Higher eGFR Research Articles

The prognostic role of activation of the complement pathways in the progression of advanced IgA nephropathy to end-stage renal disease

IntroductionThe role of complement system in late stage of IgA nephropathy (IgAN) remains unknown. We therefore investigated the effects of complement system on worsening kidney function in advanced (stage 4 CKD) IgAN.MethodsRenal specimens of 69 IgAN patients who underwent renal biopsy during stage 4 CKD between 2010 and 2021, were stained using immunofluorescence (IF) and immunohistochemistry (IHC) for glomerular complement components. The primary outcome was progression to end-stage renal disease (ESRD). Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses.ResultsDuring a median follow-up of 18.0 months, 26 (37.7%) patients progressed to ESRD and none died. C1q and C3 deposition were detected in 12 and 66 patients, respectively. Higher eGFR [hazards ratio (HR), 0.852, 95% confidence interval (CI), 0.756–0.959; P = 0.008], higher C3 intensity (HR, 2.955, 95%CI, 1.063–8.220; P = 0.038) and T1-2 score (HR, 2.576, 95%CI, 1.205–5.576, P = 0.015) were predictive of time to ESRD in CKD 4 stage IgAN. Significant expressions of C1q (P = 0.005), C4d (P < 0.001), factor B (P < 0.001), C3 (P = 0.042) and C5b-9 (P = 0.004) were identified in ESRD group than in non-ESRD group by IHC, while MBL expression was low. Although they were not associated with baseline 24 h-UP, higher factor B and C1q expressions were both correlated with a lower baseline eGFR (P < 0.001 and = 0.04, respectively) and the deterioration of kidney function during follow-up (P = 0.046 and 0.015, respectively).ConclusionComplement deposition in IgAN patients with stage 4 CKD portends a faster deterioration of kidney function. Activation of classical and alternative complement pathways plays a major role in this stage.

Short versus conventional DAPT in patients undergoing PCI with ultra-thin DES by renal function: an analysis from the HOST-IDEA trial

Abstract Background Patients with impaired renal function are known to have an elevated risk of both ischemic and bleeding events following percutaneous coronary intervention (PCI). However, there is insufficient data available on the optimal duration of dual antiplatelet therapy (DAPT), especially with the latest generation of drug-eluting stent (DES)s. Objective We investigated to assess the efficacy and safety of abbreviated duration of DAPT in patients undergoing PCI with 3rd generation DESs based on their renal function. Methods In this prespecified subgroup analysis of the HOST-IDEA trial, a total of randomized 1997 patients with available baseline estimated glomerular filtration rate (eGFR) were categorized into three groups: high eGFR (&amp;gt;90 mL/min), intermediate eGFR (60 to 90 mL/min), and low eGFR (&amp;lt;60 mL/min). The primary outcome assessed during the 1-year follow-up period was net adverse clinical events (NACE). Ischemic and bleeding endpoints were also evaluated. Results Compared to intermediate or high eGFR groups, the low eGFR group resulted in significantly worse outcomes (P &amp;lt; 0.001). 3-6 month DAPT was associated with similar risk of NACE across all eGFR groups (High eGFR: HR: 0.91; 95% CI: 0.38-2.20; Intermediate eGFR: HR: 0.76; CI: 0.33-1.73; Low eGFR: HR: 0.99; CI: 0.51-1.92). There was also no significant difference in target lesion failure (HR: 0.95; CI: 0.32-2.83, HR: 0.77; CI: 0.29-2.06, and HR: 1.14; CI: 0.47-2.75) and major bleeding (HR: 0.84; CI: 0.19-3.74, HR: 0.59 CI: 0.14-2.48; and HR 0.83 CI: 0.34-2.05) among all stratified eGFR groups. This effect was also consistent in patients of end stage of renal disease (eGFR &amp;lt;15 mL/min). Conclusions In patients undergoing PCI with third generation DESs, short DAPT was comparable to conventional DAPT regardless of their baseline renal function.

Evaluation of the Accuracy of Point-of-Care Urine Chloride Measured via Strip Test in Patients with Heart Failure

Background: In clinical practice, patient self-monitoring is crucial in achieving therapeutic goals in various diseases. In heart failure (HF), it is particularly important due to the increasing role of urine composition. Therefore, we proposed this study to assess the accuracy of urine chloride (uCl−) assessment via strip test in relation to chloride and sodium (uNa+) measurements in a gold-standard laboratory method. Methods: Urine samples were collected before administering morning medications. Afterwards, they were analyzed concurrently using the strip test and gold-standard laboratory method. Results: The study cohort comprised 66 patients (82% male, mean age 68 ± 12 years), of whom 65% were diagnosed with HF and 35% without HF. Across the entire cohort, a strong correlation was observed between uCl− measured by both methods (r = 0.85; p &lt; 0.001). However, the strip test was found to underestimate uCl− relative to the laboratory measurements (mean difference of 18 mmol/L). Furthermore, strong correlations were observed between the methods among patients with HF and without HF (r = 0.88 vs. r = 0.71, respectively; p &lt; 0.001 for both), where they presented similar relationship patterns. Interestingly, in patients with a low glomerular filtration rate (eGFR ≤ 60 mL/min/1.73 m2), the correlation between both methods was greater compared to those with high eGFR (&gt;60 mL/min/1.73 m2) (r = 0.94 vs. r = 0.76, respectively; p &lt; 0.001 for both). The relationship between uCl− from the strip test and uNa+ from the laboratory measurement was weaker than for uCl−, but it was significant. Conclusions: These findings suggest that point-of-care strip tests for assessing urinary chloride demonstrate high accuracy and potential utility, particularly in patients with reduced eGFR.

Association between estimated glomerular filtration rate and prognosis in patients with cardiovascular disease with and without sarcopenia

Abstract Background/Introduction A low estimated glomerular filtration rate (eGFR) has been identified as a poor prognostic factor in patients with cardiovascular diseases (CVD). Since serum creatinine, which defines eGFR, is a metabolite of skeletal muscle, low skeletal muscle mass can result in reduced creatinine production and potentially overestimate renal function. This raises concerns about the reliability of eGFR as a prognostic indicator in patients with both CVD and sarcopenia. The impact of this relationship, however, remains uncertain. Purpose This study aimed to explore the association between eGFR and prognosis in patients with CVD, both with and without sarcopenia. Methods We included 2,444 CVD patients (mean age 69.0 ± 13.7 years) who had assessments of eGFR and sarcopenia at discharge. Sarcopenia was diagnosed according to the 2019 Asian Sarcopenia Working Group Diagnostic Criteria. Patients were categorized into sarcopenia and non-sarcopenia groups, each further divided into high eGFR (eGFR ≥60 mL/min/1.73 m²) and low eGFR (eGFR &amp;lt;60 mL/min/1.73 m²) subgroups. Kaplan-Meier curves, log-rank tests, and multivariate Cox regression analyses were employed to compare prognoses between these groups, adjusting for age, sex, BMI, left ventricular ejection fraction (LVEF), history of myocardial infarction (MI), acute coronary syndrome (ACS), heart failure (HF), hypertension (HT), dyslipidaemia (DL), diabetes mellitus (DM), and smoking history. The primary endpoint was a composite of all-cause mortality and rehospitalization. Results Median follow-up was 1.11 (interquartile range [IQR], 0.43–2.32) years for the non-sarcopenia group and 0.94 (IQR, 0.30–2.15) years for the sarcopenia group. Event rates were 24.2% in the non-sarcopenia group and 30.8% in the sarcopenia group. Both Kaplan-Meier and log-rank tests indicated that a low eGFR, regardless of sarcopenia status, was associated with a higher incidence of composite events (p &amp;lt; 0.001). Multivariate Cox regression analysis revealed a significant association between low eGFR and increased risk of composite events in both the non-sarcopenia [hazard ratio (HR): 1.55, 95% confidence interval (CI): 1.44–1.67; p &amp;lt; 0.001] and sarcopenia groups [HR: 1.36, 95% CI: 1.25–1.48; p &amp;lt; 0.001]. Conclusion Low eGFR is associated with poor prognosis in patients with CVD, irrespective of sarcopenia status.

Menopausal status and clinical outcomes in women with heart failure with reduced ejection fraction: the GALACTIC-HF trial

Abstract Introduction Mechanisms driving disease progression and potential responsiveness to investigational therapies may theoretically differ among women with heart failure (HF) based on menopausal status. However, few data are available describing the clinical course of premenopausal and postmenopausal women with HF. We investigated differences in baseline characteristics, clinical outcomes, and response to omecamtiv mecarbil in premenopausal and postmenopausal women participants of the GALACTIC-HF trial. Methods The GALACTIC-HF trial randomized patients with symptomatic HFrEF with LVEF of 35% or less to omecamtiv mecarbil or placebo. Menopausal status at randomization was collected. When menopausal status was unknown/unreported, menopausal status was inferred based on the expected distribution of age at menopause in the general population. The risk of the primary endpoint, worsening HF event or cardiovascular death, was compared among women by menopausal status using Cox regression models adjusted for clinical covariates, including age and baseline EF. Treatment effect heterogeneity was evaluated by menopausal status. Results Of the 8,232 patients enrolled, 1,749 (21.2%) were women. Menopausal status was available at baseline in 1,483 (84.8%). One hundred women reported being potentially childbearing (pre-menopausal) and 1,383 women reported being post-menopausal. Among the 266 patients that had unknown menopausal status, those younger than 47 years were additionally classified as pre-menopausal and those older than 56 years as post-menopausal based on estimated 10th /90th percentiles extrapolated from the general population. Compared to post-menopausal women, pre-menopausal women were younger, had higher eGFR, and had fewer comorbidities. Premenopausal women also had slightly higher BMI and lower LVEF, but lower NTproBNP and troponin at baseline compared to postmenopausal women. Premenopausal and postmenopausal women had similarly high burden of symptoms as assessed by the KCCQ-total symptoms score (median 63.5 vs. 64.6; P=0.79). During a median follow-up of 22 months, premenopausal and postmenopausal women experienced similar rates of primary and secondary outcomes (Table 1). Omecamtiv mecarbil was beneficial across the entire female cohort with no effect modification by menopausal status (Pinteraction=0.39). Sensitivity analysis excluding all women with unknown menopausal status yielded similar results. Conclusions In this high-risk HFrEF cohort, premenopausal women experienced similar rates of adverse cardiovascular outcomes as post-menopausal women despite younger age, fewer comorbidities, and lower cardiac biomarkers. Additional research is necessary to understand how risk factors unique to females might influence outcomes in those with heart failure. The benefit of omecamtiv mecarbil on reducing cardiovascular risk was consistent regardless of menopausal status.Primary/secondary outcomes by menopausal

Prognostic impact of switching to the 2021 chronic kidney disease epidemiology collaboration creatinine-based equation in Caucasian patients with type 2 diabetes: the Renal Insufficiency and Cardiovascular events (RIACE) Italian Multicenter Study

BackgroundA Chronic Kidney Disease (CKD) Epidemiology Collaboration (EPI) formula not including a Black race coefficient has been recently developed and is now recommended in the US. The new (2021) equation was shown to yield higher estimated glomerular filtration rate (eGFR) values than the old (2009) one in a non-Black general population sample, thus reclassifying a significant number of individuals to a better eGFR category. However, reclassified individuals were previously shown to have a lower risk of progression to end-stage kidney disease, but higher adjusted risks for all-cause death and morbidity and mortality from cardiovascular disease than those not reclassified. This study evaluated the prognostic impact of switching from the 2009 to the 2021 CKD-EPI equation in non-Black individuals with type 2 diabetes.MethodsThe Renal Insufficiency And Cardiovascular Events (RIACE) was a prospective cohort study enrolling 15,773 Caucasian patients in 19 Italian centers in 2006–2008. Cardiometabolic risk profile, treatments, complications, and comorbidities were assessed at baseline and eGFR was calculated with the two equations. Vital status was retrieved on 31 October 2015 for 15,656 participants (99.3%).ResultsWith the 2021 equation, the eGFR value increased in all patients, except for 293 individuals with a 2009 eGFR ≥ 105 ml·min− 1·1.73 m− 2. The median difference was 4.10 ml·min− 1·1.73 m− 2 and was higher in males, older individuals and those in the G2 category. Reclassification decreased the percentage of patients with reduced eGFR from 17.28 to 13.96% and with any CKD from 36.23 to 34.03%. Reclassified individuals had better cardiometabolic risk profile and lower prevalence of complications and use of medications than non-reclassified individuals. Risk of death versus the 2009 G1 category was lower for reclassified than non-reclassified participants in all eGFR categories and, particularly, in each 2009 eGFR category, though difference was significant only in the G4-G5 category. The Receiver Operator Characteristic curves were statistically, but not clinically different with the two equations.ConclusionChanging from the 2009 to the 2021 CKD-EPI equation results in higher eGFR and lower CKD prevalence, with a lower risk of death in reclassified patients with an eGFR < 30 ml·min− 1·1.73 m− 2, but virtually no impact on mortality prediction.Trial registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

Chronic kidney disease in Kuwait: a multicenter study of two cohorts with different levels of access to public healthcare

IntroductionKuwait has a large expatriate community who experience both restricted access to public health services and lower income than Kuwaiti citizens. Given these conditions, we examined differences in characteristics and management of chronic kidney disease (CKD) between Kuwaitis and expatriates.MethodsClinical and laboratory data for adult CKD Stages 3–5 not on dialysis (CKD 3–5 ND) patients with native kidneys attending nephrology clinics in all Ministry of Health hospitals collected from January 1, 2022, to December 31, 2022. Cohort was then divided into Kuwaiti patients and expatriates patients for comparison.ResultsWe collected data from 2,610 patients (eGFR: 30.8 ml/min/1.73m2; age: 62.6 years; males: 56.7%; Kuwaitis: 62.1%). Kuwaitis were older (63.94 vs. 60.3 years, p < 0.001), with lower mean eGFR (30.4 vs. 31.5 ml/min/1.73m2, p = 0.052) than non-Kuwaitis, however, Kuwaitis had lower mean blood pressure (137.2/76.5 vs. 139.1/78.9 mmHg, p = 0.006), lower HbA1c in diabetics (7.59 vs. 7.82%, p = 0.010), and better lipid profile despite higher body mass indexes (29.6 vs. 28.9 kg/m2, p = 0.002). Both groups had high diabetes mellitus and hypertension rates. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were used in only 22.6% and renin-angiotensin-aldosterone system inhibitors (RAASi) in only 46.2%.ConclusionCKD 3–5 ND is caused by diabetes mellitus in 56.6% of cases, and the majority have hypertension. In our study, non-Kuwaitis had higher eGFR; however, restricted public healthcare access and lower income can lead to an unhealthy diet and suboptimal care, which may cause higher blood pressure, higher HbA1c, and a higher dyslipidemia rate. RAASi and SGLT2i utilization must increase to combat CKD, and antihypertensive selection must improve.

Renal Function-Stratified Comparison of Short- and Long-Term Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention With Third-Generation Drug-Eluting Stents - Post Hoc Analysis From the HOST-IDEA Randomized Clinical Trial.

The optimal duration of dual antiplatelet therapy (DAPT) in patients with chronic kidney disease undergoing percutaneous coronary intervention (PCI), especially with third-generation drug-eluting stents (DES), remains unknown. We conducted a prespecified post hoc analysis of the HOST-IDEA trial, randomizing patients undergoing PCI with third-generation DES to 3- to 6-month or 12-month DAPT. In all, 1,997 patients were grouped by their estimated glomerular filtration rate (eGFR): high (>90 mL/min/1.73 m2), intermediate (60-90 mL/min/1.73 m2), and low (<60 mL/min/1.73 m2). The primary outcome was net adverse clinical events (NACE), a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, or major bleeding (Bleeding Academic Research Consortium Type 3 or 5) at 12 months. Secondary outcomes were target lesion failure (TLF) and major bleeding. The low eGFR group had the highest rates of NACE, TLF, and major bleeding compared with the other 2 groups (P<0.001). Rates of NACE were similar in the 3- to 6-month and 12-month DAPT in the high (2.9% vs. 3.2%; P=0.84), intermediate (2.1% vs. 2.8%, P=0.51), and low (8.9% vs. 9.1%; hazard ratio 0.99; P=0.97; Pinteraction=0.88) eGFR groups. TLF and major bleeding events showed similar trends. In patients undergoing PCI with third-generation DES, 3- to 6-month DAPT was comparable to 12-month DAPT for clinical outcomes regardless of renal function.

7787 Primary Aldosteronism Medical Treatment Outcomes (PAMO): An International Consensus on Outcome Assessment Criteria and Multicentre Study

Abstract Disclosure: J. Yang: None. J. Burrello: None. J. Goi: None. T.A. Williams: None. W.F. Young: Consulting Fee; Self; Arena Pharmaceuticals, Inc.. Other; Self; Crinetics Pharmaceuticals. P.J. Fuller: None. P. Investigators: None. Primary aldosteronism (PA) is the most common endocrine cause of hypertension. Mineralocorticoid receptor antagonists, at adequate doses, lower blood pressure and cardiovascular risk in patients with PA. However, there is a lack of a standardized approach to medical therapy and subsequent outcomes assessment. We aimed to: 1) establish criteria for assessing outcomes of targeted medical treatment of PA, and 2) evaluate outcomes using these criteria across an international cohort. A panel of 31 PA experts from 31 centres across four continents used the Delphi method, including three rounds of online questionnaires, to reach consensus. Clinical data were then collected from consecutive patients with PA who started targeted medical treatment between 2016 and 2021 at the participating centres. Consensus was reached for six outcomes, including complete, partial, or absent biochemical response, and complete, partial, or absent clinical response. “Complete biochemical response” was defined as “correction of hypokalemia without potassium supplementation, and normalization of plasma renin activity or concentration”; while “absent biochemical response” was defined as “persistent hypokalemia and/or persistently suppressed or low plasma renin activity or concentration without change from baseline”. “Complete clinical response” was defined as “normal blood pressure without additional antihypertensive medications”; while “absent clinical response” was defined as “the same or increased blood pressure compared to before targeted treatment with same or more antihypertensive medications, not counting targeted therapy”. Of 1483 patients (mean age 52y, 48% female) from 28 centers, 232 (16%) had a complete clinical response, and 719 (49%) had a complete biochemical response at the most recent follow-up (median 29 months after treatment initiation). Compared to those with partial or absent clinical response, patients with complete clinical response had a significantly higher proportion of women and lower proportion with diabetes, stroke or left ventricular hypertrophy. They also had a significantly shorter duration of hypertension, lower BMI, higher eGFR and lower defined daily dose of antihypertensives at baseline. In contrast, these differences were not observed in those with a complete, partial or absent biochemical response. The defined daily dose of targeted therapy did not differ across the various response categories. In conclusion, we have established an international expert consensus for standardized criteria to evaluate the response to targeted medical treatment of PA, facilitate comparisons of outcome data and guide clinicians who manage PA. In a retrospective international cohort, less than half of medically-treated patients reached the established biochemical treatment targets. Further work is needed to increase the rate of complete response. Presentation: 6/3/2024

Renal outcomes with renin-angiotensin system blockers after unilateral nephrectomy

IntroductionDespite the benefits of renin-angiotensin system (RAS) blockers, their immediate use after nephrectomy has been limited because of concerns about impaired renal adaptation. We aimed to evaluate the effect of RAS blockers immediately following unilateral nephrectomy on renal adaptation. MethodsThis single-center retrospective cohort study included 580 patients who underwent elective unilateral nephrectomy between 2010 and 2020 and had pre-existing hypertension with antihypertensive medications. Patients were divided into groups according to the post-nephrectomy RAS blocker use. The primary outcome was renal adaptation defined as post-nephrectomy estimated glomerular filtration rate (eGFR) / pre-nephrectomy eGFR × 100 at 1 month after surgery. Secondary outcomes included hyperkalemia during the first year and mortality or end-stage kidney disease within three years. ResultsThe mean age was 65.2 years, 406 (70%) were male, and 308 (53.1%) received RAS blockers after nephrectomy. The RAS blocker group was younger (63.8 vs 66.8 years) and had a higher eGFR (79.4 vs 75.5 ml/min/1.73 m2) than the control group. There were no differences between the groups in renal adaptation at one month (67.1% vs. 66.8%, P = 0.711) or in the incidence of hyperkalemia until one year postoperatively. The RAS blocker use was associated with better dialysis-free survival [Adjusted hazard ratio of multivariable Cox-regression model, 0.531; 95% confidence interval, 0.329-0.857; P = 0.010]. ConclusionThe immediate use of RAS blockers after unilateral nephrectomy did not deteriorate renal adaptation or increase hyperkalemia. Furthermore, the RAS blockers was associated with improved prognosis in terms of end-stage kidney disease and mortality.

P3.03I.13 High EGFR Expression Confers Acquired Resistance to Adagrasib - In Vitro Study Using KRASg12C Mutated Lung Cancer Cells

P3.03I.13 High EGFR Expression Confers Acquired Resistance to Adagrasib - In Vitro Study Using KRASg12C Mutated Lung Cancer Cells

Umbilical cord mesenchymal stem cell exosomes combined with collagen sponges contribute to neovascularization and wound healing in exposed bone wounds

BackgroundUnmanaged bone exposed wounds that don't receive proper treatment can potentially lead to additional complications. Human umbilical cord mesenchymal stem cell (HUC-MSC)-derived exosomes (EXO) have a significant effect in promoting wound healing. MethodsHUC-MSCs and HUC-MSC-derived EXOs were added to a CS to prepare HUC-MSC + CS and HUC-MSC EXO + CS complexes, respectively. The CS and prepared CS complexes were observed by scanning electron microscopy and applied to bone-exposed large-area skin wounds in rabbits. Then, wound tissues were collected and analyzed. Hematoxylin and eosin and Masson staining were performed to observe histopathological features in wound tissues. Immunohistochemistry and immunofluorescence were performed to observe neovascularization and neural fiber density. The expressions of growth factors (platelet-derived growth factor receptor β [PDGFR-β], vascular endothelial growth factor receptor 2 [VEGFR2], and epidermal growth factor receptor [EGFR]) in wound tissues were detected by western blotting. ResultsOn healing days 3, 7, 10, 14, and 16, compared with the control group, wounds in the CS group healed well. Coverage by collagen fiber was evident, angiogenic factor CD34 expression and neural fiber density increased, along with high EGFR, PDGFR-β, and VEGFR2 levels. Compared with the CS group, the HUC-MSC + CS and HUC-MSC EXO + CS groups had a better neovascularization and wound healing. In particular, the HUC-MSC EXO + CS group showed abundant collagen. ConclusionIn the treatment of bone-exposed wounds, HUC-MSCs and HUC-MSC-derived EXOs loaded in CS were more efficient than CS alone, contributing to neovascularization in wounds.

Higher fasting glucose is associated with poorer survival in non-diabetic subjects having ischemia with non-obstructive coronary arteries

Subjects who have ischemia with non-obstructive coronary arteries (INOCA) experience angina pectoris with evidence of myocardial ischemia but without coronary stenosis. Few studies have investigated factors associated with its survival, especially insulin resistance. In this study, subjects with angina pectoris, without known diabetes mellites (DM), and with non-invasive tests showing myocardial ischemia were admitted for coronary angiography (CAG). Those whose CAG did not reveal stenosis and agreed to receive an oral glucose tolerance test (OGTT) 2 weeks after hospital discharge were enrolled for analysis. All-cause mortality was recorded, which served as the outcome of the study. A total of 587 subjects with INOCA, without known DM, and with OGTT data were analyzed. After OGTT and HbA1c tests, 86 subjects (14.7%) were newly diagnosed with DM and 59.8% had pre-DM. The median duration of follow-up was 7.03 years. Thirty-nine subjects died during the follow-up period. The incidence rate of mortality was 9.9 /1000 person-year. Those who died had a higher fasting glucose (101 ± 17 vs. 94 ± 13 mg/dl, p = 0.003) but a lower estimated glomerular filtration rate (eGFR) (54 ± 22 vs. 87 ± 30 ml/min, p < 0.001). In the Cox survival analysis, a higher fasting glucose (hazard ratio 1.053, p = 0.007) was associated with worse mortality for INOCA without DM (N = 501). On the contrary, a higher eGFR (hazard ratio 0.967, p = 0.012) was protective of better survival for non-diabetic INOCA (N = 501). In conclusion, for non-diabetic INOCA, higher fasting glucose was associated with worse mortality and higher eGFR was protective for better survival.

Type 1 Diabetes as a Risk Factor for Chronic Kidney Diseases and Renal Failure in Adolescents: A Systematic Review

Objectives: The purpose of this systematic review is to investigate the risk factors and association of the incidence of diabetic kidney disease in adolescents with type 1 diabetes (T1D) patients. Methods: We conducted a thorough search of PubMed, SCOPUS, Web of Science, Google Scholar, and Science Direct to find pertinent literature. Rayyan QRCI was utilized during the entire process. Results: We included eight studies with a total of 11,468 T2D patients and 4966 (43.3%) were females. The available literature on the association between T1D and CKD among adolescents lacks epidemiological data on the prevalence and sex differences. Higher eGFR, diabetes duration, low C-peptide levels, glycemic control, age at a clinic visit, advanced glycation end products, and BMI were reported as significant risk factors for developing renal impairment in adolescents with T1D. Conclusion: The results of this research point to the necessity of a standardized screening procedure for the early identification and appropriate treatment of DKD. In order to provide an accurate assessment of this illness, methodological approaches should be taken into account. Furthermore, it's imperative to educate teenagers with T1D about the possibility of DKD, which can result in renal failure and even death. Future improvements in the quality of life for teenagers with T1D are anticipated as a result of this awareness.

Prognosis for Type 1 Diabetes with Diabetic Nephropathy between 2000 and 2020 - Changes in Kidney Function Decline Over Time and Development of Cardiovascular Disease, Kidney Failure, and Mortality

IntroductionIndividuals with type 1 diabetes (T1D) and diabetic nephropathy (DN) experience progressive kidney function decline and high risk of cardiovascular disease (CVD) and mortality. This study explored changes in kidney function decline in new-onset DN between 2000-2020 and provided an updated prognosis for risk of kidney failure, CVD, and mortality. MethodsRegister-based cohort study in T1D with new-onset DN (severely increased albuminuria) between 2000-2020 at Steno Diabetes Center Copenhagen, Denmark. Data was derived from electronic health records and national registers. Kidney function development was expressed as trajectories of estimated glomerular filtration rate (eGFR) and measured GFR (mGFR) using mixed-effects models. The prognosis was presented in probabilities of developing complications, stratified by sex, prior CVD, and risk factor control by using simulations based on Poisson regression analysis. ResultsThe cohort comprised 591 individuals with median (IQR) age at DN onset of 53 (39-66) years and 57% were male. In 283 participants, mGFR were available. Plots of eGFR trajectories illustrated tendencies towards higher eGFR in more recent years, but this was not confirmed in mGFR trajectories. Poor risk factor control, prior CVD and male sex impacted mortality and morbidity rates negatively. For men/women with fair risk factor control and no prior CVD, the 10-year mortality rate from onset of DN was 28/26%. For men/women with poor risk factor control and CVD prior to DN onset, the 10-year-mortality rate was 62/62%. ConclusionThe results do not support an improved prognosis for T1D and DN, emphasizing the urgent need for new therapeutic approaches.

Causal Effects of Kidney Function and Chronic Kidney Disease on Alzheimer's Disease by Analyzing Large-Scale Genome-Wide Association Study Datasets.

Alzheimer's disease (AD) is the leading cause of dementia. Genetic components play an important role in AD and have been widely evaluated by genome-wide association studies (GWAS) and exome sequencing, and some common and rare genetic variants have been identified. In addition to genetic factors, environment factors have a role in AD. Growing evidence from observational studies linked impaired kidney function to cognitive impairment and AD; however, there are inconsistences in these findings. To determine the causal effects of impaired kidney function and chronic kidney disease (CKD) on AD. Mendelian randomization (MR) methods have been widely used to infer causal associations between exposure and outcome. Here, we conducted an MR study to investigate the causal effects of impaired kidney function and CKD on the risk of AD by analyzing large-scale GWAS datasets from FinnGen and CKD Genetics (CKDGen) Consortium. We found no significant but a suggestive effect of CKD on decreased risk of AD using inverse-variance weighted (IVW) (p = 8.46E-02) and simple mode (p = 7.60E-02) methods. We identified a statistically significant effect of the estimated glomerular filtration rate (eGFR) on increased risk of AD using IVW (p = 1.11E-02), weighted median regression (p = 5.60E-03), and weighted mode (p = 2.45E-02) methods. Together, our findings indicate that high eGFR levels may increase the risk of AD. These findings need to be verified in future studies.

The antitumor activity of osimertinib plus palbociclib in non-small cell lung cancer patient-derived xenograft (PDX)/2D/3D culture models harboring EGFR amplification and CDKN2A/2B homozygous deletions

Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by in vivo and in vitro antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had CDKN2A homozygous deletion (homdel), while 33.3 % (3/9) had CDKN2B homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype CDK4, 44.4 % (4/9) in CDK6, and 44.4 % (4/9) in EGFR. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had KRAS mutations, and 66.7 % (6/9) had TP53 mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous EGFR amp and CDKN2A/2B homdel. The data showed that NSCLC with EGFR amp and CDKN2A/2B homdel were sensitive to combined drugs. Additional oncogenic KRAS mutation reduced the drug's antitumor effect. EGFR amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype EGFR and CDK6 amp and CDKN2A/2B homdel in the absence of oncogenic KRAS mutation.

Kidney Biopsy Findings Among Patients With Diabetes in the Cleveland Clinic Kidney Biopsy Epidemiology Project

Rationale & ObjectiveDiabetic Kidney Disease (DKD) is a significant complication of diabetes mellitus, often leading to kidney failure. The absence of well-defined factors prevents distinguishing DKD from Non-Diabetic Kidney Disease (non-DKD; alternative primary diagnosis identified on kidney biopsy). Study DesignRetrospective cohort study. Setting& Participants: 1,242 patients with a history of diabetes from the Cleveland Clinic Kidney Biopsy Epidemiology Project between January 2015 and September 2021. ExposureProteinuria, retinopathy, A1c and eGFR. OutcomesNon-DKD, defined as an alternative primary diagnosis identified on kidney biopsy other than DKD. Analytical ApproachMultivariate logistic regression model with backward elimination method. ResultsAt the time of biopsy, the median (IQR) age was 63 (53-71) years, 58.8% were male, hemoglobin A1c was 6.7% (6.0-8.1), and serum creatinine was 2.5 (1.6-3.9) mg/dL. Among 1,242 patients, 462 (37.2%) had DKD alone, and 780 (62.8%) had non-DKD. Among those with non-DKD, the most common diagnoses were focal segmental glomerulosclerosis (24%), global glomerulosclerosis NOS (13%), acute tubular necrosis (9%), IgA nephropathy (8%), ANCA vasculitis (7%), and membranous nephropathy (5%). Factors associated with having non-DKD on biopsy were having no retinopathy (vs retinopathy) (adjusted odds ratio [aOR], 3.98; 95% CI, 2.69-5.90), lower A1c (<7% vs. ≥7%) (aOR, 3.08; 95%CI, 2.16-4.39), higher eGFR (≥60 vs. <60 ml/min/1.73m2) (aOR, 2.39; 95%CI 1.28-4.45), microalbuminuria (<300 vs. macroalbuminuria ≥300 [mg/g]) (aOR; 2.94; 95%CI, 1.84-4.72), and lower protein to creatinine ratio in random urine (<3 vs. ≥3mg/mg) (aOR; 1.80; 95%CI, 1.24-2.61). LimitationsSelection bias of clinically indicated biopsies, not protocol biopsies, which likely represent a ceiling (maximum) for non-DKD. ConclusionsAmong diabetic patients undergoing kidney biopsy, 63% have findings in addition to DKD on biopsy. We identified clinical parameters associated with non-DKD in the setting of diabetes. This provides valuable information for clinicians when kidney biopsy should be considered among diabetic patients to capture all etiologies of proteinuria and kidney dysfunction.

Prevalence and clinical determinants of rapid eGFR decline among patients with newly diagnosed type 2 diabetes

BackgroundDiabetic kidney disease is the most common cause of end-stage kidney disease (ESKD) in the western world. Rapid estimated glomerular filtration rate (eGFR) decline is an independent predictor of ESKD and death in the general population and in subjects with type 2 diabetes mellitus (T2D). AimWe investigated in a large sample of subjects with newly diagnosed T2D the prevalence and clinical determinants of fast eGFR decline, taking advantage from the dataset of the Associazione Medici Diabetologi (AMD) Annals initiative. MethodsThe eGFR trajectories were evaluated by applying a linear mixed model for repeated measures (LMMRM) and rapid eGFR decline defined as an eGFR decline greater than 5 mL/min/1.73 m2 per year at 3 years. ResultsAmong 105,163 (57.7% M) subjects with newly diagnosed T2D, 13,587 (12.9 %) subjects showed a rapid eGFR loss. The independent significant predictors were age, female gender, HbA1c, smoking, high baseline eGFR, albuminuria and retinopathy. ConclusionOur study demonstrates that a significant percentage of newly diagnosed T2D subjects have a rapid eGFR decline. Given the association between dynamic changes in eGFR and the risk of ESKD or death, we suggest to include this variable in the definition of CKD.

Genomics and proteomics to determine novel molecular subtypes and predict the response to immunotherapy and the effect of bevacizumab in glioblastoma

Glioblastoma (GBM) is a highly aggressive, infiltrative malignancy that cannot be completely cured by current treatment modalities, and therefore requires more precise molecular subtype signatures to predict treatment response for personalized precision therapy. Expression subtypes of GBM samples from the Cancer Genome Atlas (TCGA) were identified using BayesNM and compared with existing molecular subtypes of GBM. Biological features of the subtypes were determined by single-sample gene set enrichment analysis. Genomic and proteomic data from GBM samples were combined and Genomic Identification of Significant Targets in Cancer analysis was used to screen genes with recurrent somatic copy-number alterations phenomenon. The immune environment among subtypes was compared by assessing the expression of immune molecules and the infiltration of immune cells. Molecular subtypes adapted to immunotherapy were identified based on Tumor Immune Dysfunction and Exclusion (TIDE) score. Finally, least absolute shrinkage and selection operator (LASSO) logistic regression was performed on the expression profiles of S2, S3 and S4 in TCGA-GBM and RPPA to determine the respective corresponding best predictive model. Four novel molecular subtypes were classified. Specifically, S1 exhibited a low proliferative profile; S2 exhibited the profile of high proliferation, IDH1 mutation, TP53 mutation and deletion; S3 was characterized by high immune scores, innate immunity and adaptive immune infiltration scores, with the lowest TIDE score and was most likely to benefit from immunotherapy; S4 was characterized by high proliferation, EGFR amplification, and high protein abundance, and was the most suitable subtype for bevacizumab. LASSO analysis constructed the best prediction model composed of 13 genes in S2 with an accuracy of 96.7%, and the prediction model consisting of 17 genes in S3 with an accuracy of 86.7%, and screened 14 genes as components of the best prediction model in S4 with an accuracy of 93%. To conclude, our study classified reproducible and robust molecular subtypes of GBM, and these findings might contribute to the identification of patients responding to immunotherapy, thereby improving GBM prognosis.