Risk Of Chronic Kidney Disease Progression Research Articles

Abstract 080: The Non-steroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction In Preclinical Non-diabetic Chronic Kidney Disease

Background: The mineralocorticoid receptor (MR) plays an important role in the development of Chronic Kidney Disease (CKD) and its overactivation contributes to the progression of cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option. Finerenone, is a non-steroidal MRA recently studied in two large clinical trials showing the beneficial effects lowering the risks of CKD progression and cardiovascular events in stage 1 to 4 CKD patients with type 2 diabetes (T2D) (FIDELIO-DKD and FIGARO-DKD trials) Aim: To test whether finerenone improves renal and/or cardiac functions in preclinical non-diabetic CKD. Methods: non-diabetic CKD was induced by 5/6 nephrectomy in 6 weeks old Sprague Dawley rats. Finerenone (10 mg/kg/day) was administered as preventive or as curative treatment. Left ventricle (LV) function/hemodynamics, LV tissue perfusion and GFR were assessed in vivo at the age of 24 weeks. Results: 12 weeks after 5/6 nephrectomy, the rats showed classical signs of CKD: reduced GFR and increased kidney weight; associated with LV diastolic dysfunction confirmed by increased in LV end-diastolic pressure (LVEDP), LV relaxation constant (Tau) and LV end-diastolic pressure volume-relation (LVEDPVR), while LV perfusion was reduced. Both prevention and curative treatment with finerenone reduced significantly both LVEDPVR and Tau; and increased LV tissue perfusion. Finerenone treatment did not impact reduced kidney GFR but reduced renal hypertrophy. Conclusion: Both preventive and curative finerenone improves non-diabetic CKD related LV diastolic function, independently from changes in kidney function.

Nocturnal systolic blood pressure dipping and progression of chronic kidney disease.

The relationship between declining nocturnal blood pressure (BP) and adverse cardiovascular outcomes is well-recognized. However, the relationship between diurnal BP profile and the risk of chronic kidney disease (CKD) progression is unclear. Herein, we examined the association between nocturnal systolic SBP (SBP) dipping and CKD progression in 1061 participants at the Cardiovascular and Metabolic Disease Etiology Research Center-High Risk (CMERC-HI). The main exposure was diurnal systolic BP (SBP) profile and diurnal SBP difference ([nighttime SBP-daytime SBP] × 100/daytime SBP). The primary outcome was CKD progression, defined as a composite of ≥ a 50% decline in the estimated glomerular filtration rate from baseline or the initiation of kidney replacement therapy. During 4749 person-years of follow-up (median, 4.8 years), the composite outcome occurred in 380 (35.8%) participants. Compared to dippers, the hazard ratios (HRs) for the risk of adverse kidney outcomes were 1.02 (95% confidence interval [CI], 0.64-1.62), 1.30 (95% CI, 1.02-1.66), and 1.40 (95% CI, 1.03-1.90) for extreme dipper, non-dipper, and reverse dipper, respectively. In a continuous modeling, a 10% increase in diurnal SBP difference was associated with a 1.21-fold (95% CI, 1.07-1.37) higher risk of CKD progression. Thus, decreased nocturnal SBP decline was associated with adverse kidney outcomes in patients with CKD. Particularly, patients with non-dipping and reverse dipping patterns were at higher risk for CKD progression than those with a dipping pattern.

24-h Urinary Calcium Excretion and Renal Outcomes in Hospitalized Patients with and without Chronic Kidney Disease.

This study investigated the impact of 24-h urinary calcium excretion (UCaE) on renal function decline in hospitalized patients with and without chronic kidney disease (CKD). This study enrolled 3815 CKD patients in stages 1-4 and 1133 non-CKD patients admitted to the First Center of the Chinese PLA General Hospital between January 2014 and July 2022. The primary outcome for CKD patients was a composite of CKD progression, defined as a 40% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease. Annual eGFR change was the secondary outcome. For non-CKD patients, the primary outcome was an eGFR decline of ≥20% or CKD incidence, while annual eGFR change was the secondary outcome. The association between UCaE and kidney function decline was assessed using Cox proportional hazards and generalized linear models. Primary outcomes were observed in 813 CKD patients and 109 non-CKD patients over a median follow-up of 3.0 and 4.1 years, respectively. For CKD patients, every 1-mmol/d increase in UCaE was associated with a 15% decreased risk of CKD progression. The hazard ratio (HR) was 0.85, with a 95% confidence interval (CI) of 0.77-0.93. For non-CKD patients, the risk of renal function decline decreased by 11%. The multivariate models indicated that there was an annual decrease in eGFR in both CKD and non-CKD patients, with a reduction of 0.122 mL/min/1.73 m2/year (p < 0.001) and 0.046 mL/min/1.73 m2/year (p = 0.004), respectively, for every 1-mmol/d increase in UCaE. CKD experiences a decrease in 24-h UCaE as early as stage 1, with a significant decline in stage 4. CKD and non-CKD patients with lower UCaE levels are at an increased risk of renal decline, regardless of other variables.

Absolute and Relative Risks of Kidney Outcomes Associated With Lithium vs Valproate Use in Sweden

Among patients with bipolar disorder, discordant findings have been published on the nephrotoxic effects of lithium therapy. To quantify absolute and relative risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) in people who initiated lithium compared with valproate therapy and to investigate the association between cumulative use and elevated lithium levels and kidney outcomes. This cohort study had a new-user active-comparator design and used inverse probability of treatment weights to minimize confounding. Included patients initiated therapy with lithium or valproate from January 1, 2007, to December 31, 2018, and had a median follow-up of 4.5 years (IQR, 1.9-8.0 years). Data analysis began in September 2021, using routine health care data from the period 2006 to 2019 from the Stockholm Creatinine Measurements project, a recurrent health care use cohort of all adult residents in Stockholm, Sweden. New use of lithium vs new use of valproate and high (>1.0 mmol/L) vs low serum lithium levels. Progression of CKD (composite of >30% decrease relative to baseline estimated glomerular filtration rate [eGFR] and kidney failure), AKI (by diagnosis or transient creatinine elevations), new albuminuria, and annual eGFR decrease. Outcomes by attained lithium levels were also compared in lithium users. The study included 10 946 people (median [IQR] age, 45 [32-59] years; 6227 female [56.9%]), of whom 5308 initiated lithium therapy and 5638 valproate therapy. During follow-up, 421 CKD progression events and 770 AKI events were identified. Compared with patients who received valproate, those who received lithium did not have increased risk of CKD (hazard ratio [HR], 1.11 [95% CI, 0.86-1.45]) or AKI (HR, 0.88 [95% CI, 0.70-1.10]). Absolute 10-year CKD risks were low and similar: 8.4% in the lithium group and 8.2% in the valproate group. No difference in the risk of developing albuminuria or the annual rate of eGFR decrease was found between groups. Among more than 35 000 routine lithium tests, only 3% of results were in the toxic range (>1.0 mmol/L). Lithium values greater than 1.0 mmol/L, compared with lithium values of 1.0 mmol/L or less, were associated with increased risk of CKD progression (HR, 2.86; 95% CI, 0.97-8.45) and AKI (HR, 3.51; 95% CI, 1.41-8.76). In this cohort study, compared with new use of valproate, new use of lithium was meaningfully associated with adverse kidney outcomes, with low absolute risks that did not differ between therapies. However, elevated serum lithium levels were associated with future kidney risks, particularly AKI, emphasizing the need for close monitoring and lithium dose adjustment.

Racial Differences and Contributory Cardiovascular and Non-Cardiovascular Risk Factors Towards Chronic Kidney Disease Progression.

The prevalence of advanced chronic kidney disease (CKD) is higher in Black than in White Americans. We evaluated CKD progression in Black and White participants and the contribution of biological risk factors. We included the study of lung function (measured by forced vital capacity [FVC]), which is part of the emerging notion of interorgan cross-talk with the kidneys to racial differences in CKD progression. This longitudinal study included 2175 Black and 2207 White adult Coronary Artery Risk Development in Young Adults (CARDIA) participants. Estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were measured at study year 10 (age 27-41y) and every five years for 20 years. The outcome was CKD progression through no CKD, low, moderate, high, or very high-risk categories based on eGFR and UACR in combination. The association between race and CKD progression as well as the contribution of risk factors to racial differences were assessed in multivariable-adjusted Cox models. Black participants had higher CKD transition probabilities than White participants and more prevalent risk factors during the 20-year period studied. Hazard ratios for CKD transition for Black (vs White participants) were 1.38 from No CKD into ≥ low risk, 2.25 from ≤ low risk into ≥ moderate risk, and 4.49 from ≤ moderate risk into ≥ high risk. Racial differences in CKD progression from No CKD into ≥ low risk were primarily explained by FVC (54.8%), hypertension (30.9%), and obesity (20.8%). In contrast, racial differences were less explained in more severe transitions. Black participants had a higher risk of CKD progression, and this discrepancy may be partly explained by FVC and conventional risk factors.

CKD Progression Prediction in a Diverse US Population: A Machine-Learning Model

Chronic kidney disease (CKD) is a major cause of morbidity and mortality. To date, there are no widely used machine-learning models that can predict progressive CKD across the entire disease spectrum, including the earliest stages. The objective of this study was to use readily available demographic and laboratory data from Sonic Healthcare USA laboratories to train and test the performance of machine learning-based predictive risk models for CKD progression. Retrospective observational study. The study population was composed of deidentified laboratory information services data procured from a large US outpatient laboratory network. The retrospective data set included 110,264 adult patients over a 5-year period with initial estimated glomerular filtration rate (eGFR) values between 15-89mL/min/1.73m2. Patient demographic and laboratory characteristics. Accelerated (ie,>30%) eGFR decline associated with CKD progression within 5 years. Machine-learning models were developed using random forest survival methods, with laboratory-based risk factors analyzed as potential predictors of significant eGFR decline. The 7-variable risk classifier model accurately predicted an eGFR decline of>30% within 5 years and achieved an area under the curve receiver-operator characteristic of 0.85. The most important predictor of progressive decline in kidney function was the eGFR slope. Other key contributors to the model included initial eGFR, urine albumin-creatinine ratio, serum albumin (initial and slope), age, and sex. The cohort study did not evaluate the role of clinical variables (eg, blood pressure) on the performance of the model. Our progressive CKD classifier accurately predicts significant eGFR decline in patients with early, mid, and advanced disease using readily obtainable laboratory data. Although prospective studies are warranted, our results support the clinical utility of the model to improve timely recognition and optimal management for patients at risk for CKD progression. Defined by a significant decrease in estimated glomerular filtration rate (eGFR), chronic kidney disease (CKD) progression is strongly associated with kidney failure. However, to date, there are no broadly used resources that can predict this clinically significant event. Using machine-learning techniques on a diverse US population, this cohort study aimed to address this deficiency and found that a 5-year risk prediction model for CKD progression was accurate. The most important predictor of progressive decline in kidney function was the eGFR slope, followed by the urine albumin-creatinine ratio and serum albumin slope. Although further study is warranted, the results showed that a machine-learning model using readily obtainable laboratory information accurately predicts CKD progression, which may inform clinical diagnosis and management for this at-risk population.

#5365 T2DM MODIFIES THE RELATIONSHIP BETWEEN CAC AND ADVERSE KIDNEY OUTCOME IN PATIENTS WITH CKD

Abstract Background and Aims Kidney function decline faster in patients with type 2 diabetes mellitus (T2DM) than in those without. We previously showed that coronary artery calcification (CAC) is a strong risk of adverse kidney outcome. Here, we examined whether T2DM could modify the relationship between CAC and the progression of chronic kidney disease (CKD). Method 2067 participants from the KoreaN Cohort Study for Outcome in Patients With CKD were enrolled. The main exposures were T2DM and CAC. The primary outcome was CKD progression defined as a composite of a 50% decline in estimated glomerular filtration rate or kidney failure with replacement therapy. Multivariable cause-specific hazard function was employed to determine the association between the main exposures and the primary outcome. Results During 8633 person-years of follow-up, the primary outcome occurred in 565 (27.3%) participants. In the multivariable cause-specific hazard model, both T2DM and CAC Agatston score (CACS) &amp;gt;0 were associated with a 1.80- and a 1.41-fold increased risk of CKD progression compared with counterparts. There was a significant interaction between T2DM and CAC for the primary outcome. In patients without T2DM, CACS &amp;gt;0 was not associated with the primary outcome compared with CACS of 0. However, in patients with T2DM, CACS &amp;gt;0 was associated with a significantly higher risk of CKD progression (adjusted hazard ratio, 2.12; 95% confidence interval, 1.64-2.75). In addition, a 1-SD increase in CACS was associated with 1.11-fold higher risk of CKD progression. Notably, this association was also significant in patients with T2DM who had CACS of 0. The slope of eGFR decline was steeper in patients with T2DM and the magnitude of decline was greater when CACS &amp;gt;0. Conclusion CAC were more strongly associated with risk of CKD progression in patients with T2DM than in those without. Thus, clinical implication of CAC may differ depending on the presence of T2DM.

#5289 INTRARENAL RENIN-ANGIOTENSIN SYSTEM ACTIVATION ALTERS RELATIONSHIP BETWEEN SYSTOLIC BLOOD PRESSURE AND PROGRESSION OF CHRONIC KIDNEY DISEASE

Abstract Background and Aims Elevated blood pressure (BP) and intrarenal renin-angiotensin system (RAS) activity are closely related to chronic kidney disease (CKD) progression. However, interrelationship between BP and intrarenal RAS activity on the risk of CKD progression is unknown. Method We analyzed 2,076 participants from the Korean Cohort Study for Outcomes in Patients With CKD. The main exposure was systolic BP (SBP). The urinary angiotensinogen-to-creatinine (u-AGT/Cr) ratio was stratified according to the median value (3.65 μg/gCr). The primary outcome was a composite kidney outcome of a ≥50% decline in estimated glomerular filtration rate from baseline measurement or initiation of kidney replacement therapy. Results During 10,550 person-years of follow-up (median, 5.2 years), the composite outcome occurred in 800 (38.5%) participants. In the multivariable cause-specific hazard model, higher SBP was associated with an increased risk of CKD progression. There was a significant interaction between SBP and u-AGT/Cr ratio on the risk of the primary outcome (P-for-interaction = 0.019). In patients with u-AGT/Cr &amp;lt;3.65 μg/gCr, the hazard ratios (HRs) (95% confidence intervals [CIs]) for SBP 120–129, 130–139, and ≥140 mmHg were 1.47 (1.08-2.01), 1.74 (1.26-2.39), and 2.43 (1.76-3.37), respectively, compared with SBP &amp;lt;120 mmHg. In addition, each 10 mmHg increase in SBP was associated with an 18% higher risk of CKD progression. Moreover, there was a greater decline in the estimated glomerular filtration rate among the higher SBP categories. However, these associations were not observed in patients with u-AGT/Cr ≥3.65 μg/gCr. Conclusion Urinary angiotensinogen levels may modify the association between SBP and adverse kidney outcomes.

#3746 RISK OF PROGRESSIVE CHRONIC KIDNEY DISEASE WITH NEPHROSCLEROSIS ON KIDNEY BIOPSY DEFINED USING AGE-BASED VERSUS YOUNG ADULT-BASED THRESHOLDS

Abstract Background and Aims The tissue pathology of both aging and chronic kidney disease (CKD) is nephrosclerosis defined by globally sclerotic glomeruli (GSG) and interstitial fibrosis and tubular atrophy (IFTA). We sought to determine if risk of CKD outcomes is better predicted by age-based or young adult-based thresholds for nephrosclerosis. Method Using the Aging Kidney Anatomy study, living kidney donors, kidney tumor patients, and native kidney disease patients had kidney biopsy images analyzed morphometric to quantify %GSG, %IFTA, and IFTA foci density (Figure 1). Using normotensive donors, young (18-29 y) thresholds and age-based (18-29 y, 30-39 y, 40-49 y, 50-59 y, 60-69 y, 70+y) 95th percentile thresholds were defined. Progressive CKD was defined as a 40% decline in serum creatinine based estimated GFR or kidney failure (dialysis or transplantation) from a 4-month post-biopsy baseline (due to the nephrectomy event in tumor patients and due to the common occurrence of acute kidney injury in the native kidney disease patients at the time of biopsy). The age-adjusted risk of progressive CKD in tumor patients and native kidney disease patients was compared between those with nephrosclerosis that was “normal compared to young”, “normal for age but abnormal compared to young”, and “abnormal for age” (Figure 2). Results There were 2583 normotensive living kidney donors, 1363 tumor patients, and 314 native kidney disease patients studied. The 95th percentiles for 18-29y to 70+y age groups among normotensive donors were 1.7% to 16% for %GSG, 0.18% to 6.5% for %IFTA, and 8.2 to 59.3 per cm2 for IFTA foci density. The risk of CKD outcomes did not differ between tumor patients and native kidney disease patients with nephrosclerosis “normal compared to young” versus “abnormal compared to young but normal for age” in both cohorts. Thus, these two categories were combined into “normal for age”. The risk of progressive CKD over a median 5.5 years follow-up for tumor patients was higher with %GSG, %IFTA, and IFTA foci density that was abnormal for age vs normal for age (HRs 2.28, 2.41, and 3.11, respectively, p&amp;lt;.0001 for all). The risk of progressive CKD over a median 7.2 years follow-up for native kidney disease patients was higher with %GSG, %IFTA, and IFTA density that was abnormal for age vs normal for age (HRs 1.87, 2.65, and 3.11, respectively, p&amp;lt;.0001 for all). Conclusion There is a substantial increase in nephrosclerosis from aging alone in healthy adults that is not prognostic for CKD outcomes. Age-based thresholds better identify clinically relevant CKD.

#3901 PROGRESSION OF INCIDENT CHRONIC KIDNEY DISEASE: A DANISH NATIONWIDE POPULATION-BASED COHORT STUDY

Abstract Background and Aims The increasing global burden of kidney failure calls for targeted interventions to slow progression of chronic kidney disease (CKD). However, the understanding of progression from CKD stage G3 is limited. We aimed to characterise individuals with incident CKD stage G3 in Denmark and to examine CKD progression defined by three different measures. Method We conducted a nationwide, population-based cohort study using routinely collected individual-level data from national health and administrative databases in Denmark (population ∼5.9 million). Using creatinine tests performed in general practice and the outpatient hospital setting from 1 January 2017 to 31 December 2020, we included all adults in Denmark with incident CKD stage G3, based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria (≥2 creatinine measurements corresponding to an estimated glomerular filtration rate (eGFR) between 30-59 ml/min/1.73 m2 separated by ≥90 days). We used the 2009 CKD Epidemiology Collaboration Creatinine Equation for calculating eGFR. The three years leading up to the study period comprised a washout period to minimise inclusion of individuals with prevalent CKD. We explored CKD progression based on three outcome measures of different sensitivity, including 1) rapid CKD progression (decline in eGFR of ≥5 ml/min/1.73 m2/year, that is, for each eGFR measurement taken during follow-up, we considered this and the measurements taken in the prior year (requiring ≥3 eGFR measurements separated by ≥90 days)); 2) drop in GFR category (drop between GFR categories, 45–59 [G3a], 30–44 [G3b], 15–29 [G4], &amp;lt;15 [G5] ml/min/1.73 m2, accompanied by ≥25% drop in eGFR from baseline); and 3) kidney failure (≥2 eGFR measurements &amp;lt;15 ml/min/1.73 m2 separated by ≥90 days and/or kidney replacement therapy). The 1- and 3-year risks of CKD progression according to the three definitions and all-cause mortality were examined as cumulative incidences using the Aalen-Johansen method. Results We included 133,443 individuals with incident CKD stage G3. The median age at inclusion was 75 years (interquartile range (IQR): 69-82) and 55% were females with 59% having hypertension, 18% having diabetes and 10% having heart failure. The median eGFR at inclusion was 56 ml/min/1.73 m2 (IQR: 51-58) and the median number of eGFR measurements was 3 (IQR: 2-5) in the prior year. Among the 133,443 individuals with incident CKD stage G3, 48,997 (37%) fulfilled the criteria for rapid CKD progression at inclusion. Among the 84,446 individuals without rapid progression on the day of inclusion, the 1- and 3-year risks of rapid CKD progression were 25.0% (95% confidence interval (CI): 24.7-25.3) and 46.0% (95% CI: 45.6-46.4), respectively. The risk of a drop in GFR category was 6.9% (95% CI: 6.8-7.1) after 1 year and 16.6% (95% CI: 16.4-16.8) after 3 years. The risks of kidney failure/renal replacement therapy were 0.1% (95% CI: 0.1-0.1) and 0.3% (95% CI: 0.3-0.4) after 1 and 3 years, respectively. All-cause mortality was 6.8% (95% CI: 6.7-6.9) in the first year and the 3-year mortality was 18.1% (95% CI: 17.9-18.4) (Table 1). Conclusion This nationwide, population-based cohort study showed that a substantial proportion of individuals experienced rapid CKD progression in the 3 years following incident CKD stage G3, whereas the risk of drop in GFR category was considerably lower. Kidney failure within 3 years was rare, while all-cause mortality was relatively modest, taking the high average age into account. This highlights the potential for preventive interventions in patients at risk of rapidly deteriorating kidney function, who might benefit from regular monitoring and targeted treatment.

#3696 THE PROACT 2 PHASE 3 STUDY DESIGN: A RANDOMIZED CONTROLLED STUDY OF REACT IN PARTICIPANTS WITH TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE

Abstract Background and Aims The global burden of chronic kidney disease (CKD) is estimated at 850 million people worldwide, with diabetic kidney disease (DKD) being the main cause. Existing medical therapies may delay the deterioration of kidney function; however, many patients continue to progress to kidney failure. REACT (Renal Autologous Cell Therapy), a cell-based advanced therapy, is being developed to decrease the risk of CKD progression. REACT is composed of selected renal cells (SRC), isolated from a participant's own kidney, which are involved in the process of kidney repair and regeneration. Preclinical studies in multiple animal models of DKD have demonstrated that SRC injected directly into the kidney cortex produced a regenerative response improving overall kidney function and histology. Encouraging early clinical results from phase 2 studies with REACT resulted in RMAT (Regenerative Medicine Advanced Therapy) designation by the Food and Drug Administration in the USA. Method Description of therapy - REACT is derived from the participant's kidney tissue obtained by percutaneous biopsy in an outpatient setting. Renal cells are culture expanded ex vivo, and SRC are isolated. SRC are cryopreserved at a concentration of 100 × 106 cells/mL and shipped to the clinical site approximately 12 weeks after the biopsy. REACT will be percutaneously reinjected by specially trained interventional proceduralists utilizing CT guidance and a non-cutting 25-gauge needle inserted into the kidney cortex. A single REACT dose will be injected into each kidney, approximately 3 months apart. Participants - The study will enroll 600 participants from approximately 250 global sites (including 38 sites in the EU)) with up to 60 months of follow-up. Patients aged 30-80 years with type 2 diabetes who have an estimated glomerular filtration rate (eGFR) of 20-50 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) 300-5000 mg/g will be eligible. Participants will be randomized 1:1 to REACT or sham biopsy/injection in a single blind manner. Standard-of care therapies including renin angiotensin system inhibitors and sodium glucose cotransporter inhibitors may be given as per local guidance. Results Study Endpoints - The primary endpoint for proact 2 is the time from first injection to the earliest of ≥40% eGFR decline, eGFR &amp;lt; 15 mL/min/1.73m2 sustained for 30 days, initiation of chronic dialysis or kidney transplantation, or cardiovascular or renal death. proact 2 is an endpoint driven trial with 80% power to detect a hazard ratio of 0.6 for the primary outcome. Key secondary outcomes will include time to these individual components as well as annualized change in eGFR and change from baseline in UACR. Conclusion proact 2 is a global Phase 3 randomized controlled trial that will evaluate the safety and efficacy of REACT on major kidney disease endpoints, among participants with type 2 diabetes and moderate-severe CKD. This trial is part of a comprehensive phase 3 development program with an estimated start date of June 2023. REACT, a novel autologous cell therapy composed of SRC, has the potential to directly improve kidney function with a goal to prevent kidney failure.

Association between different dementia diagnosis and kidney function decline: A Swedish registry study

AbstractBackgroundPopulation studies have shown that chronic kidney disease(CKD) and CKD progression are associated with dementia, particularly Alzheimer’s dementia(AD) and vascular dementia(VD). However, the impact of different brain pathogenesis on these associations is not known.MethodObservational study of patients with recently diagnosed dementia disorders from the Swedish Dementia Registry(SveDem) 2007‐2018 linked with complete information of kidney function tests [estimated glomerular filtration rate(eGFR)] over time from the Stockholm CREAtinine Measurements(SCREAM) registry. The study exposure were different dementia diagnosis [AD, VD, mixed dementia, dementia with Lewy Bodies(DLB) and Parkinson’s disease dementia(PDD), frontotemporal dementia(FTD), unspecified dementia(UNS) and other dementia types]. The study outcome was CKD progression, defined as the composite of a sustained eGFR decline of&gt;30% from baseline, initiation of kidney replacement therapy or death attributed to kidney disease. We performed competing risk analyses where death from non‐renal causes was considered as competing events for CKD progression. Confounders included demographics, comorbidities, and baseline kidney function.ResultWe included 20,618 patients, of whom, 6,452(31%) had AD, 7,012(34%) had mixed dementia, 3,987(19%) had VD, 764(4%) had DLB or PDD, 312(2%) had FTD, and 2,091(10%) patients were diagnosed with unspecified or other dementia diagnoses. The mean age was 80 years (60%female). During median follow‐up time of 2.5 (IQR1.0‐4.5) years, 2,225(11%) events of CKD progression occurred, along with 8,684(42%) non‐renal deaths. After adjusting for confounders and accounting for competing risks, a higher risk of CKD progression compared to patients with AD was observed for patients with VD [sub‐HR, 95%CI 1.19;1.05‐1.34], mixed (1.13;1.02‐1.26), UNS or other dementia types (1.13;0.96‐1.32), while patients with DLB or PDD dementia had 46% lower risk of CKD progression (0.54;0.39‐0.76), and those with FTD showed no difference compared to AD (0.99;0.64‐1.51).ConclusionVD and mixed dementia (vs AD diagnosis) were associated with a higher risk of CKD progression, whereas DLB or PDD dementia were associated with lower risk of CKD progression. Since DLB and PDD dementia involve less and VD and mixed dementia more vascular pathology, this suggests that vascular mechanisms may play an important role in the brain‐kidney axis. Future studies are needed to explore this hypothesis.

Plasma arginine metabolites in health and chronic kidney disease.

Elevated plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) are risk factors for chronic kidney disease (CKD) and cardiovascular disease. Using plasma cystatin C (pCYSC)-based estimated glomerular filtration rate (eGFR) trajectories, we identified a cohort at high risk of poor kidney-related health outcomes amongst members of the Dunedin Multidisciplinary Health and Development Study (DMHDS). We therefore examined associations between methylarginine metabolites and kidney function in this cohort. ADMA, SDMA, L-arginine and L-citrulline were measured in plasma samples from 45-year-olds in the DMHDS cohort by liquid chromatography-tandem mass spectrometry. In a healthy DMHDS subset (n=376), mean concentrations were: ADMA (0.40±0.06µmol/L), SDMA (0.42±0.06µmol/L), L-arginine (93.5±23.1µmol/L) and L-citrulline (24.0±5.4µmol/L). In the total cohort (n=857), SDMA correlated positively with serum creatinine (Pearson's r=0.55) and pCYSC (r=0.55), and negatively with eGFR (r=0.52). A separate cohort of 38 patients with stage 3-4 CKD (eGFR 15-60mL/min/1.73 m2) confirmed significantly higher mean ADMA (0.61±0.11µmol/L), SDMA (0.65±0.25µmol/L) and L-citrulline (42.7±11.8µmol/L) concentrations. DMHDS members classified as high-risk of poor kidney health outcomes had significantly higher mean concentrations of all four metabolites compared with individuals not at risk. ADMA and SDMA individually predicted high-risk of poor kidney health outcomes with areas under the ROC curves (AUCs) of 0.83 and 0.84, and together with an AUC of 0.90. Plasma methylarginine concentrations facilitate stratification for risk of CKD progression.

Cardiorenal syndrome and diabetes: an evil pairing.

Cardiorenal syndrome (CRS) is a pathology where the heart and kidney are involved, and the deterioration of one of them leads to the malfunction of the other. Diabetes mellitus (DM) carries a higher risk of HF and a worse prognosis. Furthermore, almost half of people with DM will have chronic kidney disease (CKD), which means that DM is the main cause of kidney failure. The triad of cardiorenal syndrome and diabetes is known to be associated with increased risk of hospitalization and mortality. Cardiorenal units, with a multidisciplinary team (cardiologist, nephrologist, nursing), multiple tools for diagnosis, as well as new treatments that help to better control cardio-renal-metabolic patients, offer holistic management of patients with CRS. In recent years, the appearance of drugs such as sodium-glucose cotransporter type 2 inhibitors, have shown cardiovascular benefits, initially in patients with type 2 DM and later in CKD and heart failure with and without DM2, offering a new therapeutic opportunity, especially for cardiorenal patients. In addition, glucagon-like peptide-1 receptor agonists have shown CV benefits in patients with DM and CV disease in addition to a reduced risk of CKD progression.

Glycemic Control and Adverse Clinical Outcomes in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: Results from KNOW-CKD.

The optimal level of glycosylated hemoglobin (HbA1c) to prevent adverse clinical outcomes is unknown in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We analyzed 707 patients with CKD G1-G5 without kidney replacement therapy and T2DM from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD), a nationwide prospective cohort study. The main predictor was time-varying HbA1c level at each visit. The primary outcome was a composite of development of major adverse cardiovascular events (MACEs) or all-cause mortality. Secondary outcomes included the individual endpoint of MACEs, all-cause mortality, and CKD progression. CKD progression was defined as a ≥50% decline in the estimated glomerular filtration rate from baseline or the onset of end-stage kidney disease. During a median follow-up of 4.8 years, the primary outcome occurred in 129 (18.2%) patients. In time-varying Cox model, the adjusted hazard ratios (aHRs) for the primary outcome were 1.59 (95% confidence interval [CI], 1.01 to 2.49) and 1.99 (95% CI, 1.24 to 3.19) for HbA1c levels of 7.0%-7.9% and ≥8.0%, respectively, compared with <7.0%. Additional analysis of baseline HbA1c levels yielded a similar graded association. In secondary outcome analyses, the aHRs for the corresponding HbA1c categories were 2.17 (95% CI, 1.20 to 3.95) and 2.26 (95% CI, 1.17 to 4.37) for MACE, and 1.36 (95% CI, 0.68 to 2.72) and 2.08 (95% CI, 1.06 to 4.05) for all-cause mortality. However, the risk of CKD progression did not differ between the three groups. This study showed that higher HbA1c levels were associated with an increased risk of MACE and mortality in patients with CKD and T2DM.

Proteomics: Progress and Promise of High-Throughput Proteomics in Chronic Kidney Disease

Current proteomic tools permit the high-throughput analysis of the blood proteome in large cohorts, including those enriched for chronic kidney disease (CKD) or its risk factors. To date, these studies have identified numerous proteins associated with cross-sectional measures of kidney function, as well as with the longitudinal risk of CKD progression. Representative signals that have emerged from the literature include an association between levels of testican-2 and favorable kidney prognosis and an association between levels of TNFRSF1A and TNFRSF1B and worse kidney prognosis. For these and other associations, however, understanding whether the proteins play a causal role in kidney disease pathogenesis remains a fundamental challenge, especially given the strong impact that kidney function can have on blood protein levels. Prior to investing in dedicated animal models or randomized trials, methods that leverage the availability of genotyping in epidemiologic cohorts—including Mendelian randomization, colocalization analyses, and proteome-wide association studies—can add evidence for causal inference in CKD proteomics research. In addition, integration of large-scale blood proteome analyses with urine and tissue proteomics, as well as improved assessment of posttranslational protein modifications (e.g., carbamylation), represent important future directions. Taken together, these approaches seek to translate progress in large-scale proteomic profiling into the promise of improved diagnostic tools and therapeutic target identification in kidney disease.

Machine-learning enhancement of urine dipstick tests for chronic kidney disease detection.

Screening for chronic kidney disease (CKD) requires an estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) from a blood sample and a proteinuria level from a urinalysis. We developed machine-learning models to detect CKD without blood collection, predicting an eGFR less than 60 (eGFR60 model) or 45 (eGFR45 model) using a urine dipstick test. The electronic health record data (n = 220018) obtained from university hospitals were used for XGBoost-derived model construction. The model variables were age, sex, and 10 measurements from the urine dipstick test. The models were validated using health checkup center data (n = 74380) and nationwide public data (KNHANES data, n = 62945) for the general population in Korea. The models comprised 7 features, including age, sex, and 5 urine dipstick measurements (protein, blood, glucose, pH, and specific gravity). The internal and external areas under the curve (AUCs) of the eGFR60 model were 0.90 or higher, and a higher AUC for the eGFR45 model was obtained. For the eGFR60 model on KNHANES data, the sensitivity was 0.93 or 0.80, and the specificity was 0.86 or 0.85 in ages less than 65 with proteinuria (nondiabetes or diabetes, respectively). Nonproteinuric CKD could be detected in nondiabetic patients under the age of 65 with a sensitivity of 0.88 and specificity of 0.71. The model performance differed across subgroups by age, proteinuria, and diabetes. The CKD progression risk can be assessed with the eGFR models using the levels of eGFR decrease and proteinuria. The machine-learning-enhanced urine-dipstick test can become a point-of-care test to promote public health by screening CKD and ranking its risk of progression.

Renal function in patients with chronic kidney disease and hypertension degree 1–2 against the background of SARS-CoV-2

Renal function in patients with chronic kidney disease and hypertension degree 1–2 against the background of SARS-CoV-2

Ultraprocessed Foods and Kidney Disease Progression, Mortality, and Cardiovascular Disease Risk in the CRIC Study

Ultraprocessed foods are widely consumed in the United States and are associated with cardiovascular disease (CVD), mortality, and kidney function decline in the general population. We investigated associations between ultraprocessed food intake and chronic kidney disease (CKD) progression, all-cause mortality, and incident CVD in adults with chronic kidney disease (CKD). Prospective cohort study. Chronic Renal Insufficiency Cohort Study participants who completed baseline dietary questionnaires. Ultraprocessed food intake (in servings per day) classified according to the NOVA system. CKD progression (≥50% decrease in estimated glomerular filtration rate [eGFR] or initiation of kidney replacement therapy), all-cause mortality, and incident CVD (myocardial infarction, congestive heart failure, or stroke). Cox proportional hazards models adjusted for demographic, lifestyle, and health covariates. There were 1,047 CKD progression events observed during a median follow-up of 7 years. Greater ultraprocessed food intake was associated with higher risk of CKD progression (tertile 3 vs tertile 1, HR, 1.22; 95% CI, 1.04-1.42; P=0.01 for trend). The association differed by baseline kidney function, such that greater intake was associated with higher risk among people with CKD stages 1/2 (eGFR≥60mL/min/1.73m2; tertile 3 vs tertile 1, HR, 2.61; 95% CI, 1.32-5.18) but not stages 3a-5 (eGFR<60mL/min/1.73m2; P=0.003 forinteraction). There were 1,104 deaths observed during a median follow-up of 14 years. Greater ultraprocessed food intake was associated with higher risk of mortality (tertile 3 vs tertile 1, HR, 1.21; 95% CI, 1.04-1.40; P=0.004 for trend). Self-reported diet. Greater ultraprocessed food intake may be associated with CKD progression in earlier stages of CKD and is associated with higher risk of all-cause mortality in adults with CKD. Ultraprocessed foods are industrial formulations produced using ingredients and processes that are not commonly used in culinary preparations and contain few, if any, intact unprocessed foods. Ultraprocessed foods are widely consumed in the United States, and high intakes of such foods have been linked to cardiovascular disease, kidney disease, and mortality in the general population. In this study, we found that greater intake of ultraprocessed foods was associated with higher risk of kidney disease progression and mortality in adults with chronic kidney disease. Our findings suggest that patients with kidney disease may benefit from greater consumption of fresh, whole, and homemade or hand-prepared foods and fewer highly processed foods.

Triglyceride-glucose index is associated with the risk of chronic kidney disease progression in type 2 diabetes.

The study aimed to investigate the association of TyG index with chronic kidney disease (CKD) progression in type 2 diabetes mellitus (T2DM). A total of 179 T2DM patients with CKD were retrospectively included. CKD progression was defined as a doubling of baseline serum creatinine or onset of end-stage kidney disease (ESKD). Internal validation was performed by the Kidney Failure Risk Equation (KFRE) model and Net reclassification improvement (NRI). The optimal cut-off value of the TyG index was 9.17. The cumulative incidence of kidney outcomes was significantly higher in the high-TyG group (v.s low-TyG group, P = 0.019). In addition, the high-TyG index was associated with a greater risk of CKD progression (HR 1.794, 95% CI 1.026-3.137, P = 0.040). And reclassification analyses confirmed the final adjusted model improved NRI (61.90% v.s model 2, 43.80% v.s model 1). The further RCS curves presented an inverted S-shaped relationship between the TyG index and the risk of CKD progression. Internal validation verified that a higher TyG index was associated with 2.10-fold increased odds of 2-year ESKD risk >10% (95% CI 1.82-8.21). Moreover, subgroup analysis suggested that the association was more pronounced in those at relatively early CKD stages (higher than stage 2) and with no medication history of oral hypoglycemic agents. An elevated TyG index was associated with a higher risk of CKD progression in T2DM patients. Our findings suggested that timely targeting insulin sensitivity at the early stages of T2DM might be associated with declined future risk of CKD development.