Mild CKD Research Articles

Development and validation of a prediction model for people with mild chronic kidney disease in Japanese individuals

BackgroundChronic kidney disease (CKD) poses significant health risks due to its asymptomatic nature in early stages and its association with increased cardiovascular and kidney events. Early detection and management are critical for improving outcomes.ObjectiveThis study aimed to develop and validate a prediction model for hospitalization for ischemic heart disease (IHD) or cerebrovascular disease (CVD) and major kidney events in Japanese individuals with mild CKD using readily available health check and prescription data.MethodsA retrospective cohort study was conducted using data from approximately 850,000 individuals in the PREVENT Inc. database, collected between April 2013 and April 2023. Cox proportional hazard regression models were utilized to derive and validate risk scores for hospitalization for IHD/CVD and major kidney events, incorporating traditional risk factors and CKD-specific variables. Model performance was assessed using the concordance index (c-index) and 5-fold cross-validation.ResultsA total of 40,351 individuals were included. Key predictors included age, sex, diabetes, hypertension, and lipid levels for hospitalization for IHD/CVD and major kidney events. Age significantly increased the risk score for both hospitalization for IHD/CVD and major kidney events. The baseline 5-year survival rates are 0.99 for hospitalization for IHD/CVD and major kidney events are 0.99. The developed risk models demonstrated predictive ability, with mean c-indexes of 0.75 for hospitalization for IHD/CVD and 0.69 for major kidney events.ConclusionsThis prediction model offers a practical tool for early identification of Japanese individuals with mild CKD at risk for hospitalization for IHD/CVD and major kidney events, facilitating timely interventions to improve patient outcomes and reduce healthcare costs. The models stratified patients into risk categories, enabling identification of those at higher risk for adverse events. Further clinical validation is required.

Secondary prophylaxis of venous thromboembolism (VTE) with low dose apixaban or rivaroxaban in major-thrombophilia carriers.

Direct oral anticoagulants (DOACs) are widely used for treatment and secondary prophylaxis of venous thromboembolism (VTE) and represent the gold standard for VTE secondary prophylaxis, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit widespread DOACs usage there are few literature data regarding their efficacy and safety in major thrombophilia carriers and almost no data is available for low intensity apixaban and rivaroxaban as secondary VTE prophylaxis in such patients. The aim of our study is to evaluate and confront the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis, in major thrombophilia carriers vs patients at high risk of VTE recurrence for other reasons. We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5mg BID or rivaroxaban 10mg daily and that were screened for thrombophilia. The examined patients were 339. Baseline characteristics such as sex, age, obesity rate, smoking, number of previous VTEs and comorbidities (such as cardiovascular diseases, diabetes, mild CKD) were equally distributed in either group. The median low-dose DOACs administration time was 19.20months (IQR 12.17-35.67). During low-dose DOACs treatment, 13 (3.8%) VTE recurrences were observed; 14 bleeding events were registered (4,1%), with no major bleeding (MB), 6 clinically relevant non major bleeding (CRNMB) (1.8%) and 8 minor bleeding (2.3%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between major thrombophilia carriers and non-major thrombophilia carriers. In multivariate analysis increased risk of VTE recurrence was found for patients with cardiovascular comorbidities (HR 4.00 - p = 0.034) and for patients with more than one previous VTE episode (HR 5.14-p = 0.034). Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis for carriers of major thrombophilia with no increase in VTE recurrence and/or bleeding risk.

Mild CKD Is Predictive of Higher Mortality in Rural Uganda and Kenya

Mild CKD Is Predictive of Higher Mortality in Rural Uganda and Kenya

#1515 Myocardial remodeling is associated with redistribution of phosphate, PIT1/ERK1/2 up-regulation and signaling pathways alterations in mild CKD model

Abstract Background and Aims Patients with CKD have significantly increased cardiovascular risk, and heart failure is a leading cause of morbidity and mortality in these patients. Myocardial hypertrophy is a hallmark of cardiac remodeling and dysfunction in CKD and is known to be mediated by angiotensin II, catecholamines, hyperphosphatemia, hyperparathyroidism, increase in FGF23, decrease in Klotho and alterations in various signaling pathways including calcineurin, mitogen-activated protein kinase ERK1/2, calmodulin-dependent protein kinase II etc. Less well understood are the mechanisms of fibrosis and intramyocardial arterial remodeling in CKD, which may be related to hyperphosphatemia and decreased renal and systemic Klotho. The aim of this study was to evaluate the molecular and cellular features of myocardial remodeling in experimental mild CKD. Method We induced CKD by 3/4 nephrectomy (Nx) in adult male spontaneously hypertensive rats (SHR) with a follow-up period of 4 months. Animals were fed standard chow containing 0.6% phosphate. Sham-operated Wistar rats and SHR served as controls. We measured serum creatinine, renal interstitial fibrosis area, systolic blood pressure (BP), myocardial mass index (MMI), histological indices of myocardial hypertrophy, interstitial fibrosis and intramyocardial artery (IA) remodeling (H&E, Masson's trichrome, von Kossa stain), myocardial phosphorus content, serum levels of inorganic phosphate (Pi), PTH and FGF23. Myocardial expression of phosphate transporters PiT1, ERK1/2, WNT, BMP, Notch, Hedgehog signaling pathways and LRG4 molecules was evaluated by PCR-RT, IHC and IF (Zeiss LSM 710; study performed at the Centre for Collective Use “Confocal Microscopy” of the Pavlov Institute of Physiology, Russian Academy of Sciences). Results Chronic kidney injury and phosphate regulatory factors did not differ, whereas BP and MMI were higher in sham SHR vs. Wistar rats (Fig. 1). Nx rats showed features of mild chronic kidney injury before the elevation of serum PTH, FGF23 levels (Fig. 1). Myocardial P content and serum Pi were higher in Nx and in the combined SHR group and directly correlated with indices of IA remodeling. Cardiomyocyte diameter, myocardial interstitial and perivascular fibrosis were higher in Nx (Figs 1, 2a) and accompanied with upregulation in Ppp3ca mRNA (calcineurin A, Fig. 2b), Mapk1 mRNA (ERK2, Fig. 2b), phospho-ERK1/2 (Figs 1, 3), PiT1 (Figs 1, 2c), Lgr4 (Fig. 2c) and downregulation of Hes1 mRNA (Fig. 2b). PiT1 and pospho-ERK1/2 were co-expressed in IA media from SHR (Fig. 2c). In Nx, nestin and LGR4 were expressed by IA adventitia and media cells, myocardial interstitial cells, and occasionally co-localized (Fig. 2c). Hes1 expression was detected in IA and capillary endothelial cells and co-localised with Gli1 in IA media; Gli1 was also detected in cardiomyocyte nuclei (Fig. 2c). In SHR, beta-catenin expression in cardiomyocytes was more pronounced in Nx (Fig. 2c). Conclusion Mild CKD is associated with histological and molecular features of cardiomyocyte hypertrophy, myocardial fibrosis and intramyocardial arterial remodeling, which are probably modulated by phosphate redistribution and its tissue retention involving upregulation of PiT1 and ERK1/2, as well as alterations in signals related to progenitor regulation and myocyte hypertrophy.

Long-term safety of total knee arthroplasty in patients with chronic kidney disease in Taiwan: A retrospective cohort study

BackgroundChronic kidney disease (CKD) is a prevalent condition in Taiwan, and the incidence of total knee arthroplasty (TKA) is on the rise. This study aimed to evaluate the postoperative results of patients with different degrees of CKD after TKA, using data from the Taiwan National Health Insurance Research Database. MethodsThe study analyzed 3078 patients who received TKA from 2012 to 2017, equally divided into three groups: none-CKD, mild CKD (without dialysis), and severe CKD (with dialysis). Propensity score matching was used to minimize selection bias. ResultsAfter TKA, there was no significant difference in the risk of debridement surgery for infection between the three groups (adjusted HR of mild CKD: 0.71 95% CI=0.36–1.38, p=0.3073; adjusted HR of severe CKD: 1.14, 95% CI=0.63–2.06, p=0.6616). However, CKD patients requiring dialysis had a significantly higher risk of mortality (adjusted HR: 1.98, 95% CI=1.57–2.50, p<0.001) and readmission within 90days of any causes (adjusted HR: 1.83, 95% CI=1.48–2.26, p<0.001) than non-CKD and mild CKD patients. ConclusionSevere CKD patients needing dialysis after TKA have a higher risk of mortality and readmission rates than that of the non-CKD or mild CKD patients. If the patient is in the early stage of CKD, their prognosis after receiving TKA is expected to be as good as non-CKD patients. Level of evidenceIV; well-designed cohort study.

Stroke, mortality, and major bleeding among patients with atrial fibrillation and chronic kidney disease; insights from a contemporary large-scale population study

Abstract Introduction Chronic kidney disease (CKD) and atrial fibrillation (AF) frequently coexist, sharing a complex interplay. Although both conditions are prothrombotic, the prognostic role of CKD in AF remains uncertain, and anticoagulation effect on clinical outcomes is unclear. Methods A historical population-based study based on the "Clalit" health organization computerized database, including patients &amp;gt;21 years first diagnosed with AF between January 1st, 2010, and January 1st, 2020. The study population was stratified according to the estimated glomerular filtration rate (eGFR) at baseline to: No or mild CKD (eGFR≥60mL/min/1.73m2), moderate-CKD (eGFR above 30 and below 60 mL/min/1.73m2) and advanced-CKD (eGFR≤30 mL/min/1.73m2). Multivariable Cox-regression analyses were performed to evaluate the association between CKD stages and the 5-year risk of death, stroke, intracranial hemorrhage (ICH), and gastrointestinal bleeding (GIB). The association of anticoagulation treatments and possible interaction with CKD with the risk for the study outcomes were also examined. Results We identified 87,804 patients with incident AF. Of them, 3.2% had advanced CKD, and 25% had moderate CKD. 39,421 patients (45%) received anticoagulation. In multivariable models, moderate and advanced CKD were associated with increased risk for death in an incremental manner (moderate CKD: adjusted-hazard ratio (aHR) 1.17; 95% CI 1.14-1.20, p&amp;lt;0.001) (advanced CKD: aHR 1.85; 95% CI 1.76 -1.96; p&amp;lt;0.001). Both moderate CKD (aHR 1.1; 95% CI 1.00-1.20, p&amp;lt;0.05) and advanced CKD (aHR 1.37; 95% CI 1.13-1.67; p=0.001) were associated with increased risk of stroke. Renal function was not associated with increased risk for ICH, yet it was associated with increased risk of GIB. DOAC therapy reduced the risk of stroke (aHR 0.7; 95% CI 0.57-0.86, p=0.001) and death (aHR 0.83; 95% CI 0.77-0.78, p&amp;lt;0.001) while warfarin treatment did not. The association of anticoagulation treatment with reduced risk for stroke was consistent across CKD strata (p-for-interaction=0.19). Conclusions In this contemporary registry of AF patients, worse CKD was incrementally and independently associated with an increased risk of death, stroke and gastrointestinal bleeding among patients with AF. DOAC therapy was associated with a reduced risk for stroke and death without evident increase in ICH or GI bleeding. The inverse association between DOACs and stroke was consistent across all CKD categories. If confirmed by others, CKD ought to be added to stroke risk scores in AF.5 year stroke risk5 year death risk

Mitochondrial and contractile dysfunction in a swine model of early chronic kidney disease

Abstract Background Numerous clinical trials have demonstrated that patients with kidney damage have an increased chance of developing heart failure, and the risk is compounded in people with diabetes. Cardiac remodeling occurs at very early stages of kidney injury but studies undertaken to pinpoint the common biomarkers of cardiorenal signaling are still inadequate, which may be due to the fact that research done on rodent models does not fully reflect the complexity of the disease. We and our collaborators established swine models for diabetes (DM- insulin gene INS mutation) and chronic kidney disease (CKD- renal microembolisation) to overcome the translational gap associated with rodent models. Purpose In order to provide mechanistic as well as therapeutic insights, we used proteomic analyses to elucidate the pathophysiological effects of DM and CKD on the heart. Methods We used microspheres to embolise both kidneys of wild type and diabetic swine at 10-12 weeks of age and 6 months later we performed quantitative LC-MS-MS based proteomic analyses of left ventricular tissue from these four groups (wild type (WT), wild type with CKD (WT_CKD), diabetic (DM) and diabetic with CKD (DM_CKD). STRING bioinformatics software was used to identify significantly enriched pathways. Results Masson Trichrome staining confirmed the presence of kidney damage and fibrosis in CKD animals (Fig1 A). Quantitative proteomic analysis detected significant differences in the left ventricle of the WT or DM swine when compared to those with CKD using a volcano plot (Fig1B,C). STRING pre-ranked functional analysis showed pathway enrichments in both the comparisons (Fig2A,B). We found that proteins involved in the remodeling of the extracellular matrix (ECM), such as C3, F9, Col6A2, and FBN1, were downregulated in both groups (WT CKD and DM CKD as compared to WT and DM respectively). Interestingly, in WT_CKD we found that mitochondrial proteins like cytochrome oxidase (MT-CO2) and ATP5 synthase subunit were downregulated suggesting mitochondrial dysfunction. Strong indicators of this dysfunction include pathways with altered regulation of reactive oxygen species like hydrogen peroxide and substantial downregulation of contractile proteins like phospholamban, which maintains the Ca2+ homeostasis. DM_CKD on the other hand when compared to DM suggested presence of an inflammatory milieu with alterations of metabolic, wound healing and immune cell regulation pathways. Conclusions Our proteomic data in swine model provides strong evidence that mild CKD can induce early alterations in contractile proteins of the heart due to mitochondrial dysfunction along with ECM remodeling. In the presence of diabetes, metabolic and immune cells play a more predominant role in early part of the disease. Thus, we aim to further our understanding by applying our proteomic findings in conjunction with functional hemodynamic data in this swine model of cardiorenal disease.Figure 1Figure 2

Successful Application of PTRA in a Patient with AKI Due to Severe Unilateral Renal Artery Stenosis: A Case Report with 4-Year Follow-up and Review of Literature

Introduction: Renal artery stenosis (RAS) is defined by a decrease in the internal diameter of one or both of the renal arteries. This can lead to renal insufficiency. RAS mostly occurs due to atherosclerosis; however, other conditions can cause this complication. Case Presentation: We present a 66-year-old man who was initially presented with abrupt bilateral lower limbs and scrotal edema in Shahid Beheshti Hospital of Qom. The patient had been regularly visiting the nephrology clinic for mild CKD. Due to the increased levels of creatinine (Cr) and urea in serum, he underwent angiography with suspicion of RAS, and 99% stenosis was confirmed in the left renal artery. Immediately after the diagnosis, we subjected the patient to angioplasty. After removing the arterial stenosis, the patient passed 8 liters of urine during one day, and his symptoms, including generalized edema, weight gain, and dyspnea, were improved gradually. The patient was discharged after 8 days of hospitalization with dramatically improved kidney function and relatively good general conditions. Conclusions: This patient had an uncommon presentation for a unilateral RAS and significant narrowing in the healthy renal artery. Angioplasty and stenting yielded a satisfactory result as a definite and effective treatment, and the patient enjoyed a relatively normal life with preserved kidney function during 4 years of follow-up.

A Novel Titratable Pig Model of Mild, Moderate, and Severe CKD

A Novel Titratable Pig Model of Mild, Moderate, and Severe CKD

Prevalence of chronic kidney disease in Kazakhstan: evidence from a national cross-sectional study

To date, there have been no large-scale national studies of the prevalence of chronic kidney disease in Kazakhstan. It includes the research based on the analysis of the estimated glomerular filtration rate (eGFR). The aim of this study was to investigate the population prevalence of CKD and associated risk factors in Kazakhstan. The cross-sectional study consisted of a nationally representative sample of n = 6 720 adults aged 18 to 69 from 14 regions and 3 major cities in Kazakhstan. The study covered the period from October 2021 to May 2022. The WHO STEPS questionnaire was used for the survey. For the diagnosis of CKD, creatinine levels in collected blood samples were measured to assess eGFR. Demographic characteristics were collected and studied. The total and adjusted prevalence of factors associated with the presence of CKD were calculated and analysed using logistic regression. 73.5% (n = 4940) of participants had normal eGFR, while 25.2% (n = 1695) had mild CKD (eGFR = 60–89 mL/min/1.7 m2). The overall prevalence of CKD with eGFR < 60 ml/min/1.7 m2 was 1.3% (n = 85), of which 0.2% (n = 15) had eGFR < 45 ml/min/1.7 m2. A mild degree of CKD was most often determined in residents of the East Kazakhstan region in 10.4%, and in 7.8–8.0% of cases. The majority of CKD patients was detected in the East Kazakhstan region and Almaty city, 15.3% and 10.6% of cases respectively. In mild and CKD with GFR < 60 ml/min/1.7 m2, the age of participants was 50–69 years in 61.5% and 78.8% of cases, respectively (p < 0.001). In addition to the association with the place of residence, a statistically significant relationship was found between the risk of developing CKD and underweight (OR 1.43, 95% CI (1.09–1.88), p < 0.001), as well as the presence of obesity (OR 1.24, 95% CI (0.99–1.53), p = 0.04). We observed the prevalence of CKD with eGFR < 60 ml/min/1.7 m2 at the level of 1.3%. However, a fairly large part of study participants had a mild CKD (25.2%). The results of this study can be used for the optimization of the doctors workload and the timely provision of care to patients with CKD.

Physiologically-based pharmacokinetic modeling for single and multiple dosing regimens of ceftriaxone in healthy and chronic kidney disease populations: a tool for model-informed precision dosing.

Introduction: Ceftriaxone is one of commonly prescribed beta-lactam antibiotics with several label and off-label clinical indications. A high fraction of administered dose of ceftriaxone is excreted renally in an unchanged form, and it may accumulate significantly in patients with impaired renal functions, which may lead to toxicity. Methods: In this study, we employed a physiologically-based pharmacokinetic (PBPK) modeling, as a tool for precision dosing, to predict the biological exposure of ceftriaxone in a virtually-constructed healthy and chronic kidney disease patient populations, with subsequent dosing optimizations. We started developing the model by integrating the physicochemical properties of the drug with biological system information in a PBPK software platform. A PBPK model in an adult healthy population was developed and evaluated visually and numerically with respect to experimental pharmacokinetic data. The model performance was evaluated based on the fold error criteria of the predicted and reported values for different pharmacokinetic parameters. Then, the model was applied to predict drug exposure in CKD patient populations with various degrees of severity. Results: The developed PBPK model was able to precisely describe the pharmacokinetic behavior of ceftriaxone in adult healthy population and in mild, moderate, and severe CKD patient populations. Decreasing the dose by approximately 25% in mild and 50% in moderate to severe renal disease provided a comparable exposure to the healthy population. Based on the simulation of multiple dosing regimens in severe CKD population, it has been found that accumulation of 2g every 24h is lower than the accumulation of 1g every 12h dosing regimen. Discussion: In this study, the observed concentration time profiles and pharmacokinetic parameters for ceftriaxone were successfully reproduced by the developed PBPK model and it has been shown that PBPK modeling can be used as a tool for precision dosing to suggest treatment regimens in population with renal impairment.

Application of GFR estimating equations to children with normal, near-normal, or discordant GFR.

The objective was to determine the extent that eGFR formulas correspond to measured plasma iohexol clearance (iGFR) in children with normal or near normal kidney function, particularly how different eGFR formulas yield discordant results. iGFR from 2 (iGFR-2pt) and 4 (iGFR-4pt) time points along with creatinine and/or cystatin C-based eGFR were measured in children with mild CKD, stages 1-2. eGFR was calculated using 6 equations: 3 under 25 (U25) formulas from the Chronic Kidney Disease in Children (CKiD) study, the full age-combined cystatin C (cysC) and creatinine spectrum (FAS-combined), the European Kidney Function Consortium (EKFC-creatinine) equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-epi) cysC-based equation. Twenty-nine children were included, of which 22 had discordant creatinine vs. cystatin C-based eGFR by ≥ 15mL/min/1.73m2. Overall, the FAS-combined had the least bias, while the U25 most accurately identified children with an eGFR < 90 mL/min/1.73m2. When Cr-eGFR was ≥ 15 mL/min higher than CysC-eGFR, the U25 creatinine eGFR was closest to iGFR-4pt. When CysC eGFR was higher, the U25-combined was closest to iGFR-4pt. The formulas that most closely approximated the measured GFR varied depending on the pattern of discordant eGFR results. Based on the results, we recommend using the CKiD U25-combined formula to screen for children with a low GFR. Either the CKiD U25-combined or FAS-combined would be recommended for changes in eGFR longitudinally. However, because all formulas were discordant from the iGFR-4pt in over a third of participants, further refinement of pediatric eGFR formulas is needed at the normal/near-normal range. A higher resolution version of the Graphical abstract is available as Supplementary information.

#3078 MILD EXPERIMENTAL CKD IS ASSOCIATED WITH MYOCARDIAL FIBROSIS AND NOTCH/HEDGEHOG SIGNALING DYSREGULATION

Abstract Background and Aims Chronic kidney disease (CKD) is an independent cardiovascular risk factor. The initial mechanisms of myocardial remodeling (MR) in CKD are poorly understood. The major developmental signaling pathways Notch, Hedgehog, Wnt, and Bmp seem to be involved in many crucial steps of MR (cardiomyocytes survival and regeneration, fibrotic response, angiogenesis), while their role in MR due to CKD was not previously studied. Phosphate (Pi) is essential for cellular signaling and its redistribution to the cardiovascular compartment in CKD could be a one of the mechanisms of MR. Here we investigated the involvement of Pi/PPi transport, and reactivation of developmental signaling pathways in myocardial alterations associated with mild CKD. Method We induce mild CKD by 3/4 nephrectomy in adult male SHRs (SHR-Nx, n=8) with normal phosphate intake (0.6%) and 2-month follow-up. Controls were sham-operated SHR (SHR-Sham, n=8) and Wistar Kyoto rats (WKY-Sham, n=8). We analyzed chronic kidney injury and Pi exchange parameters, serum intact parathyroid hormone (PTH), intact fibroblast growth factor 23 (FGF23), myocardial phosphorus content (ICP-AES), histomorphometry, PiT1 and PiT2 expression (IHC), and mRNA expression of Slc20a1, Slc20a2, Ankh, Mapk1, Mapk3, Bmp2, Bmp4, Ctnnb1, Fzd2, Sfrp2, Dkk1, Wif1, Numb, Notch1, Jag1, Hes1, Lgr4, Tnfrsf11b, Tnfsf11, Ptch1. Results Systolic blood pressure and myocardial mass index (MMI) were higher in SHRs vs WKY-Sham (Table 1). Decrease in creatinine clearance by 30% and an increase in albuminuria corresponded to mild CKD in SHR-Nx model (Table 1). In SHR-Nx, myocardial interstitial fibrosis was significantly higher (Figure 1), while MMI and cardiomyocyte diameter did not differ compared to SHR-Sham (Table 1). Myocardial alterations were accompanied by the increase in myocardium phosphorus content (Figure 1), down-regulation in PPi-exporter Ankh, and up-regulation in Hes1 and decline in Ptch1 mRNA expression (Figure 2). We found no changes in Slc20a1 and Slc20a2 mRNA levels (Figure 2). An appearance of PiT2-positive fibroblasts-like cells in myocardial interstitium was apparent in SHR-Nx rats (data not shown). Conclusion Myocardial alterations in mild CKD are manifested in an increase in its phosphorus content, interstitial fibrosis, and dysregulation in genes likely related to the induction of the myofibroblasts and extracellular matrix remodeling.

#4703 IMPACT OF THE EARLY STAGES OF CKD WITH AND WITHOUT PROTEINURIA ON CARDIOVASCULAR OUTCOMES IN THE UK BIOBANK COHORT

Abstract Background and Aims Chronic kidney disease (CKD) is an established predictor of cardiovascular disease. However, the relationship between cardiovascular disease and the early stages of CKD defined as stage 1 (eGFR &amp;gt; 90 mL/min per 1.73 m2 + albuminuria) and stage 2 (eGFR 60–89 mL/min per 1.73 m2) with and without proteinuria, is lacking. In this study, we explored the incidence of major adverse cardiovascular events (MACE), heart failure (HF) and all-cause mortality of participants with early stages of CKD in the UK Biobank population. Method 456,015 participants from the UK Biobank were categorised into CKD stages. We calculated eGFR using the CKD-EPI 2021 equation and proteinuria was ascertained by the urinary protein creatinine ratio (defined as &amp;gt; 30mg/ mmol). We demonstrated the survival probability of adverse outcomes using unadjusted Kaplan-Meier curves and performed an adjusted Cox proportional hazard analysis to include MACE, HF, MACE and HF and all-cause mortality across CKD stages. Results Among the participants (mean age ± standard deviation, 56.5 ± 8.1 years) 282,121 (61.9%) had normal kidney function, 33,582 (7.4%) stage 1 CKD, 121,358 (26.6%) stage 2 CKD without proteinuria, 10,788 (2.4%) stage 2 CKD with proteinuria, 4,654 (1.0%) CKD stage 3A (eGFR 59-45mL/min per 1.73 m2) without proteinuria, 1034 (0.2%) stage 3A with proteinuria and 1,478 (0.3%) with more advanced CKD defined as stages 3B and above. Using Cox regression setting normal kidney function as the reference group, with the exception of stage 2 CKD without proteinuria; there was a progressive increase in the hazard ratio (HR) in all other stages of CKD with respect to MACE, HF, MACE and HF (Figure 1). Significantly, stage 2 CKD without proteinuria was associated with a lower incidence of adverse events than stage 1 CKD and had a comparable prognosis to normal renal function. There was a statistically significant association between stage 2 with proteinuria and MACE (HR 1.33, CI: 1.26 – 1.41), which was comparable to stage 3A without proteinuria (HR 1.32, CI: 1.22 – 1.42). Preliminary analysis of the ongoing cardiac magnetic resonance imaging (cMRI) data from this cohort shows similar progressive changes, apart from stage 2 CKD without proteinuria. Conclusion The presence of proteinuria in patients with mild CKD is a significant risk factor for MACE, HF, cMRI changes and all-cause mortality independent of age, sex, ethnicity, height, BMI, hypertension, diabetes, smoking status, and hyperlipidaemia. We recommend that in order to better risk stratify patients for prognostication and early treatment, stage 2 CKD should be considered as a significant cardiovascular risk only in the presence of proteinuria.

Perturbed gut microbiome and fecal and serum metabolomes are associated with chronic kidney disease severity

BackgroundChronic kidney disease (CKD) is a severe public health problem associated with a disordered gut microbiome. However, the functional alterations of microbiota and their cross talk with metabolism pathways based on disease severity remain unclear.ResultsWe performed metagenomics and untargeted metabolomics in a cohort of 68 patients with CKD of differing severities and 20 healthy controls to characterize the complex interplay between the gut microbiome and fecal and serum metabolites during CKD progression. We identified 26 microbial species that significantly changed in patients with CKD; 18 species changed as the disease progressed, and eight species changed only in a specific CKD group. These distinct changes in gut microbiota were accompanied by functional alterations in arginine and proline, arachidonic acid, and glutathione metabolism and ubiquinone and other terpenoid-quinone biosynthesis pathways during CKD progression. Further metabolomic analyses revealed that the distributions of toxic and pro-oxidant metabolites from these four essential metabolic pathways varied in the feces and serum as CKD progressed. Furthermore, we observed a complex co-occurrence between CKD severity-related bacteria and the characterized metabolites from the four essential metabolic pathways. Notably, Ruminococcus bromii, fecal hydroquinone, and serum creatinine were identified as the main contributors to the integrated network, indicating their key roles in CKD progression. Moreover, a noninvasive model including R. bromii and fecal hydroquinone, L-cystine, and 12-keto-tetrahydro-LTB4 levels classified the CKD severity (area under the curve [AUC]: > 0.9) and had better performance than the serum creatinine level for mild CKD (AUC: 0.972 vs. 0.896).ConclusionsPerturbed CKD severity-related gut microbiota may contribute to unbalanced toxic and pro-oxidant metabolism in the gut and host, accelerating CKD progression, which may be an early diagnostic and therapeutic target for CKD.5fQUC17u92h1vMeJ2rz_WVVideo

Appropriateness of drug prescriptions in patients with chronic kidney disease in primary care: a double-center retrospective study

BackgroundChronic kidney disease (CKD) is a highly prevalent disease worldwide. A basic pillar for the management of a patient with CKD is the safe use of drugs. Inadequate dosing of medication or contraindicated drugs in renal impairment can lead to negative outcomes. The primary objective was to analyse the drug prescriptions of patients with CKD from two primary care centres to see if they were optimally adapted to the patient's estimated glomerular filtration rate (eGFR).MethodsA retrospective observational study was conducted in two urban primary care centres. The study period was between September–October 2019. Patients over 18 years of age, with established CKD and with an eGFR less than 60 mL/min/1.73m2 for at least three months were included. Their demographic data (age and sex) and clinical variables such as associated comorbidities, eGFR value were retrospectively registered. Finally, their medication plans were reviewed in order to detect: inappropriate prescribing (IP), defined as an incorrect dose/frequency or contraindicated drug according to the renal function of the patient; nephrotoxic drugs and drugs with a high sodium content.ResultsA total of 273 patients were included. The most common patient profile was an elderly woman, polymedicated, with other concomitant diseases and with mild CKD. Two hundred and one IPs were detected, 13.9% of which were contraindicated drugs. Of all patients, 49.1% had been prescribed at least one IP on their medication plan, 93.8% had some potentially nephrotoxic drug and 8.4% had drugs with a high sodium content prescribed.ConclusionsPatients with CKD are at increased risk of medication-related problems. It is necessary to implement measures to improve the safety in the prescription of drugs in patients with CKD.

Assessment of Cystatin C Level for Risk Stratification in Adults With Chronic Kidney Disease

Kidney function is usually estimated from serum creatinine level, whereas an alternative glomerular filtration marker (cystatin C level) associates more closely with future risk of cardiovascular disease (CVD) and mortality. To evaluate whether testing concordance between estimated glomerular filtration rates based on cystatin C (eGFRcys) and creatinine (eGFRcr) levels would improve risk stratification for future outcomes and whether estimations differ by age. A prospective population-based cohort study (UK Biobank), with participants recruited between 2006-2010 with median follow-up of 11.5 (IQR, 10.8-12.2) years; data were collected until August 31, 2020. Participants had eGFRcr greater than or equal to 45 mL/min/1.73 m2, albuminuria (albumin <30 mg/g), and no preexisting CVD or kidney failure. Chronic kidney disease status was categorized by concordance between eGFRcr and eGFRcys across the threshold for hronic kidney disease (CKD) diagnosis (60 mL/min/1.73 m2). Ten-year probabilities of CVD, mortality, and kidney failure were assessed according to CKD status. Multivariable-adjusted Cox proportional hazards models tested associations between CVD and mortality. Area under the receiving operating curve tested discrimination of eGFRcr and eGFRcys for CVD and mortality. The Net Reclassification Index assessed the usefulness of eGFRcr and eGFRcys for CVD risk stratification. Analyses were stratified by older (age 65-73 years) and younger (age <65 years) age. There were 428 402 participants: median age was 57 (IQR, 50-63) years and 237 173 (55.4%) were women. Among 76 629 older participants, there were 9335 deaths and 5205 CVD events. Among 351 773 younger participants, there were 14 776 deaths and 9328 CVD events. The 10-year probability of kidney failure was less than 0.1%. Regardless of the eGFRcr, the 10-year probabilities of CVD and mortality were low when eGFRcys was greater than or equal to 60 mL/min/1.73 m2; conversely, with eGFRcys less than 60 mL/min/1.73 m2, 10-year risks were nearly doubled in older adults and more than doubled in younger adults. Use of eGFRcys better discriminated CVD and mortality risk than eGFRcr. Across a 7.5% 10-year risk threshold for CVD, eGFRcys improved case Net Reclassification Index by 0.7% (95% CI, 0.6%-0.8%) in older people and 0.7% (95% CI, 0.7%-0.8%) in younger people; eGFRcr did not add to CVD risk estimation. The findings of this study suggest that eGFRcr 45 to 59 mL/min/1.73 m2 includes a proportion of individuals at low risk and fails to capture a substantial proportion of individuals at high-risk for CVD and mortality. The eGFRcys appears to be more sensitive and specific for CVD and mortality risks in mild CKD.

Dietary Contributions to Metabolic Acidosis.

Eating a net acid-producing diet can produce an "acid stress" of severity proportional to the diet net acid load, as indexed by the steady-state renal net acid excretion rate. Depending on how much acid or base is ingested or produced from endogenous metabolic processes and how well our homeostatic mechanisms can buffer or eliminate the additional acids or bases, we can alter our systemic acid-base balance. With increasing age, the kidney's ability to excrete daily net acid loads declines (a condition similar to that of mild CKD), invoking increased utilization of potential base stores (eg, bone, skeletal muscle) on a daily basis to mitigate the acid accumulation, thereby contributing to development of osteoporosis, loss of muscle mass, and age-related renal insufficiency. Patients suffering from more advanced CKD often present with more severe acid stress or metabolic acidosis, as the kidney can no longer excrete the entire acid load. Alkaline diets based on fruits and vegetables may have a positive effect on long-term preservation of renal function while maintaining nutritional status. This chapter discusses the biochemistry of dietary precursors that affect acid or base production.

Association of combined fractional excretion of phosphate and FGF23 with heart failure and cardiovascular events in moderate and advanced renal disease.

High levels of FGF23 associate with adverse events in CKD. The urinary fractional excretion of phosphate (FePi) might modify this association, although data are limited in moderate and advanced CKD. We investigated the association of combined FePi and serum FGF23 with incident heart failure, cardiovascular events and mortality in patients withCKD stages2-4. Patients from the Chronic Renal Insufficiency Cohort were divided into four groups according to the median of FePi and FGF23: low-FePi/low-FGF23, reference group; high-FePi/low-FGF23; low-FePi/high-FGF23; high-FePi/high-FGF23. Primary outcomes were: the composite of cardiovascular death or hospitalization for heart failure; cardiovascular death; hospitalization for heart failure; and death from any cause. Survival analysis and adjusted regression analyses were performed. We analyzed 3684 patients with a mean age of 58 ± 11years of whom 45% were male. Mean eGFR was 44 ± 15ml/min/1.73m2. The median time of follow-up was 12 (IQR 7-13) years. The risk of the composite of cardiovascular death or hospitalization for heart failure was increased in the low-FePi/high-FGF23 group (HR 1.35; 95%CI 1.09-1.67) and in the high-FePi/high-FGF23 group (HR 1.50; 95%CI 1.20-1.86), compared to the low-FePi/low-FGF23 group. Cardiovascular death and hospitalization for heart failure were also increased in both groups with high FGF23. Death from any cause was increased in the low-FePi/high-FGF23 group (HR 1.56 (95%CI 1.30-1.89) and in the high-FePi/high-FGF23 (HR 1.57 (95%CI 1.29-1.90)). High FGF23 was associated with heart failure and cardiovascular death in patients with low FePi and high FePi with moderate to advanced CKD. This contrasts with reports in mild CKD.

Abstract TP163: Effect Of Renal Impairment On Clinical Outcomes Among Acute Ischemic Stroke Patients Treated With Endovascular Therapy- A Bi-center Study.

Objective: To investigate the effect of renal impairment on clinical outcomes among acute ischemic stroke (AIS) patients treated with endovascular therapy (EVT). Methods: We performed a retrospective analysis from January to December 2020 involving AIS patients with CKD and premorbid modified Rankin Scale (mRS) ≤2, undergoing EVT in two large academic comprehensive stroke centers. Our primary efficacy outcome of interest was mRS at 90 days. Secondary outcomes included: inpatient mortality, length of hospitalization and reperfusion status based on Thrombolysis in Cerebral Infarction (TICI) score. CKD was defined as estimated glomerular filtration rate (eGFR) ranging from mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min) or severe (eGFR 15-29 mL/min). We performed ordinal regression, multinomial logistic regression and binomial logistic regression analyses. In our subgroup analysis, we compared outcomes among AIS patients diagnosed with mild, moderate and severe CKD. We additionally performed a sensitivity analysis comparing patients with treated with combined intravenous thrombolysis (IVT) and EVT vs EVT only. Results: A total of 484 AIS patients underwent EVT at both stroke centers during the study period. After excluding patients for missing data and baseline mRS &gt;2, total of 300 AIS patients who underwent EVT (176 CKD and 124 patients with normal renal function) were included. Patients with CKD was associated with worse clinical outcomes [4 (2-6) vs 3 (1-6)]; adjusted odds ratio [aOR] 1.70, 95% confidence interval [CI] 1.10 - 2.61, p =0.02] based on 90-day mRS shift analysis and increased odds of in-hospital mortality (aOR 2.63, 95% CI; 1.08-6.38, p =0.03). Rates of TICI 2b/3 reperfusion ( p =0.84) and length of stay ( p =0.42) were similar between the two groups. Subgroup analyses found no difference between CKD and normal renal function groups for primary and secondary outcomes (all p &gt;0.05). Similarly, sensitivity analyses demonstrated no difference in clinical outcomes between patients receiving combined IVT and EVT compared to EVT only (all p &gt;0.05). Conclusion: Among AIS patients undergoing EVT, renal impairment was independently associated with worsening functional outcomes at 90 days and a higher rate of inpatient mortality.