Absence Of Chronic Kidney Disease Research Articles

#382 Unexpected diagnoses of ADTKD-MUC1 with the help of VNtyper

Abstract Background and Aims Autosomal dominant tubulointerstitial kidney disease (ADTKD) due to pathogenic variants in the MUC1 gene is difficult to diagnose since these variants lie in a large variable number tandem repeats (VNTR) and require specialized genetic testing, such as SNaPshot minisequencing. We recently developed a computational pipeline, VNtyper, for easier reliable detection of MUC1 VNTR pathogenic variants and have applied this tool to a large cohort of patients with various phenotypes of kidney disease. The aim of this study is to clinically describe patients in whom MUC1 pathogenic variants were unexpectedly detected with the help of VNtyper. Method We applied a computational pipeline, VNtyper, to a large cohort of patients with suspected hereditary kidney disease referred for genetic testing, regardless of their phenotype. This cohort included patients evaluated from 2017 to 2023 in the Molecular Genetics Department of Necker-Enfants Malades Hospital (Paris, France). Clinical characteristics were collected from patients in whom we detected new MUC1 VNTR pathogenic variants. Results 44 out of 3735 patients tested (1.2%) were newly diagnosed with a MUC1 pathogenic variant. Of these patients, ADTKD was clinically suspected in only 31 out of 44 patients (70%). In 2 patients, there was a pathogenic variant in another gene that could explain the phenotype, in addition to the MUC1 pathogenic variant. In fact, one 52-year-old patient had polycystic kidneys, nephrolithiasis, hematuria and normal kidney function. Her mother also had kidney cysts with absence of chronic kidney disease (CKD). This patient had a pathogenic variant in IFT140 gene (c.2399+1G>T) which could explain her autosomal dominant polycystic kidney disease (ADPKD) phenotype. Whether the MUC1 variant contributes to her disease remains unclear, especially seeing as her kidney function is normal at the age of 52 years. On the other hand, one patient had kidney cysts discovered at 3 days of age. A heterozygous HNF1B deletion was detected which could explain the phenotype. The following detection of a pathogenic MUC1 variant was thus an incidental finding and seemed de novo, although parents declined to get tested. These incidental findings can be challenging, especially when it comes to counselling and follow-up. There was no family history of kidney disease in 7 out of 44 patients (16%), and in one patient, we were able to confirm de novo disease since her parents were tested and were negative. It was unfortunately not possible to get DNA from the parents of the other patients. This is the first case of proven de novo ADTKD-MUC1 described to our knowledge. De novo variants in ADTKD-MUC1 are not surprising since the 7C stretch found in VNTR is a hotspot for mutagenesis. Interestingly, these patients seemed to have a more severe clinical presentation with an early onset of disease (median age at diagnosis 28 years [18, 32]). However, this could be due to a selection bias. In fact, young age of onset of CKD may have prompted clinicians to refer these patients for genetic testing despite negative family history, whereas older patients with possible ADTKD-MUC1 and no family history of kidney disease might be presumed to have another etiology of CKD. One way to confirm this would be to test a large cohort of patients with CKD from unknown etiology with no family history of CKD. Considering the nonspecific clinical manifestations of ADTKD-MUC1 and the phenotypic variability, it has previously been suggested that the most important clue to diagnosis is the presence of CKD in first-degree family. The possibility of de novo cases makes the clinical diagnosis of ADKTD-MUC1 even more challenging. Conclusion With VNtyper, we were able to diagnose new cases of ADTKD-MUC1 in a large cohort of patients with various phenotypes, with a significant prevalence of 1.2%. ADTKD-MUC1 was not suspected in 30% of these patients who would have maybe never been diagnosed otherwise. This is also the first study in which we describe a proven de novo case of ADTKD-MUC1. Pathogenic variants in the MUC1 gene should thus be in the differential diagnosis of all unspecified CKD, even if there is no family history since de novo variants are also possible.

Serum Levels of Growth Differentiation Factor 15 as a Biomarker for Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus

Background: Growth Differentiation Factor 15 (GDF-15) has been identified as a biomarker of cellular stress conditions and has demonstrated functional implications in kidney disease, metabolic disorders, and diabetes. However, the relationship between GDF-15 and the coexistence of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) remains unclear. This study aims to investigate the association between GDF-15 levels and the presence of CKD in patients with T2DM, then analyze the cut off value. Method: A cross-sectional study was conducted, enrolling a total of 60 patients. T2DM patients were categorized into two groups based on the presence or absence of CKD. Serum GDF-15 levels were quantified using an enzyme-linked immunosorbent assay (ELISA) kit. Results: The study population (n=60) predominantly consisted of male individuals with an average age of 53 years. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.846 (95% CI = 0.748 – 0.945) with a statistically significant p-value of < 0.001. The optimal cut-off value for serum GDF-15 to detect the presence of CKD was determined as 362.80 pg/mL, with corresponding sensitivity and specificity values of 77% and 79%, respectively. Furthermore, a significant association between GDF-15 levels and both T2DM without CKD and T2DM with CKD was observed (p < 0.001). Conclusion: There is a significant association observed between serum GDF-15 levels in patients with type 2 diabetes mellitus (DM) and the presence of CKD. The cut of value GDF-15 to detect the presence of CKD was determined as 362.80 pg/mL with sensitivity and specificity values of 77% and 79%, this is can be considered as a potential biomarker for the detection of CKD in individuals with T2DM.

Impact of heart rate changes during hospitalization on outcome in heart failure with preserved ejection fraction.

The benefits of lowering heart rate (HR) in heart failure (HF) with preserved ejection fraction (HFpEF) patients are still a matter of debate. This study aimed to investigate the relationship between changes in HR during hospitalization and cardiovascular (CV) events and all-cause death in hospitalized HFpEF patients. Hospitalized HF patients between January 2017 and December 2021 were consecutively enrolled in a national, multicentred, and prospective registry database, the China Cardiovascular Association Database-HF Center Registry. HF patients with a left ventricular ejection fraction of ≥50% were defined as HFpEF patients. The study analysed admission/discharge HR, change in HR during hospitalization (∆HR), and ∆HR ratio (∆HR/admission HR). The patients were categorized into three groups: no HR dropping group (ΔHR ratio>0.0%), moderate HR dropping group (-15%<ΔHR ratio≤0.0%), and excessive HR dropping group (ΔHR ratio≤-15%). All patients were followed up for 12months. The primary endpoint was CV events (CV death or HF rehospitalization). The secondary endpoint was all-cause death. A total of 19510 HFpEF patients (9750 males, mean age 71.9±12.2years) were included, with 4575 in the no HR dropping group, 8434 in the moderate HR dropping group, and 6501 in the excessive HR dropping group. Excessive HR dropping during hospitalization was significantly associated with an increased risk of CV events (17.1%) compared with the no HR dropping group (14.5%, P<0.001) or the moderate HR dropping group (14.0%, P<0.001), although all-cause mortality was similar among the three groups. After adjusting for multiple confounding factors, excessive HR dropping remained an independent predictor of increased CV event risk [hazard ratio 1.197, 95% confidence interval (CI) 1.078-1.328]. Subgroup analysis revealed that the prognostic impact of excessive HR dropping on increased CV event risk remained in the subgroups of older age, New York Heart Association class IV, ischaemic HF, higher left ventricular ejection fraction, absence of chronic kidney disease, and use of beta-blockers or ivabradine. Independent determinants associated with excessive HR dropping during admission included use of beta-blockers [odds ratio (OR) 1.683, 95% CI 1.558-1.819], lower discharge diastolic blood pressure (OR 0.988, 95% CI 0.985-0.991), no pacemaker (OR 0.501, 95% CI 0.416-0.603), coexisting atrial fibrillation or atrial flutter (OR 1.327, 95% CI 1.218-1.445), and use of digoxin (OR 1.340, 95% CI 1.213-1.480). In hospitalized HFpEF patients, excessive HR dropping during hospitalization is associated with an increased risk of CV death or HF rehospitalization. These findings highlight the importance of HR monitoring and avoiding excessively slowing down HR in hospitalized HFpEF patients to reduce the risk of CV events.

Intervención coronaria percutánea guiada por tomografía de coherencia óptica frente a guiada por ecografía intravascular en pacientes con infarto agudo de miocardio

Introduction and objectivesOptical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) yields clinical outcomes comparable to intravascular ultrasound (IVUS)-guided PCI in patients with stable ischemic heart disease. However, there is a scarcity of data comparing the clinical outcomes of OCT-guided and IVUS-guided PCI in the setting of acute myocardial infarction (AMI). We sought to compare the clinical outcomes of OCT-guided vs IVUS-guided PCI for patients with AMI in the era of second-generation drug-eluting stent (DES). MethodsWe identified 5260 consecutive patients who underwent PCI with a second-generation DES for AMI under IVUS or OCT guidance from pooled data derived from a series of Korean AMI registries between 2011 and 2020. The primary endpoint was the 1-year rate of target lesion failure, defined as a composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization. ResultsA total of 535 (10.2%) and 4725 (89.8%) patients were treated under OCT and IVUS guidance, respectively. The 1-year target lesion failure rates were comparable between the OCT and IVUS groups before and after propensity score matching (hazard ratio, 0.92; 95%CI, 0.42-2.05, P=.84). The OCT utilization rate did not exceed 5% of total patients treated with second-generation DES implantation during the study period. The primary factors for the selection of OCT over IVUS were the absence of chronic kidney disease, non-left main vessel disease, single-vessel disease, stent diameter <3mm, and stent length ≤ 25mm. ConclusionsOCT-guided PCI in patients with AMI treated with a second-generation DES provided comparable clinical outcomes for 1-year target lesion failure compared with IVUS-guided PCI.

Characterization of the plasma proteomic profile of Fabry disease: Potential sex- and clinical phenotype-specific biomarkers

Fabry disease (FD) is a X-linked rare lysosomal storage disorder caused by deficient α-galactosidase A (α-GalA) activity. Early diagnosis and the prediction of disease course are complicated by the clinical heterogeneity of FD, as well as by the frequently inconclusive biochemical and genetic test results that do not correlate with clinical course. We sought to identify potential biomarkers of FD to better understand the underlying pathophysiology and clinical phenotypes. We compared the plasma proteomes of 50 FD patients and 50 matched healthy controls using DDA and SWATH-MS. The >30 proteins that were differentially expressed between the 2 groups included proteins implicated in processes such as inflammation, heme and haemoglobin metabolism, oxidative stress, coagulation, complement cascade, glucose and lipid metabolism, and glycocalyx formation. Stratification by sex revealed that certain proteins were differentially expressed in a sex-dependent manner. Apolipoprotein A-IV was upregulated in FD patients with complications, especially those with chronic kidney disease, and apolipoprotein C-III and fetuin-A were identified as possible markers of FD with left ventricular hypertrophy. All these proteins had a greater capacity to identify the presence of complications in FD patients than lyso-GB3, with apolipoprotein A-IV standing out as being more sensitive and effective in differentiating the presence and absence of chronic kidney disease in FD patients than renal markers such as creatinine, glomerular filtration rate and microalbuminuria. Identification of these potential biomarkers can help further our understanding of the pathophysiological processes that underlie the heterogeneous clinical manifestations associated with FD.

Post-Coronary Artery Bypass Grafting Outcomes of Patients with/without Type-2 Diabetes Mellitus and Chronic Kidney Disease Treated with SGLT2 Inhibitor Dapagliflozin: A Single-Center Experience Analysis.

Increasingly, SGLT2 inhibitors save patients with heart failure and comorbidities such as type-2 diabetes mellitus (T2DM) and chronic kidney disease (CKD); the inhibition of sodium-glucose cotransporter 2 (SGLT2) was first studied in patients with diabetes as a solution to lower glucose levels by preventing glucose reabsorption and facilitating its elimination; in the process, researchers took notice of how SGLT2 inhibitors also seemed to have beneficial cardiovascular effects in patients with both diabetes and cardiovascular disease. Our single-center prospective study assesses outcomes of post-coronary artery bypass grafting (CABG) rehabilitation and SLGT2 inhibition in CABG patients with/without T2DM and with/without CKD. One hundred twenty consecutive patients undergoing CABG were included in the analysis. Patients were divided into four subgroups: diabetes patients with chronic kidney disease (T2DM + CKD), diabetes patients without chronic kidney disease (T2DM-CKD), prediabetes patients with chronic kidney disease (PreD+CKD), and prediabetes patients without chronic kidney disease (PreD-CKD). Echocardiographic and laboratory investigations post-surgery (phase I) and 6 months later (phase II) included markers for cardiac ischemia, glycemic status, and renal function, and metabolic equivalents were investigated. One hundred twenty patients participated, mostly men, overweight/obese, hypertensive, smokers; 65 had T2DM (18 with CKD), and 55 were prediabetic (17 with CKD). The mean ejection fraction increased by 8.43% overall but significantly more in the prediabetes group compared to the T2DM group (10.14% vs. 6.98%, p < 0.05). Overall, mean heart-type fatty-acid-binding protein (H-FABP) levels returned to normal levels, dropping from 68.40 ng/mL to 4.82 ng/mL (p = 0.000), and troponin data were more nuanced relative to an overall, strongly significant decrease of 44,458 ng/L (p = 0.000). Troponin levels in patients with CKD dropped more, both in the presence of T2DM (by 82,500 ng/L, p = 0.000) and in patients without T2DM (by 73,294 ng/L, p = 0.047). As expected, the overall glycated hemoglobin (HbA1c) levels improved significantly in those with prediabetes (from 6.54% to 5.55%, p = 0.000); on the other hand, the mean HbA1c changed from 7.06% to 6.06% (p = 0.000) in T2DM, and the presence or absence of CKD did not seem to make any difference: T2DM+CKD 7.01-6.08% (p = 0.000), T2DM-CKD 7.08-6.04% (p = 0.000), PreD+CKD 5.66-4.98% (p = 0.014), and PreD-CKD 6.03-4.94% (p = 0.00). Compared to an overall gain of 11.51, the GFRs of patients with CKD improved by 18.93 (68.15-87.07%, p = 0.000) in the presence of established diabetes and 14.89 (64.75-79.64%, p = 0.000) in the prediabetes group. Regarding the patients' cardiac statuses, the results from our single-center analysis revealed a significant decrease in ischemic risk (H-FABP and hs-cTnI levels) with improvements in mean ejection fraction, glycemic status, and renal function in patients post-CABG with/without T2DM, with/without CKD, and with SGLT2 inhibitor dapagliflozin treatment while undergoing cardiac rehabilitation.

Optical coherence tomography-guided versus intravascular ultrasound-guided percutaneous coronary intervention in patients with acute myocardial infarction

Introduction and objectivesOptical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) yields clinical outcomes comparable to intravascular ultrasound (IVUS)-guided PCI in patients with stable ischemic heart disease. However, there is a scarcity of data comparing the clinical outcomes of OCT-guided and IVUS-guided PCI in the setting of acute myocardial infarction (AMI). We sought to compare the clinical outcomes of OCT-guided vs IVUS-guided PCI for patients with AMI in the era of second-generation drug-eluting stent (DES). MethodsWe identified 5260 consecutive patients who underwent PCI with a second-generation DES for AMI under IVUS or OCT guidance from pooled data derived from a series of Korean AMI registries between 2011 and 2020. The primary endpoint was the 1-year rate of target lesion failure, defined as a composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization. ResultsA total of 535 (10.2%) and 4725 (89.8%) patients were treated under OCT and IVUS guidance, respectively. The 1-year target lesion failure rates were comparable between the OCT and IVUS groups before and after propensity score matching (hazard ratio, 0.92; 95%CI, 0.42-2.05, P=.84). The OCT utilization rate did not exceed 5% of total patients treated with second-generation DES implantation during the study period. The primary factors for the selection of OCT over IVUS were the absence of chronic kidney disease, non-left main vessel disease, single-vessel disease, stent diameter <3mm, and stent length ≤ 25mm. ConclusionsOCT-guided PCI in patients with AMI treated with a second-generation DES provided comparable clinical outcomes for 1-year target lesion failure compared with IVUS-guided PCI.

Incidence and Factors Associated With Post-Sternotomy Pain Syndrome in the National Heart Institute, Malaysia

To determine the incidence of poststernotomy pain syndrome (PSPS) after open cardiac surgery in 2021. To determine characteristics and assess the severity of symptoms in patients diagnosed with PSPS. To identify factors that can be associated with patients who were positive for PSPS. This study used a retrospective observational approach. Logistic regression analysis was employed to identify factors associated with the positive group. This study included all adult patients who underwent open cardiac surgery at the National Heart Institute, Malaysia, in 2021. A total of 1,395 patients were enrolled. The study involved conducting phone interviews to assess the presence of PSPS, followed by administering the Brief Pain Inventory questionnaire in the positive group to identify characteristics and severity of chronic pain. The incidence of PSPS after open cardiac surgery in 2021 was 20.35%. A total of 17.7% of patients reported that pain affected their daily activities, sleep, or emotions. Univariate analysis identified factors associated with PSPS, including age <60 years old, body mass index >30 kg/m2, history of previous percutaneous coronary intervention, ejection fraction <50%, the absence of chronic kidney disease (CKD), and internal mammary artery harvesting (p < 0.05). Multivariate analysis revealed that 4 independent factors were associated with PSPS: age <60 years old, history of previous percutaneous coronary intervention, ejection fraction <50%, and the absence of CKD (as compared with CKD) (p < 0.05). Poststernotomy pain syndrome is a complex issue affected by various factors. Although the pain score may not be as severe as previously believed, it remains crucial to recognize PSPS because a significant proportion of patients are affected.

Synergistic adverse impact of diabetes and chronic kidney disease on cardiovascular mortality in patients underwent percutaneous coronary intervention

Abstract Background Diabetes and chronic kidney disease (CKD) are frequently complicated each other. While approximately 40% of patients have diabetes among those with CKD, it is the most major (40-50%) and clinically important complication of diabetic patients which critically effects on their quality of life and outcomes. Moreover, numerous previous evidence has indicated the adverse prognostic impact by each of diabetes and CKD particularly in the secondary prevention of patients with established coronary artery disease (CAD). Nevertheless, to date, limited data is available regarding the synergistic impact of these two major risk factors on outcomes of patients with CAD. Purpose We studied the synergistic adverse effects of diabetes and chronic kidney disease on cardiovascular mortality in patients undergoing percutaneous coronary intervention (PCI). Methods This study is a part of a single-center prospective registry database of patients underwent PCI, which launched at 1984. A total of 4880 patients who underwent their first PCI (index PCI) at our university hospital between 2000 and 2018 were enrolled for the study. Participants were divided into 4 groups by the presence or absence of CKD and DM: DM−/CKD− (n=2028, 41.6%), DM+/CKD− (n=1411, 28.9%), DM−/CKD+ (n=754, 15.5%), and DM+/CKD+ (n=687, 14.1%). The endpoint was set as cardiovascular-related death (CV death). The median follow-up duration was 5.2 years since PCI procedure. Results During follow-up, 288 (5.9%) CV deaths were identified, in which 79.1% had DM or CKD. Unadjusted Kaplan-Meier curves showed patients with DM+/CKD+ had a significantly higher cumulative incidence of CV death compared to those with DM-/CKD- (log-rank p&amp;lt;0.0001) and DM-/CKD+ (p=0.03) (Figure 1). Moreover, multivariate Cox-proportional hazard analysis set DM-/CKD- as a reference and adjusted by age, gender, body mass index, hemoglobin, ejection fraction, acute coronary syndrome, statin and smoking history showed significantly increased risk of having both of diabetes and CKD (Hazard ratio (HR) and 95% confidence interval (CI) of DM and CKD: 3.1,: 1.9-5.1, p&amp;lt;0.0001) than having each of these (HR and 95% CI of DM alone: 1.2, 0.7-2.0, p=0.5, and of CKD alone: 1.8, 1.1-3.0, p=0.02 (Figure 2). Conclusions Findings in the present study indicated that CKD is a significant risk for CV death in patients following PCI, while only DM without CKD was not a significant risk factor in this population. Moreover, the risk for CV death was synergistically increased, when a patient had both of DM and CKD, compared to having each of these.Kaplan-Meier curves in CV deathAdjusted Cox hazard model in CV death

Association between a high triglyceride–glucose index and chronic kidney disease in adult patients with latent autoimmune diabetes

BackgroundInsulin resistance (IR) is one of the risk factors for chronic kidney disease (CKD) and diabetes. The triglyceride–glucose (TyG) index is considered a reliable alternative marker of IR. We investigated the correlation between the TyG index and the severity of CKD in patients with latent autoimmune diabetes in adults (LADA).MethodsThis cross-sectional study included 288 patients with LADA in the department of endocrinology at our hospital between January 2018 and January 2022. The TyG index was calculated as Ln [TG (mg/dl) × fasting blood glucose (FBG) (mg/dl) / 2]. All individuals were divided into either a LADA + CKD group or a LADA + non-CKD group according to the presence or absence of CKD. A correlation analysis, logistic regression analysis and receiver operating characteristics curve analysis were performed.ResultsA total of 130 (45.1%) participants were identified as having CKD. Compared with the non-CKD group, the CKD group had a longer disease duration and a higher proportion of smokers; patients were more likely to have hypertension and higher serum creatinine, triglyceride, cholesterol, low-density lipoprotein cholesterol, FBG, uric acid estimated glomerular filtration rates (eGFR) and TyG levels as well as lower high-density lipoprotein cholesterol levels (all P < 0.05). The positive relationship between the TyG index and the urinary albumin/creatinine ratio was significant (r = 0.249, P = 0.010). There was also a significant correlation between the TyG index and the eGFR (r = − 0.211, P = 0.034) after adjusting for confounding factors. The area-under-the-curve value of the TyG index was 0.708 (95% confidence interval: 0.61–0.81, P < 0.001).ConclusionsThe TyG index is significantly associated with the severity of CKD in patients with LADA. This conclusion supports the clinical application of the TyG index for the assessment of kidney disease in patients with LADA.

#2804 ALBUMINURIA IS ASSOCIATED WITH DECREASED SEVR AND ANKLE-BRACHIAL INDEX IN PATIENTS WITHOUT CKD

Abstract Background and Aims Albuminuria signifies subclinical vascular damage in the kidneys and other organs and is associated with systemic endothelial dysfunction and increased future cardiovascular risk. Subendocardial viability ratio (SEVR) is defined as diastolic to systolic pressure-time integral ratio and is a marker of subendocardial perfusion. Reduced SEVR has been uncovered in patients with chronic kidney disease (CKD) and simultaneous albuminuria. Albuminuria is also considered a risk factor for peripheral artery disease, especially in patients with additional atherosclerosis risk factors or diabetes mellitus. The aim of our study was to determine the impact of albuminuria on SEVR and ankle-brachial index (ABI) in patients without known CKD. Method We included 111 patients (73% male, mean age 64.2±9.3 years) that were hospitalized at our Cardiology department between 2016-2020 due to elective cardiac catheterization. Albuminuria was determined by urine albumin to creatinine ratio (UACR) from a random urine specimen. SEVR was determined by using applanation tonometry on radial artery (Sphygmocor, Atcor Medical, Australia). Ankle-brachial index (ABI) was measured by using an automated, non-invasive waveform analysis device (MESIÒ, Slovenia), mean ABI between the left and right side was used. Glomerular filtration rate was estimated (eGFR) by using the CKD-EPI 2009 creatinine equation. All the data were obtained prior to cardiac catheterization and only patients with eGFR ³60 ml/min/1.73 m2 were included. Statistical analysis was performed with the Statistical Package for Social Sciences version 22.0 (SPSS Inc, USA). Results Basic descriptive statistics, comorbidities, and medications are presented in Tables 1 and 2. Spearmann's correlation test showed significant correlation between UACR and SEVR (r = - 0.238; p = 0.017) and UACR and ABI (r = - 0.304; p = 0.003). Multiple regression analysis with SEVR as the dependent variable and waist-to-hip ratio, body mass index (BMI), arterial hypertension, diabetes, dyslipidemia, eGFR and UACR as independent variables, showed a significant association between UACR and SEVR (b = - 0.232; p = 0.029). The same model was used for ABI as the dependent variable, and a significant association was found only between UACR and ABI (b = - 0.232; p = 0.029). Conclusion Albuminuria is independently associated with decreased SEVR and ABI even in the absence of CKD.

#4554 FRAX® ASSOCIATION, BONE DENSITOMETRY, BIOCHEMICAL PARAMETERS OF BONE MINERAL METABOLISM AND ADVANCED CHRONIC KIDNEY DISEASE

Abstract Background and Aims Currently, there are calculation tools that predict the risk of fractures (fx), one of which is the Fracture Risk Assessment Tool (FRAX®). Patients with advanced chronic kidney disease (CKD) have a higher risk of fx than the general population and it is an independent factor for fx. However, this tool does not consider the presence or absence of CKD, where alterations in bone mineral metabolism have important clinical consequences and their prevention should be the objective of CKD control. The aim of our study is to evaluate the FRAX® tool in patients with advanced CKD and to analyze possible relationships with parameters of bone mineral metabolism. Method Observational, descriptive, retrospective study of a series of cases of patients with advanced chronic kidney disease in our center, where demographic data, FRAX® calculation, personal history of Diabetes Mellitus, etiology of CKD, personal history of fx, measurement of bone mineral densitometry by dual energy X-ray absorptiometry (DXA), estimated glomerular filtration rate (CKD-EPI), levels of serum calcium and phosphorus, vitamin D 1. 25 levels, Parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), use of phosphorus chelating treatment and vitamin D were collected. Descriptive results of continuous variables are expressed as mean and standard deviation or median and interquartile range (IQR) according to their distribution. For categorical data, frequency and percentage are reported. To analyze the impact of the variables on the event to be studied, a univariate and multivariate Cox regression model was used. Results 59 patients with advanced CKD with DXA performed within one year of the FRAX® analysis were analyzed. The median age was 66 years (IQR 22). 59.3% were male. 35.6% had a personal history of diabetes mellitus. The most frequent etiology of CKD was unknown etiology (18.6%), followed by vascular (16.9%). History of some type of fx:13.6% (3.6% vertebral). Estimated glomerular filtration rate CKD-EPI: 20.7 ml/min/1,73 m2 (IQR 7.5). 16.9% had osteoporosis of the femoral neck and 22% of the spine. DXA decreased in femoral neck 78% and in spine 59.3%. Low risk of major osteoporotic fracture according to FRAX® of 76.3% and 64.3% (without and with DXA) and elevated risk of major osteoporotic fracture according to FRAX® 5.1% and 8.5% (without and with DXA). Risk of hip fracture 25.4% and 30.5% (without and with DXA). These data are summarized in Figure 1 and Figure 2. In the multivariate analysis there is no relationship between bone mineral metabolism parameters and DXA. The results showed a negative correlation between glomerular filtration rate CKD-EPI and FRAX® hip (HR -1.7; 95% CI 1.46-9.6 p = 0.027) which would suggest an association between loss of renal function and loss of DXA. Patients with diabetes mellitus have a higher risk of fx (HR 3.7; 95% CI 1.46-9.6 p = 0.009). Conclusion In patients with advanced CKD, FRAX® index identifies patients at high fracture risk for whom active treatment for osteoporosis should be instituted. In patients with advanced chronic kidney disease, FRAX® underestimates those patients with decreased bone mass and elevated risk of osteoporosis. We did not find any association with biochemical parameters of bone mineral metabolism which could guide us in anticipating the treatment of osteoporosis. The loss of renal function accelerates the loss of bone mass, so we believe that the introduction of this variable is necessary in the equation, especially in this profile of patients.

Comparison of the effectiveness and safety of 2 aspirin doses in secondary prevention of cardiovascular outcomes in patients with chronic kidney disease: A subgroup analysis of ADAPTABLE

Among patients with established cardiovascular disease, the ADAPTABLE trial found no significant differences in cardiovascular events and bleeding rates between 81 mg and 325 mg of aspirin (ASA) daily. In this secondary analysis from the ADAPTABLE trial, we studied the effectiveness and safety of ASA dosing in patients with a history of chronic kidney disease (CKD). ADAPTABLE participants were stratified based on the presence or absence of CKD, defined using ICD-9/10-CM codes. Within the CKD group, we compared outcomes between patients taking ASA 81 mg and 325 mg. The primary effectiveness outcome was defined as a composite of all cause death, myocardial infarction, or stroke and the primary safety outcome was hospitalization for major bleeding. Adjusted Cox proportional hazard models were utilized to report differences between the groups. After excluding 414 (2.7%) patients due to missing medical history, a total of 14,662 patients were included from the ADAPTABLE cohort, of whom 2,648 (18%) patients had CKD. Patients with CKD were older (median age 69.4 vs 67.1 years; P < .0001) and less likely to be white (71.5% vs 81.7%; P < .0001) when compared to those without CKD. At a median follow-up of 26.2 months, CKD was associated with an increased risk of both the primary effectiveness outcome (adjusted HR 1.79 [1.57, 2.05] P < .001 and the primary safety outcome (adjusted HR 4.64 (2.98, 7.21), P < .001 and P < .05, respectively) regardless of ASA dose. There was no significant difference in effectiveness (adjusted HR 1.01 95% CI 0.82, 1.23; P=.95) or safety (adjusted HR 0.93; 95% CI 0.52, 1.64; P=.79) between ASA groups. Patients with CKD were more likely than those without CKD to have adverse cardiovascular events or death and were also more likely to have major bleeding requiring hospitalization. However, there was no association between ASA dose and study outcomes among these patients with CKD.

Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from the EMPEROR-Preserved trial.

In the EMPEROR-Preserved trial, empagliflozin improved clinical outcomes of patients with heart failure (HF) with preserved ejection fraction. In this pre-specified analysis, we aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function. Patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (CKD defined by an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 or urine albumin to creatinine ratio >300 mg/g). The primary and key secondary outcomes were (i) a composite of cardiovascular death or first HF hospitalization (primary outcome); (ii) total number of HF hospitalization, (iii) eGFR slope; and a pre-specified exploratory composite kidney outcome including a sustained ≥40% decline in eGFR, chronic dialysis or renal transplant. The median follow-up was 26.2 months. A total of 5988 patients were randomized to empagliflozin or placebo, of whom 3198 (53.5%) had CKD. Irrespective of CKD status, empagliflozin reduced the primary outcome (with CKD: hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69-0.94; without CKD: HR 0.75, 95% CI 0.60-0.95; interaction p = 0.67) and total (first and recurrent) hospitalizations for HF (with CKD: HR 0.68, 95% CI 0.54-0.86; without CKD: HR 0.89, 95% CI 0.66-1.21; interaction p = 0.17). Empagliflozin slowed the slope of eGFR decline by 1.43 (1.01-1.85) ml/min/1.73 m2 /year in patients with CKD and 1.31 (0.88-1.74) ml/min/1.73 m2 /year in patients without CKD (interaction p = 0.70). Empagliflozin did not reduce the pre-specified kidney outcome in patients with or without CKD (with CKD: HR 0.97, 95% CI 0.71-1.34; without CKD: HR 0.92, 95% CI 0.58-1.48; interaction p = 0.86) but slowed progression to macroalbuminuria and reduced the risk of acute kidney injury. The effect of empagliflozin on the primary composite outcome and the key secondary outcomes was consistent across five baseline eGFR categories (all interaction p >0.05). Empagliflozin was well tolerated independent of CKD status. In EMPEROR-Preserved, empagliflozin had a beneficial effect on the key efficacy outcomes in patients with and without CKD. Overall, the benefit and safety of empagliflozin was consistent across a wide range of kidney function spectrum, down to a baseline eGFR of 20 ml/min/1.73 m2 .

Assessing the Risk of Postoperative Complications for Proximal Humeral Fractures Treated by Open Reduction and Internal Fixation in Patients With Diabetes and Chronic Kidney Disease

The prevalence of diabetes mellitus (DM) and chronic kidney disease (CKD) has markedly risen over the past three decades. Patients with DM and CKD are at increased risk of infection, immune dysfunction, as well as bone and mineral disorders. Although we know that patients with DM and CKD have these risks, we do not know how these translate to proximal humeral fracture (PHF) healing. We sought to analyze whether these established comorbidities had increased rates of complications after open reduction and internal fixation (ORIF) for PHF treatment. Using a national insurance database, 72,365 patients with PHF managed with ORIF were identified using records from 2010 to 2022. Patients were initially split into those with DM and those without and were further stratified by the presence or absence of CKD. For our comparison baseline cohort, patients were not diagnosed with either DM or CKD. Post-ORIF complication rates were assessed looking specifically at nonunion, postoperative infection, and all-cause revision surgery. A logistic regression statistical analysis was also conducted. Of the 72,365 patients with PHF treated by ORIF, 41,047 were non-DM without CKD (comparison); 17,025 had DM alone (no CKD); 11,729 had DM and CKD; and 2564 had CKD alone (non-DM). Multivariate analysis indicated that patients with DM and/or CKD were at increased risk of developing nonunion (odds ratio [OR] = 1.37, 1.48, 1.23) and all-cause revision surgery (OR = 1.21, 1.11, 1.18) after ORIF for PHF compared with our comparison cohort. In addition, all patients with DM alone (non-CKD) and DM with CKD had an increased risk of postoperative infection (OR = 1.39, 1.26). The management of PHF is a controversial topic, particularly regarding the degree of intervention and optimal treatment choice. Regardless, using a pragmatic design and reviewing a national insurance database, this study provides information for patients in high-risk populations, specifically patients with DM and CKD, and may prove beneficial when selecting a patient-specific treatment plan. Additional studies are needed to assess varying stages of both DM and CKD in patients who sustain PHF treated by ORIF along with postoperative strategies to minimize complications.

Periodontitis deteriorates renal fibrosis and macrophage infiltration in rats with chronic kidney disease.

The objective of this study was to examine the effect of periodontitis on renal function and morphology in rats with or without nephrectomy (Nx)-induced chronic kidney disease (CKD). Rats were divided into sham surgery (Sham), Sham with tooth ligation (ShamL), Nx, and NxL groups. Periodontitis was induced by tooth ligation at 16-week olds. Creatinine, alveolar bone area, and renal histopathology were analyzed at 20-week olds. Creatinine did not differ between the Sham and ShamL groups or between the Nx and NxL groups. The ShamL and NxL groups (both p=0.002) had less alveolar bone area than the Sham group. The NxL group had fewer glomeruli than the Nx group (p < 0.000). The periodontitis groups demonstrated more tubulointerstitial fibrosis (Sham vs. ShamL p=0.002, Nx vs. NxL p < 0.000) and macrophage infiltration (Sham vs. ShamL p=0.002, Nx vs. NxL p=0.006) than the groups without periodontitis. Only the NxL group had greater renal TNFα expression than the Sham group (p < 0.003). These suggest that periodontitis increases renal fibrosis and inflammation in the presence or absence of CKD but does not affect renal function. Periodontitis also increases TNFα expression in the presence of CKD.

Serum Magnesium Levels and Cardiovascular Outcomes in Systolic Blood Pressure Intervention Trial Participants

Serum magnesium levels have been inversely yet inconsistently associated with cardiovascular (CV) outcomes. In this study, we examined the association of serum magnesium levels with CV outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT) participants. Case-control post hoc analysis of SPRINT. A total of 2,040 SPRINT participants with available serum samples at baseline level were included in this study. Case participants (n=510) who experienced a CV event during the SPRINT observation period (median follow-up of 3.2 years) and control participants (n=1,530) without CV events were sampled in a 1:3 ratio for measurements of serum magnesium level at baseline and 2-year follow-up. Baseline serum magnesium levels and 2-year percentage change in serum magnesium levels (ΔSMg). SPRINT primary composite CV outcome. Multivariable conditional logistic regression analysis, accounting for matching factors, was used to evaluate the association of baseline and ΔSMg with CV outcomes. Individual matching of cases and controls was based on the SPRINT treatment arm allocation (standard vs intensive) and prevalence of chronic kidney disease (CKD). The median serum magnesium level at baseline was similar among the case and control groups. In a fully adjusted model, each standard deviation (SD) (0.18mg/dL) higher of the baseline serum magnesium level was independently associated with a lower risk for composite CV outcomes in all study participants (adjusted odds ratio 95% CI, 0.79 [0.70-0.89]). This association was similar when serum magnesium levels were analyzed in quartiles but dissipated in the standard (vs intensive) arm of SPRINT (0.88 [0.76-1.02] vs 0.65 [0.53-0.79], respectively; Pinteraction=0.06). The presence or absence of CKD at baseline did not modify this association. ΔSMg was not independently associated with CV outcomes occurring after 2 years. ΔSMg was small in magnitude, limiting effect size. Higher baseline serum magnesium levels were independently associated with reduced risk for CV outcomes in all study participants, but ΔSMg was not associated with CV outcomes.

Clinical utility gains from incorporating comorbidity and geographic location information into risk estimation equations for atherosclerotic cardiovascular disease.

There are over 363 customized risk models of the American College of Cardiology and the American Heart Association (ACC/AHA) pooled cohort equations (PCE) in the literature, but their gains in clinical utility are rarely evaluated. We build new risk models for patients with specific comorbidities and geographic locations and evaluate whether performance improvements translate to gains in clinical utility. We retrain a baseline PCE using the ACC/AHA PCE variables and revise it to incorporate subject-level information of geographic location and 2 comorbidity conditions. We apply fixed effects, random effects, and extreme gradient boosting (XGB) models to handle the correlation and heterogeneity induced by locations. Models are trained using 2 464 522 claims records from Optum©'s Clinformatics® Data Mart and validated in the hold-out set (N = 1 056 224). We evaluate models' performance overall and across subgroups defined by the presence or absence of chronic kidney disease (CKD) or rheumatoid arthritis (RA) and geographic locations. We evaluate models' expected utility using net benefit and models' statistical properties using several discrimination and calibration metrics. The revised fixed effects and XGB models yielded improved discrimination, compared to baseline PCE, overall and in all comorbidity subgroups. XGB improved calibration for the subgroups with CKD or RA. However, the gains in net benefit are negligible, especially under low exchange rates. Common approaches to revising risk calculators incorporating extra information or applying flexible models may enhance statistical performance; however, such improvement does not necessarily translate to higher clinical utility. Thus, we recommend future works to quantify the consequences of using risk calculators to guide clinical decisions.

Evaluation of Cytogenetic Alterations in Patients of Chronic Kidney Disease.

In recent years, there has been a rise in chronic kidney disease (CKD), and it has been estimated that by 2040, CKD will be the fifth most common cause of death globally. In addition to diabetes, hypertension, obesity, hyperlipidemia, and nonalcoholic fatty liver disease commonly associated with CKD, exposure to various toxins as a result of pollution or industrial disasters is also discussed as a cause for multi-organ pathology including kidneys. Although few cytogenetic studies were undertaken to assess the genetic damage in survivors of the disaster, no studies are available on the cytogenetic damage of toxic-gas exposed population having CKD. Therefore, the present multi-group cross-sectional study was undertaken to assess the independent role of CKD as well as toxic gas exposure on cytogenetics. The cytogenetic alterations were evaluated through chromosomal aberration analysis and micronuclei assay. The study included 608 study participants divided into four groups on the basis of history of exposure to the leaked gas and presence or absence of CKD. The results of the study showed no statistically significant difference in cytogenetic damage between gas-exposed and non-exposed patients of CKD, whereas significantly higher cytogenetic damage was observed among gas-exposed participants having CKD compared to gas-exposed participants free from CKD, suggesting that cytogenetic changes could be due to CKD itself. Thus, to conclude, the cytogenetic alterations observed in the study can be partly attributed to the disease itself.

Impact of renal-replacement therapy strategies on outcomes for patients with chronic kidney disease: a secondary analysis of the STARRT-AKI trial.

To assess whether pre-existing chronic kidney disease (CKD) modified the relationship between the strategy for renal-replacement theraphy (RRT) initiation and clinical outcomes in the STARRT-AKI trial. This was a secondary analysis of a multi-national randomized trial. We included patients who had documented pre-existing estimated glomerular filtration rate (eGFR) data prior to hospitalization, and we defined CKD as an eGFR ≤ 59mL/min/1.73 m2. The primary outcome was all-cause mortality at 90days. Secondary outcomes included RRT dependence and RRT-free days at 90days. We used logistic and linear regression and interaction testing to explore the effect of RRT initiation strategy on outcomes by CKD status. We studied 1121 patients who had pre-hospital measures of kidney function. Of these, 432 patients (38.5%) had CKD. The median (IQR) baseline serum creatinine was 130 (114-160) and 76 (64-90) µmol/L for those with and without CKD, respectively. Patients with CKD were older and more likely to have cardiovascular comorbidities and diabetes mellitus. Patients with CKD had higher 90-day mortality (47% vs. 40%, p < 0.001) compared to those without CKD, though this was not significant after covariate adjustment (adjusted odds ratio [aOR], 1.05; 95% CI, 0.79-1.41). Patients with CKD were more likely to remain RRT dependent at 90days (14% vs. 8%; aOR, 1.89; 95% CI, 1.05-3.43). CKD status did not modify the effect of RRT initiation strategy on 90-day mortality. Among patients with CKD, allocation to the accelerated strategy conferred more than threefold greater odds of RRT dependence at 90days (aOR 3.18; 95% CI, 1.41-7.91) compared with the standard strategy, whereas RRT initiation strategy had no effect on this outcome among those without CKD (aOR 0.71; 95% CI, 0.34-1.47, p value for interaction, 0.009). In this secondary analysis of the STARRT-AKI trial, an accelerated strategy of RRT initiation conferred a higher risk of 90-day RRT dependence among patients with pre-existing CKD; however, no effect was observed in the absence of CKD.