR and increased susceptibility to chronic renal injury in later life that is associated with an enhanced renal inflammatory response to injury.

A scheme based on ICD-10 diagnoses and drug prescriptions to stage chronic kidney disease severity in healthcare administrative records.

BackgroundInformation about renal function is important for drug safety studies using administrative health databases. However, serum creatinine values are seldom available in these registries. Our aim was to develop and test a simple scheme for stratification of renal function without access to laboratory test results.MethodsOur scheme uses registry data about diagnoses, contacts, dialysis and drug use. We validated the scheme in the Stockholm CREAtinine Measurements (SCREAM) project using information on approximately 1.1 million individuals residing in the Stockholm County who underwent calibrated creatinine testing during 2006–11, linked with data about health care contacts and filled drug prescriptions. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPI formula and used as the gold standard for validation of the scheme.ResultsWhen the scheme classified patients as having eGFR <30 mL/min/1.73 m2, it was correct in 93.5% of cases. The specificity of the scheme was close to 100% in all age groups. The sensitivity was poor, ranging from 68.2% in the youngest age quartile, down to 10.7% in the oldest age quartile. Age-related decline in renal function makes a large proportion of elderly patients fall into the chronic kidney disease (CKD) range without receiving CKD diagnoses, as this often is seen as part of normal ageing.ConclusionsIn the absence of renal function tests, our scheme may be of value for identifying patients with moderate and severe CKD on the basis of diagnostic and prescription data for use in studies of large healthcare databases.

Use of nonsteroidal anti-inflammatory drugs and renal failure in nursing home residents-results of the study "Inappropriate Medication in Patients with Renal Insufficiency in Nursing Homes".

Use of potentially inappropriate medications may result in increased morbidity, mortality and resource utilisation. Due to polypharmacy and age-related decline in renal function the elderly population is at particular risk. Therefore, the Beers Criteria include use of nonsteroidal anti-inflammatory drugs in chronic renal failure stage 4 and 5 as these drugs may worsen renal function. According to the summary of product characteristics, the nonsteroidal anti-inflammatory drugs ibuprofen and diclofenac are contraindicated in these patients. Objective was to assess the extent of nonsteroidal anti-inflammatory drug use in nursing homes with a focus on residents with severe renal failure. Multi-centre cross-sectional study in 21 German nursing homes. The study population comprised residents for whom at least one serum creatinine value and information about sex were available, so that creatinine clearance rate could be estimated. In all, 685 of 852 residents were included as they fulfilled the abovementioned criteria. Renal failure was severe (estimated creatinine clearance rate < 30ml/min) in 106 residents (15.5 %). Approximately one-fifth was treated with at least one nonsteroidal anti-inflammatory drug in both the total study population (20.3 %) and that with severe renal failure (20.8 %). With one exception, all residents prescribed nonsteroidal anti-inflammatory drugs with severe renal failure were treated with at least one nonsteroidal anti-inflammatory drug that was contraindicated due to the underlying renal function. Notwithstanding their classification as potentially inappropriate medications and underlying contraindications, use of nonsteroidal anti-inflammatory drugs is common among nursing home residents with severe renal failure.

Accelerated age-related decline in renal and vascular function in female rats following early-life growth restriction.

Many studies report sexual dimorphism in the fetal programming of adult disease. We hypothesized that there would be differences in the age-related decline in renal function between male and female intrauterine growth-restricted rats. Early-life growth restriction was induced in rat offspring by administering a low-protein diet (LPD; 8.7% casein) to dams during pregnancy and lactation. Control dams were fed a normal-protein diet (NPD; 20% casein). Mean arterial pressure (MAP) and renal structure and function were assessed in 32- and 100-wk-old offspring. Mesenteric artery function was examined at 100 wk using myography. At 3 days of age, body weight was ∼24% lower (P < 0.0001) in LPD offspring; this difference was still apparent at 32 wk but not at 100 wk of age. MAP was not different between the male NPD and LPD groups at either age. However, MAP was greater in LPD females compared with NPD females at 100 wk of age (∼10 mmHg; P < 0.001). Glomerular filtration rate declined with age in the NPD male, LPD male and LPD female offspring (∼45%, all P < 0.05), but not in NPD female offspring. Mesenteric arteries in the aged LPD females had reduced sensitivity to nitric oxide donors compared with their NPD counterparts, suggesting that vascular dysfunction may contribute to the increased risk of disease in aged females. In conclusion, females growth-restricted in early life were no longer protected from an age-related decline in renal and arterial function, and this was associated with increased arterial pressure without evidence of renal structural damage.

Fibroblast Growth Factor-23, Sclerostin, and Bone Microarchitecture in Patients With Osteoporotic Fractures of the Proximal Femur: A Cross-sectional Study

This cross-sectional observational cohort study was designed to simultaneously investigate bone microarchitecture and serum markers of bone metabolism in elderly osteoporotic patients experiencing a trochanteric or femoral neck fracture. Special emphasis was put on renal function, sclerostin and fibroblast growth factor-23 (FGF-23). Eighty-two patients (median age: 84 years; 49 trochanteric fractures) scheduled for emergency surgery due to an osteoporotic fracture participated. Bone specimens for ex vivo microcomputed X-ray tomography were sampled during surgery. Blood samples for laboratory workup were collected before surgery (t0) and 1 day afterward (t1). Fifty-eight patients consented to dual-energy X-ray absorptiometry scanning of the lumbar spine and/or contralateral femoral neck after recovery during the in-patient stay. Samples were grouped according to the site of fracture. Regression coefficients were controlled for age and/or estimated glomerular filtration rate (eGFR), if appropriate. Patients experiencing a femoral neck fracture presented with better preserved renal function (eGFR) and lower C-terminal fragment of fibroblast growth factor-23 (cFGF-23) concentrations compared to those with trochanteric fractures. By contrast, serum sclerostin was similar at both time points and did not differ between groups. Age-adjusted correlation analysis revealed negative associations between eGFR and cFGF-23 determined at t1 (R = −0.34; p < 0.05) as well as between eGFR and sclerostin levels at t0 (R = −0.45; p < 0.05) in patients with trochanteric and femoral neck fractures, respectively. Our study provides evidence that not only an age-related decline of renal function but also the type of skeletal injury may contribute to the circulating concentrations of cFGF-23.

PS14 Does CTA Surveillance after EVAR Accelerate Age-Related Decline in Renal Function?

PS14 Does CTA Surveillance after EVAR Accelerate Age-Related Decline in Renal Function?

Renal function in familial longevity: the Leiden Longevity Study

Studying renal function in subjects with a familial propensity for longevity may provide insight in (un)known mechanisms that determine the age-related decline in renal function of normal subjects. In the Leiden Longevity Study, middle-aged offspring of non-agenarian siblings and their partners as environmentally matched controls were included. Information was collected on lifestyle, medical history, medication use, and a non-fasting blood sample was drawn. Renal function (estimated glomerular filtration rate, eGFR) was assessed with the Chronic Kidney Disease epidemiology collaboration (CKD-EPI) formula. Linear mixed models were used to account for familial dependencies within the offspring and all analyses were stratified by sex. eGFR was similar between female offspring and female controls (0.44ml/min/1.73m2 (SE 0.72) difference, p=0.54, age-adjusted). Male offspring had a higher eGFR compared to male controls (1.78ml/min/1.73m2 (SE 0.78) difference, p=0.022, age-adjusted), and further adjustments for various characteristics did not materially change this difference. Among men with a history of hypertension, or myocardial infarction and/or stroke, offspring had a higher eGFR compared to controls (4.74ml/min/1.73m2 (SE 1.53) difference, p=0.002, age-adjusted, and 6.21ml/min/1.73m2 (SE 2.85) difference, p=0.033, age-adjusted, respectively). Middle-aged men, but not women, with a propensity for longevity have better renal function compared to environmentally matched controls, especially among those with a history of cardiovascular disease.

Experience with Vildagliptin in Patients ≥75 Years with Type 2 Diabetes and Moderate or Severe Renal Impairment

IntroductionPatients with type 2 diabetes (T2DM) are at increased risk for renal impairment (RI) and, in addition, there is an age-related decline in renal function. At the same time, T2DM treatment is more complex and treatment options are more limited in elderly patients as well as patients with RI, with the patient population ≥75 years with moderate or severe RI posing unique challenges, in particular, the high risk and more severe consequences of hypoglycemia. It was, therefore, of interest to assess the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor vildagliptin in patients with T2DM ≥75 years who also have moderate or severe RI.MethodsIn this sub-analysis of data derived from a previously described randomized, double-blind, parallel-group, 24-week study, 105 patients (50 randomized to vildagliptin 50 mg qd and 55 to placebo) ≥75 years (mean age ~78 years) with T2DM and moderate or severe RI (mean baseline estimated glomerular filtration rate ~35 ml/min/1.73 m2) were included.ResultsThe adjusted mean change in glycated hemoglobin (HbA1c) with vildagliptin was −1.0% from a baseline of 7.8% (between-group difference −0.8%; p < 0.001). This improvement in glycemic control was not associated with an increased risk of hypoglycemia; the rate of confirmed hypoglycemia was 0.49 events per patient-year with vildagliptin and 0.96 events per patient-year with placebo (not significant). Weight remained stable with vildagliptin treatment. Adverse events (AEs) (58.0% vs. 72.7%), serious AEs (14.0% vs. 16.4%), discontinuations due to AEs (4.0% vs. 9.1%) and deaths (0% vs. 5.5%) were reported at a comparable or lower frequency in patients receiving vildagliptin versus patients receiving placebo.ConclusionIn this uniquely fragile elderly population ≥75 years with T2DM and moderate or severe RI, vildagliptin was well tolerated and efficacious, with no increase in the rate of hypoglycemia compared to placebo despite the marked improvement in glycemic control.

Post-mortem toxicology in the elderly

Thearticle by Professor Byard on the ‘‘post-mortem toxicology in the elderly’’ provides timely advice on the substantial difficulties encountered in the interpretation of toxicology results in this population [1]. Aging in humans results in gradual deterioration of organ function; and particularly important when dealing with the pharmacokinetics of drugs are the heart, liver and kidney. These changes mainly affect protein binding, drug clearance and distribution; all of which may increase the sensitivity to drugs in the elderly, and in some require the use of smaller doses. However, these changes do not occur suddenly at age 65, but occur gradually, and importantly, vary significantly from one person to another. For example, in a study by Shi and Klotz one-third of elderly persons showed no decrease in renal function while in about twothirds of elderly subjects the age-related decline of renal function was associated with coexisting cardiovascular diseases and other risk factors [2]. Co-morbidity is a significant factor, if not for the effect of the diseases on drug clearance and associated clinical effects, but for the presence of a number of drugs that increase the risk of adverse effects [3]. As Prof Byard rightly points out, underlying disease will be higher in this age group, but it will be very difficult, if not impossible in most cases, to differentially separate out disease as a cause of death from drugs which have the potential (at least) to contribute to sudden death. One of the more common examples is the presence of morphine (or other opioids) in a person with terminal disease (e.g., cancer) when one or more critical organ is affected. Any concentration can be toxic depending on the established tolerance and the circumstances. While pharmacokinetic (and other) changes with age may have occurred the development of tolerance will be a far bigger factor. Unfortunately this cannot be assessed from a blood (or tissue) concentration. As with all deceased persons, young or old, the availability of relevant medical information such as dose information and vital signs such as blood pressure, pulse, breathing rate, oxygen tension are required to establish if any impending opioid toxicity was developing. This information may be available in a hospital death, but would rarely all be available in other settings. In the elderly a large inter-individual variability in drug disposition is particularly prominent [2] however this is not unique to the older population since most drugs show only a poor correlation with blood concentration and pharmacological effect. Hence it will always be difficult to ascertain what a particular concentration means, particularly if it has also changed in concentration after death [4]. These post-mortem changes are dynamic, with concentrations increasing and then decreasing as the post-mortem intervals increase, as typified by the antipsychotics [5]. While the elderly provide more difficulties in the interpretation of post-mortem toxicology results, the interpretation of drug concentrations in deceased persons provide great difficulties at all ages and as usual require a thorough appraisal of available information.