Risk Of Chronic Kidney Disease Progression Research Articles

Skipping Breakfast and Progression of Chronic Kidney Disease in the General Japanese Population: The Iki City Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD)

Introduction: Breakfast-skipping habits are associated with adverse health outcomes including coronary heart disease, metabolic syndrome, and diabetes mellitus. However, it remains uncertain whether skipping breakfast affects chronic kidney disease (CKD) risk. This study aimed to examine the association between skipping breakfast and progression of CKD. Methods: We retrospectively conducted a population-based cohort study using the data from the Iki City Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD). Between 2008 and 2019, we included 922 participants aged 30 years or older who had CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or proteinuria) at baseline. Breakfast skippers were defined as participants who skipped breakfast more than 3 times per week. The outcome was CKD progression defined as a decline of at least 30% in the estimated glomerular filtration rate (eGFR) from the baseline status. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD progression, adjusted for other CKD risk factors. Results: During a follow-up period with a mean of 5.5 years, CKD progression occurred in 60 (6.5%) participants. The incidence rate (per 1,000 person-years) of CKD progression was 21.5 in the breakfast-skipping group and 10.7 in the breakfast-eating group (p = 0.029), respectively. The multivariable-adjusted HR (95% CI) for CKD progression was 2.60 (95% CI: 1.29–5.26) for the breakfast-skipping group (p = 0.028) compared with the group eating breakfast. There were no clear differences in the association of skipping breakfast with CKD progression in subgroup analyses by sex, age, obesity, hypertension, diabetes mellitus, baseline eGFR, and baseline proteinuria. Conclusion: Skipping breakfast was significantly associated with higher risk of CKD progression in the general Japanese population.

Matrix Metalloproteinase-2 and CKD Progression: The Chronic Renal Insufficiency Cohort (CRIC) Study

Matrix metalloproteinase 2 (MMP-2) plays an important role in the development of fibrosis, the final common pathway of chronic kidney disease (CKD). This study aimed to assess the relationship between repeated measures of MMP-2 and CKD progression in a large, diverse prospective cohort. In a prospective cohort of Chronic Renal Insufficiency Cohort (CRIC) participants (N=3,827), MMP-2 was measured at baseline. In a case-cohort design, MMP-2 was additionally measured at year 2 in a randomly selected subcohort and cases of estimated glomerular filtration rate (eGFR) halving or kidney replacement therapy (KRT) (N= 1,439). CRIC is a multicenter prospective cohort of adults with CKD. MMP-2 measured in plasma at baseline and at year2. A composite kidney endpoint (KRT/eGFR halving). Weighted Cox proportional hazards models for case-cohort participants. Participants were followed for a median of 4.6 years from year 2 and 6.9 years from the baseline. Persistently elevated MMP-2 (≥300ng/mL at both baseline and year 2) increased the hazard of the composite kidney endpoint (HR, 1.61; 95% CI, 1.07-2.42; P=0.09) after adjusting for covariates. The relationship of persistently elevated MMP-2 was modified by levels of inflammation, with a 2.6 times higher rate of the composite kidney endpoint in those with high-sensitivity C-reactive protein<2.5g/dL at study entry. Heterogeneity of effect was found with proteinuria, with a baseline MMP-2 level of≥300ng/mL associated with an increased risk of the composite kidney endpoint (HR, 1.30; 95% CI, 1.09-1.54) only with proteinuria≥442mg/g. The observational study design limits causal interpretation. Elevated MMP-2 is associated with CKD progression, particularly among those with low inflammation and those with proteinuria. Future investigations are warranted to confirm the reduction in risk of CKD progression among these subgroups of patients with CKD.

#594 Long-term risk of incident/progressive chronic kidney disease, or end-stage kidney disease post-acute kidney injury: systematic review, meta-analysis

Abstract Background and Aims Little is known about which patients to follow-up after an episode of acute kidney injury (AKI) for future risks. The aim of this review is to assess the association between AKI and the incidence or progression of chronic kidney disease (CKD) or end-stage kidney disease (ESKD), stratified by subcategories of AKI-stages, -durations, and clinical settings. Method A systematic search of the literature in PubMed and Embase was performed by two reviewers to identify studies that examined CKD incidence (development of CKD stage ≥3), CKD progression (worsening of kidney function in patients with CKD stage ≥3), or ESKD, in patients with AKI versus patients without AKI. The risk of bias was assessed using the Newcastle-Ottawa Scale. Relative effect estimates (odds and hazard ratios) were pooled using a random effects model. Results In total, 48 retrospective and 13 prospective studies, encompassing 140.985 patients with AKI, were included in this review. All the studies were of moderate or high quality. The pooled effect ratio was 3.36 (95% confidence interval (CI) 2.68-4.03) for CKD incidence (n = 31 studies). This remained 3.40 (95% CI 1.79-5.00) in a sub analysis including patients with a recovered kidney function post-AKI, and 1.49 (95% CI 1.44-1.55) in a sub analysis including patients with an AKI lasting less than 3 days (Fig. 1). Overall, the effect ratio for CKD progression (n = 11 studies) was 1.70 (95% CI 1.38-2.01) and 3.81 (95% CI 2.58-5.04) for ESKD (n = 24 studies). The increased risk of these two outcomes were not seen in the sub analyses only including patients with AKI lasting less than 3 days. Overall, there is an observable higher risk for CKD incidence, CKD progression, and ESKD with increased AKI staging, although not always statistically significant. Minimal variations were observed across clinical settings. Conclusion In our review, including over 60 studies, we found that AKI was associated with an increased risk of CKD incidence, CKD progression, and ESKD. Patients with higher AKI-stages had even larger risks. Notably, even brief episodes of AKI (lasting less than 3 days) were associated with a higher risk of CKD incidence compared to patients without AKI. In contrary, the risk for ESKD is not enlarged in a sub analysis including patients with recovered kidney function compared to patients without AKI. These result warrant close monitoring of the kidney function post-AKI, specifically in patients with AKI lasting 3 days or longer. Future research should focus more on the risk of CKD progression in order to tailor follow-up care in these more vulnerable patients.

#1200 Coronary artery calcium modifies the relationship between blood pressure and adverse kidney outcome: results from KNOW-CKD

Abstract Background and Aims Previous studies evidenced that elevated coronary artery calcium (CAC) score is associated with higher chronic kidney disease (CKD) progression. However, the use of CAC score to guide CKD management has not been adequately evaluated. Here, we evaluated whether presence of CAC modify the association between systolic blood pressure (SBP) and CKD progression in patients with CKD. Method We analyzed 1693 participants with CKD stages G1 to G5 from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Key exclusion criteria were kidney failure with replacement therapy (KFRT) and missing data for CAC and SBP information. We categorized participants according to baseline SBP and CAC score (Controlled BP, SBP &amp;lt; 120 mmHg; Elevated BP without CAC, SBP 120-140 mmHg and CAC score = 0; Elevated BP with CAC, SBP 120-140 mmHg and CAC score &amp;gt;0; Uncontrolled BP, SBP &amp;gt;140 mmHg) and compared the CKD progression. The CKD progression was defined as a composite of halving eGFR from baseline value or onset of KFRT. Results During 10,023 person-years of follow-up (median 6.2 years), the composite outcome occurred in 689 (40.7%) participants, and 108 (6.4%) participants died among the KNOW-CKD participants. There was significant interaction between CAC score and SBP for CKD progression (P &amp;lt; 0.001). There were 181/568 (31.9%), 167/424 (39.4%), 128/314 (40.8%) 213/387 (55.0%), composite outcomes in controlled BP, elevated BP without CAC, elevated BP with CAC, uncontrolled BP group, respectively. In crude Cox regression, compared to controlled BP, elevated BP with CAC group showed similar CKD progression risk (Hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.95-1.44), whereas other strata group showed increased risk of CKD progression (elevated BP with CAC; HR, 1.59; 95% CI 1.31-1.94 and uncontrolled BP, HR, 1.94; 95% CI 1.56-2.41). Similar elevated risk in elevated BP with CAC was observed even after adjustment of age, sex, diabetes mellitus, estimated glomerular filtration ratio, and proteinuria (HR, 1.26; 95% CI, 1.02-1.56). However, the risk of CKD progression in elevated BP without CAC group was comparable to controlled BP group (HR, 1.20; 95% CI, 0.87-1.66). Conclusion Elevated SBP was more strongly associated with an increased risk of adverse kidney outcomes in patients with coronary calcification.

#2546 CKD-PC risk model for CKD progression: validation and association with outcomes in the FIDELITY population

Abstract Background and Aims The Chronic Kidney Disease Prognosis Consortium (CKD-PC) recently developed risk models to predict the 3-year risk of a ≥40% decrease in estimated glomerular filtration rate (eGFR) or to predict kidney failure in the general population. Unlike the kidney failure risk equation, the CKD-PC model is valid for all levels of eGFR (above and below 60 mL/min/1.73 m2) and includes chronic kidney disease (CKD) progression risk factors besides age, sex, eGFR and albuminuria; namely: systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, body mass index, glycated hemoglobin, insulin use, and oral diabetes medication use [1]. We evaluated whether the CKD-PC model, developed using electronic health record data, is valid for use in a contemporary clinical population using the FIDELITY pooled dataset from international randomized clinical trials of finerenone [2]. Additionally, to inform clinical practice, we evaluated the efficacy of finerenone using categories of 3-year CKD progression risk as predicted by the model. Method FIDELITY was an individual, patient-level, prespecified, pooled efficacy and safety analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials of patients with CKD and type 2 diabetes (T2D), randomized 1:1 to finerenone or placebo. The 3-year CKD progression risk of these patients was predicted and the validity of the CKD-PC model was evaluated using area under the curve (AUC) score (with higher scores indicating better risk prediction), Brier score (lower scores indicating better prediction), and by calibration plots of observed versus predicted risk by deciles of 3-year CKD progression risk. To evaluate the efficacy of finerenone, 3-year risk was categorized in quartiles and the effect of finerenone versus placebo on a kidney composite outcome, defined as kidney failure, a sustained ≥40% decrease in eGFR from baseline over ≥4 weeks, or renal death, was assessed. Results The FIDELITY population comprised 13,026 individuals with a mean eGFR of 58 mL/min/1.73 m2 and urine albumin-to-creatinine ratio of 515 mg/g. The median follow-up was 3 years and there were 1849 total kidney outcome events. Of 12,968 patients analyzed, the median 3-year risk of kidney failure was 15% (Q1–Q3: 9–24%). Overall, the model demonstrated good discrimination to predict a ≥40% kidney composite outcome for patients with CKD and T2D in FIDELITY: AUC score 0.726 (95% confidence interval [CI] 0.712–0.739) and Brier score 0.100 (95% CI 0.097–0.103). The predicted 3-year risk was generally slightly higher than the observed risk (Fig. 1). Finerenone was effective in preventing CKD progression across the risk quartiles (p-interaction = 0.094) with a trend towards greater efficacy in the higher risk quartiles (3-year risk of CKD progression ≥10%) (Fig. 2). All risk groups showed benefit with finerenone compared to placebo regarding eGFR decline in the chronic phase. Conclusion The CKD-PC risk model for CKD progression performed well in a large global clinical trial population of patients with CKD and T2D. Finerenone was effective across the range of baseline risk of CKD progression.

#1743 Kidney outcomes associated with SGLT2 inhibitors compared to other glucose-lowering drugs: a real-world study from China

Abstract Background and Aims Currently, there is insufficient real-world study on the kidney outcomes of SGLT2i in mainland Chinese patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). This study aimed to investigate the association between the utilization of Sodium-dependent glucose cotransporters inhibitors (SGLT2i) in real-world settings and kidney outcomes in patients with T2D and CKD in mainland China. Method In a retrospective analysis of electronic medical records from West China Hospital of Sichuan University, patients with T2D and CKD were included. Patients were divided into two groups, those initiating treatment with SGLT2i and those receiving other glucose-lowering drugs (oGLDs). The primary focus lies in examining the impact of SGLT2i on the decline slope of eGFR and major kidney events in these patients. Results We enrolled 944 patients diagnosed with both T2D and CKD. Out of these, 605 patients were prescribed SGLT2i, while the remaining 339 patients received oGLDs. The median follow-up duration were 16.8 months and 20.6 months, respectively. Throughout the follow-up period, we observed a significant decrease in the rate of eGFR decline in patients using SGLT2i (4.94 ml/min/1.73 m2 per year reduction compared to oGLDs, 95% CI: 4.73–5.15). A total of 101 kidney composite endpoint events occurred, with 31 events in the SGLT2i group and 70 events in the oGLDs group. The use of SGLT2i was associated with a 65% decrease in the risk of kidney composite endpoint events (hazard ratio 0.35, 95% CI 0.19–0.63). Conclusion In clinical practice, SGLT2i have shown favorable effects on kidney prognosis in patients with T2D and CKD in mainland China. These effects remain consistent across patients with varying risks of CKD progression.

#1117 Skipping breakfast and progression of chronic kidney disease in a general Japanese population

Abstract Background and Aims Unhealthy eating habits such as skipping breakfast are associated with adverse health outcomes including coronary heart disease, metabolic syndrome and diabetes mellitus. However, it remains uncertain whether skipping breakfast affects chronic kidney disease (CKD) risk. The aim of this study was to investigate the association between skipping breakfast and progression of CKD. Method Between 2008 and 2019, we conducted a retrospective cohort study using annual health check data in Iki City, Nagasaki, Japan. A total of 922 participants aged 30 years or older who had CKD (estimated glomerular filtration rate &amp;lt;60 mL/min/1.73 m2 and/or proteinuria) at baseline were included in the present analysis. The breakfast-skipping group was defined as participants who skipped breakfast more than 3 times per week. The outcome was CKD progression defined as a decline of at least 30% in the eGFR from the baseline status. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD progression, adjusted for other CKD risk factors. Results During a follow-up period with a mean of 5.5 years, CKD progression occurred in 60 (6.5%) participants. The incidence rate (per 1,000 person-years) of CKD progression was 21.5 in the breakfast-skipping group and 10.7 in the breakfast-eating group (p = 0.029), respectively. The multivariable-adjusted HR (95% CI) for CKD progression was 2.60 (95% CI 1.29‒5.26) for the breakfast-skipping group (p = 0.028) compared with the group eating breakfast. There were no clear differences in the association of skipping breakfast with CKD progression in subgroup analyses by sex, age, obesity, hypertension, diabetes mellitus, baseline eGFR and baseline proteinuria. Conclusion Skipping breakfast was significantly associated with higher risk of CKD progression in a general Japanese population.

#2293 Cardiac autonomic neuropathy: an independent risk factor for renal decline in diabetic kidney disease

Abstract Background and Aims Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end stage kidney disease (ESKD) in the UK and worldwide. Due to its unpredictability and incurable nature, novel risk factors associated with incidence and progression of DKD need to be identified. One such factor is cardiac autonomic neuropathy (CAN). Many studies over last 30 years had demonstrated a significant relationship between CAN and incidence and progression of DKD using estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) as end points. However, no prospective studies have looked into relationship between CAN diagnosed by gold standard cardiac autonomic reflex tests (CARTs) and DKD with different prognostic risks as per KDIGO classification. The aim of the study is to examine this relationship further. Method Data from 91 participants (type 1 and type 2 DM) with eGFR &amp;gt;30 ml/min/1.73 m2 who underwent assessment for CAN using CARTs as per O'Brien's and Ewing's criteria during baseline visits performed between 2007 and 2010 were collected. Additional participants (n = 113) were also recruited in 2021 as part of iBEAt study which is an EU-funded, multi-centre renal imaging study to identify novel biomarkers for DKD. Data analysis for 204 participants in total was performed for this study. CAN was defined as 2 or more abnormal CARTs out of 5 (Table 1). The level of prognostic risk was calculated based on eGFR (G1-G5) and UACR (A1-A3), following KDIGO risk table from 2012 CKD guidelines. eGFR was calculated by chronic kidney disease epidemiology collaboration (CKD-EPI) equation and UACR was assessed by early morning urine sample. Participants were categorised as follow: low risk, moderate risk and high risk. Due to limited numbers of participants with G3 in eGFR, we have combined ‘high risk’ and ‘very high risk’ into one group. CAN was divided into 2 groups—with and without CAN. Differences in proportions were examined using chi-square test. The association between baseline CAN and risk of renal decline was assessed using multinominal logistic regression adjusted for baseline age, HbA1c, ACEi/ARBs use, retinopathy status, total cholesterol and triglyceride. If significant differences were found, individual groups were compared by Bonferroni post hoc test. All analyses were performed in SPSS (version 29.0) and correlations were considered significant if p &amp;lt; 0.05. Results We analysed data of 204 participants (130 T1DM, 74 T2DM), 44.6% (n = 91) of them were women, mean (SD) age at baseline visit was 51 (15.7) years, eGFR 82.6 (13) ml/min/1.73 m2, UACR 5.2 (21.8) mg/mmol, duration of diabetes at baseline 19.7 (12.3) years and 36.8% had hypertension. Baseline eGFR and UACR were available for 198 and 193 participants respectively. Of these, 42.9% (85/198) had G1, 47.5 (94/198) had G2 and 9.6 (19/198) had G3. For UACR, 80.8% (156/193) had A1, 15.5% (30/193) had A2 and 3.6% (7/193) had A3. 53.4% (103/204) of participants had CAN and 46.6% (101/204) had no CAN. A higher proportion of participants was in low prognostic risk category 77.8% (154/198), followed by 13.1% (26/198) with moderate risk and 9.8% (18/198) with high risk for CKD progression. The risk of DKD progression was significantly associated with presence of CAN in multinominal logistic regression analysis (p = 0.020). The presence of CAN was closely related to low risk (95% CI: 1.44 to 22.04, p = 0.013) and moderately increased risk (95% CI: 1.03 to 24.7, p = 0.04). The participants with moderate and high risk had lower eGFR (p &amp;lt; 0.001) and higher UACR with increased risk (p &amp;lt; 0.001) (Table 2). This finding was independent of baseline age, HbA1C, retinopathy, ACEI/ARB use, type of diabetes, cholesterol and triglyceride levels at baseline as measured by logistic regression. Conclusion To our knowledge, this is one of the first studies to examine the relationship between presence of CAN in three stages of prognostic risk in DKD. We demonstrated that presence of CAN was an independent risk factor for decline in renal function in DKD. Further large prospective studies are required to confirm the findings of this study and examine the underlying mechanisms how CAN leads to greater risk of DKD.

#1905 Sex differences in primary distal renal tubular acidosis: a single-centre retrospective study

Abstract Background and Aims The kidney has been described as one of the most estrogen-responsive organs after reproductive ones. Many non-X-linked renal diseases present with sex differences. Although not completely elucidated, an influence of estrogens has been described in several transporters along the renal tubule such as the Na+/phosphate cotransporter (NaPi-IIa) in the proximal tubule, the Na+/K+/2Cl⁻ cotransporter (NKCC) in the thick ascending limb of the loop of Henle, the thiazide-sensitive Na+/Cl⁻ cotransporter (NCC) in the distal convoluted tubule and the epithelial sodium channel (ENaC) expressed by the principal cells of the collecting duct. Our study aimed to investigate possible phenotypic sex differences over the natural history of primary distal renal tubular acidosis (dRTA), a rare genetic condition characterized by impaired urinary acidification in the collecting duct that results in non-anion gap metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, which can lead to chronic kidney disease (CKD). Method We included a cohort of 31 genetically confirmed dRTA patients (19 women and 12 men) followed at the London Tubular Centre. We retrospectively collected data from 2012 to 2023. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPIcr formula. Hypokalemia was defined as serum potassium &amp;lt; 3.5 mmol/L, hypercalciuria was defined as urinary calcium/creatinine (uCa/Cr) &amp;gt; 0.7 mmol/mmol and acidosis was defined as HCO3− ≤ 22 mmol/L. Data were analyzed using non-parametric Mann-Whitney as appropriate (Prism GraphPad 8.0.2). A p value &amp;lt; 0.05 was considered as statistically significant. Results Baseline characteristics and prevalence of different mutations are shown in Table 1. At baseline, both cohorts were young, with preserved kidney function. 60% of women were acidotic compared to 50% of men, and 30% of men were hypokalemic compared to 8% of women. The majority of patients in both cohorts presented with overt hypercalciuria (60% of women vs 90% of men). Prevalence of nephrolithiasis and nephrocalcinosis was similar among women and men. At baseline, no statistically significant difference between sexes was found for serum or urinary parameters. Interestingly, men exhibited a tendency towards higher annual mean slope of eGFR (−3.3 ± 2.5 mL/min/1.73 m2) compared to women (−0.5 ± 1.5 mL/min/1.73 m2) in a statistically significant fashion (Fig. 1a). Although not statically significant, we noticed a tendency towards higher fractional excretion of phosphate (FEPO4) (Fig. 1b) and dyslipidemia in men (Fig. 1c). There was no difference in PTH between the two groups (Fig. 1c). Conclusion Men affected by primary dRTA are at increased risk of CKD progression, tend to have a more severe phenotype at baseline and appear to be more dyslipidemic than women. This is consistent with findings in the literature that report accelerated CKD progression and higher cardiovascular morbidity and mortality in men. To our knowledge, this is the first study reporting sex differences in primary dRTA.

Individualized Risk of CKD Progression among US Adults.

Chronic kidney disease (CKD) is currently defined using glomerular filtration rate (GFR) or albuminuria. This is based on the relative risk of mortality and kidney outcomes compared to a healthy population and does not consider an individual's absolute risk of CKD progression. Using National Health and Nutrition Examination Survey data from 1999-2020, we characterized the individual-level absolute 3-year risk of ≥40% decline in estimated GFR (eGFR, mL/min/1.73 m2) or kidney failure (3-year risk) among US adults. We categorized the 3-year risk and considered ≥5% high risk. Among 199.81 million US adults, 8.42 million (4%) had a 3-year risk ≥5%, including 1.04 million adults without CKD (eGFR ≥60 and albuminuria <30 mg/g). These high-risk adults without CKD as currently defined had risk factors including hypertension (98%), heart failure (72%), and diabetes (44%). 15.51 million adults had CKD with preserved eGFR (eGFR ≥60 and albuminuria ≥30 mg/g)-3.73 million had a 3-year risk ≥5%, 41% of whom did not have diabetes and thus would not be screened for albuminuria using current screening recommendations. The 3-year risk of CKD progression was low (risk <5%) in 94% of the 5.66 million US adults with CKD stage G3a-A1 (eGFR 45 to <60 and albuminuria <30 mg/g). Assessment of the individual's absolute risk of CKD progression allows further risk stratification of patients with CKD and identifies individuals without CKD, as currently defined, that are at high risk of CKD progression.

Tubular biomarkers in proteinuric kidney disease: histology correlation and kidney prognosis of tubular biomarkers.

Proteinuria is not only a biomarker of chronic kidney disease (CKD) but also a driver of CKD progression. The aim of this study was to evaluate serum and urinary tubular biomarkers in patients with biopsied proteinuric kidney disease and to correlate them with histology and kidney outcomes. A single-center retrospective study was conducted on a cohort of 156 patients from January 2016 to December 2021. The following urinary and serum biomarkers were analyzed on the day of kidney biopsy: beta 2 microglobulin (β2-mcg), alpha 1 microglobulin (α1-mcg), neutrophil gelatinase-associated lipocalin (NGAL), urinary kidney injury molecule-1 (uKIM-1), monocyte chemoattractant protein-1 (MCP-1), urinary Dickkopf-3 (uDKK3), uromodulin (urinary uUMOD), serum kidney injury molecule-1 (sKIM-1) and serum uromodulin (sUMOD). A composite outcome of kidney progression or death was recorded during a median follow-up period of 26 months. Multivariate regression analysis identified sUMOD (β-0.357, P<.001) and uDKK3 (β 0.483, P<.001) as independent predictors of interstitial fibrosis, adjusted for age, estimated glomerular filtration rate (eGFR) and log proteinuria. Elevated levels of MCP-1 [odds ratio 15.61, 95% confidence interval (CI) 3.52-69.20] were associated with a higher risk of cortical interstitial inflammation >10% adjusted for eGFR, log proteinuria and microhematuria. Upper tertiles of uDKK3 were associated with greater eGFR decline during follow-up. Although not a predictor of the composite outcome, doubling of uDKK3 was a predictor of kidney events (hazard ratio 2.26, 95% CI 1.04-4.94) after adjustment for interstitial fibrosis, eGFR and proteinuria. Tubular markers may have prognostic value in proteinuric kidney disease, correlating with specific histologic parameters and identifying cases at higher risk of CKD progression.

Mineralocorticoid receptor antagonists and reno-protection: What's the evidence & where do they fit? A guide for non-specialists.

The role of aldosterone has yet to be well appreciated in chronic kidney disease (CKD). Two variables define CKD: an estimated glomerular filtration rate of <60 ml/min/1.73 m2 and a spot urine albumin-creatinine ratio of >30 mg/g. Both are needed for an accurate diagnosis. The presence of CKD at this level is associated with an elevated risk of cardiovascular death and a greater risk of CKD progression to kidney failure and subsequent dialysis. This paper presents an overview of aldosterone's importance in CKD and its contribution to the inflammatory processes involved in CKD development. Data on outcomes, both surrogate and hard, related to outcomes on CKD progression will also be discussed in the context of mineralocorticoid blockade. Based on recent epidemiological data as well as data examining markers of diabetic kidney disease progression, it is clear that use of both renin-angiotensin system inhibitors and aldosterone receptor antagonists have a significant role in altering the natural history of kidney disease progression itself, as well as reducing the risk of cardiovascular events that generally accompany long-standing kidney disease. This paper will discuss these issues and the management of consequent hyperkalaemia when both steroidal and non-steroidal mineralocorticoid receptor antagonists are used in detail.

Protocol for a systematic review of the application of the kidney failure risk equation and Oxford classification in estimating prognosis in IgA nephropathy

BackgroundIgA nephropathy (IgAN) is a common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Outcomes are highly variable and predicting risk of disease progression at an individual level is challenging. Accurate risk stratification is important to identify individuals most likely to benefit from treatment. The Kidney Failure Risk Equation (KFRE) has been extensively validated in CKD populations and predicts the risk of ESRD at 2 and 5 years using non-invasive tests; however, its predictive performance in IgAN is unknown. The Oxford classification (OC) describes pathological features demonstrated on renal biopsy that are associated with adverse clinical outcomes that may also inform prognosis. The objective of this systematic review is to compare the KFRE with the OC in determining prognosis in IgAN.MethodsA systematic review will be conducted and reported in line with PRISMA guidelines (PRISMA-P checklist attached as Additional file 1). Inclusion criteria will be cohort studies that apply the KFRE or OC to determine the risk of CKD progression or ESRD in individuals with IgAN. Multiple databases will be searched in duplicate to identify relevant studies, which will be screened first by title, then by abstract and then by full-text analysis. Results will be collated for comparison. Risk of bias and confidence assessments will be conducted independently by two reviewers, with a third reviewer available if required.DiscussionIdentifying individuals at the highest risk of progression to ESRD is challenging in IgAN, due to the heterogeneity of clinical outcomes. Risk prediction tools have been developed to guide clinicians; however, it is imperative that these aids are accurate and reproducible. The OC is based on observations made by specialist renal pathologists and may be open to observer bias, therefore the utility of prediction models incorporating this classification may be diminished, particularly as in the future novel biomarkers may be incorporated into clinical practice.Systematic review registrationPROSPERO CRD42022364569

Evaluación de eventos clínicos y costes asociados a la adición de dapagliflozina al tratamiento de la enfermedad renal crónica: análisis de compensación de costes

Background and objectivesChronic kidney disease (CKD) is a serious health problem with an increasing clinical, social and economic impact in advanced stages. Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor that reduces the risk of CKD progression, in addition to provide cardiovascular benefits and reduce all-cause mortality. The aim of this study was to determine the short-term clinical and economic impact of dapagliflozin as an add-on to renin-angiotensin-aldosterone system inhibitors (RAASi) standard therapy for CKD in Spain. Materials and methodsA cost-offset model was used to compare the costs of clinical events and pharmacological per 100,000 CKD patients in a virtual cohort treated with dapagliflozin added to RAASi standard therapy versus RAASi standard therapy alone. Renal (progression to renal failure and acute kidney injury), cardiovascular (hospitalisation for heart failure [HF]), and all-cause mortality events were assessed. The incidence of clinical events by treatment arm was obtained from the DAPA-CKD study, and costs were obtained from national databases and the literature. ResultsOver 3 years, treatment with dapagliflozin would reduce progression to renal failure (−33%; 7,221 vs. 10,767), hospitalisation for HF (−49%; 2,370 vs. 4,683) and acute kidney injury (−29%; 4,110 vs. 5,819). The savings associated with this reduction in events was €258 million per 100,000 patients, of which 63.4% is due to the avoidance of dialysis for renal failure. Considering the event and pharmacological treatment costs, the total net savings were estimated at €158 million per 100,000 patients. ConclusionsDelaying progression of CKD and reducing the incidence of clinical events thanks to the treatment with dapagliflozin could generate savings for the Spanish National Health System, even when pharmacological costs are taken into account.

CARDIOVASCULAR IMPACT OF DISCONTINUATION OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS IN ADVANCED CHRONIC KIDNEY DISEASE

Objective: Hypertension is a major problem in chronic kidney disease (CKD) with a prevalence approaching 100%, contributing to the risk of CKD progression, cardiovascular events and all-cause mortality. Renin-angiotensin system inhibitors (RASi) are the first-line therapy for antihypertensive treatment in patients with CKD, due to its protective effects. However, it is common practice stopping RASi in advanced CKD to attempt to delay kidney replacement therapy (KRT) initiation and/or to prevent drug-related acute kidney injury. Design and method: From the CKD-Rein prospective cohort, which included 3033 outpatients from nephrology clinics in France, we selected participants with an estimated glomerular filtration rate (eGFR) &lt;30 mL/min/1.73m2 and who were treated with RASi for at least 3 months. We used the G-formula to deal with time-fixed (age, sex, diabetes, heart failure, lung diseases) and time-varying confounding (eGFR, systolic blood pressure, serum sodium and potassium, diuretic prescription) to compare two treatment strategies: to discontinue or to continue RASi. The outcome, MACE, was the composite of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure. Competing risks were initiation of KRT and non-cardiovascular death. Results: From the 1,472 patients included (median age 69 years, median eGFR 25mL/min/1.73m2, 34% women), 27% discontinued RASi over a median follow-up of 35 [17-51] months. The crude rate of RASi discontinuation was higher in the presence of cardiovascular comorbidities and more severe CKD. The number of reported serious adverse reactions over the follow-up (such as acute kidney injury or hyperkalemia) was low, but higher in the discontinuation than in the continuation group (47 versus 23 per 1,000 person-years). After taking the afore-mentioned potential confounders into account, the 36-month risk of MACE was twice as high in the discontinuation group as that in the continuation group (RR 2.13, 95%CI 1.60-2.85). Conclusions: RASi discontinuation was significantly associated with MACE risk, the leading cause of morbidity and mortality in advanced CKD. Our results, along with other published data, suggest that the risk-benefit balance favors continued use of RASi in this population.

Risk factors for severe COVID-19 infection and the impact of COVID-19 infection on disease progression among patients with AAV

To identify risk factors for COVID-19 infection and investigate the impact of COVID-19 infection on chronic kidney disease (CKD) progression and vasculitis flare in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This cohort study retrospectively analyzed the prevalence and severity of COVID-19 infection in 276 patients with AAV who were followed up. Logistic regression was employed to estimate the risk of COVID-19 infection as well as CKD progression and vasculitis flare upon COVID-19 infection. During the 6-month observation period, 213 (77.2%) of 276 patients were diagnosed with COVID-19 infection. Of these 213 patients, 49 (23.0%) had a COVID-19-related inpatient admission, including 17 patients who died of COVID-19 infection. AAV patients with severe COVID-19 infection were more likely to be male (OR 1.921 [95% CI 1.020–3.619], P = 0.043), suffered from worse kidney function (serum creatinine [Scr], OR 1.901 [95% CI 1.345–2.687], P < 0.001), had higher C-reactive protein (CRP) (OR 1.054 [95% CI 1.010–1.101], P = 0.017) and less likely to have evidence of initial vaccination (OR 0.469 [95% CI 0.231–0.951], P = 0.036), and Scr and COVID-19 vaccination were proven to be significantly associated with severe COVID-19 infection even after multivariable adjustment. Severe COVID-19 infection was significantly associated with subsequent CKD progression (OR 7.929 [95% CI 2.030–30.961], P = 0.003) and vasculitis flare (OR 11.842 [95% CI 1.048–133.835], P = 0.046) among patients with AAV. AAV patients who were male, and with worse kidney function were more susceptible to severe COVID-19 infection, which subsequently increased the risk of CKD progression and vasculitis flare.

A Chinese patent medicine's long-term efficacy on non-dialysis patients with CKD stages 3-5: a retrospective cohort study.

Chinese patent medicine is commonly used in China as an important treatment mechanism to thwart the progression of chronic kidney disease (CKD) stages 3-5, among which Niaoduqing granules are a representative Chinese patent medicine; however, its long-term efficacy on CKD prognosis remains unclear. Patients were grouped according to Niaoduqing granule prescription duration (non-Niaoduqing granule (non-NDQ) group vs Niaoduqing granule (NDQ) group). Serum creatinine (SCr) variation was compared using a generalized linear mixed model (GLMM). Multivariate Cox regression models were constructed, adjusting for confounding factors, to explore the risk of composite outcomes (receiving renal replacement therapy (RRT) or having an estimated glomerular filtration rate (eGFR)<5mL/min/1.73 m2, ≥50% decline in the eGFR from the baseline, and doubling of SCr) in individuals consuming Niaoduqing granules. A total of 1,271 patients were included, with a median follow-up duration of 29.71 (12.10, 56.07) months. The mean SCr Z-scores for the non-NDQ group and NDQ group were -0.175 and 0.153, respectively, at baseline (p = 0.015). The coefficients of the NDQ group from visit 1 to visit 5 were -0.207 (95% CI: -0.346, -0.068, p = 0.004), -0.214 (95% CI: 0.389, -0.039, p = 0.017), -0.324 (95% CI: 0.538, -0.109, p = 0.003), -0.502 (95% CI: 0.761, -0.243, p = 0.000), and -0.252 (95% CI: 0.569, 0.065, p = 0.119), respectively. The survival probability was significantly higher in the NDQ group (p = 0.0039). Taking Niaoduqing granules was a significant protective factor for thwarting disease progression (model 1: HR 0.654 (95% CI 0.489-0.875, p = 0.004); model 2: HR 0.646 (95% CI 0.476, 0.877, p = 0.005); and model 3: HR 0.602 (95% CI 0.442, 0.820, p = 0.001)). The long-term use of Niaoduqing granules improved SCr variation and lowered the risk of CKD progression by 39.8%.

Association between progression of coronary artery calcification and development of kidney failure with replacement therapy: Findings from KNOW-CKD study

Background and aimsHigh coronary artery calcification (CAC) burden is a significant risk factor for adverse cardiovascular and kidney outcomes. However, it is unknown whether changes in the coronary atherosclerotic burden can accompany changes in kidney disease progression. Here, we evaluated the relationship between CAC progression and the risk of kidney failure with replacement therapy (KFRT). MethodsWe analyzed 1173 participants with chronic kidney disease (CKD) G1 to G5 without kidney replacement therapy from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Participants were categorized into three groups according to the change in the CAC score between enrollment and year 4 (non-progressors, ≤0 AU; moderate progressors, 1–199 AU; and severe progressors, ≥200 AU). The primary outcome was the development of KFRT. ResultsDuring a follow-up period of 4690 person-years (median, 4.2 years), the primary outcome occurred in 230 (19.6 %) participants. The incidence of KFRT was 37.6, 54.3, and 80.9 per 1000 person-years in the non-, moderate, and severe progressors, respectively. In the multivariable cause-specific hazard model, the hazard ratios (HRs) for the moderate and severe progressors were 1.71 (95 % confidence interval [CI], 1.02–2.87) and 2.55 (95 % CI, 1.07–6.06), respectively, compared with non-progressors. A different definition of CAC progression with a threshold of 100 AU yielded similar results in a sensitivity analysis. ConclusionsCAC progression is associated with an increased risk of KFRT in patients with CKD. Our findings suggest that coronary atherosclerosis changes increase the risk of CKD progression.

Electronic Health Record Population Health Management for Chronic Kidney Disease Care

Large gaps in clinical care in patients with chronic kidney disease (CKD) lead to poor outcomes. To compare the effectiveness of an electronic health record-based population health management intervention vs usual care for reducing CKD progression and improving evidence-based care in high-risk CKD. The Kidney Coordinated Health Management Partnership (Kidney CHAMP) was a pragmatic cluster randomized clinical trial conducted between May 2019 and July 2022 in 101 primary care practices in Western Pennsylvania. It included patients aged 18 to 85 years with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2 with high risk of CKD progression and no outpatient nephrology encounter within the previous 12 months. Multifaceted intervention for CKD comanagement with primary care clinicians included a nephrology electronic consultation, pharmacist-led medication management, and CKD education for patients. The usual care group received CKD care from primary care clinicians as usual. The primary outcome was time to 40% or greater reduction in eGFR or end-stage kidney disease. Among 1596 patients (754 intervention [47.2%]; 842 control [52.8%]) with a mean (SD) age of 74 (9) years, 928 (58%) were female, 127 (8%) were Black, 9 (0.6%) were Hispanic, and the mean (SD) estimated glomerular filtration rate was 36.8 (7.9) mL/min/1.73m2. Over a median follow-up of 17.0 months, there was no significant difference in rate of primary outcome between the 2 arms (adjusted hazard ratio, 0.96; 95% CI, 0.67-1.38; P = .82). Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker exposure was more frequent in intervention arm compared with the control group (rate ratio, 1.21; 95% CI, 1.02-1.43). There was no difference in the secondary outcomes of hypertension control and exposure to unsafe medications or adverse events between the arms. Several COVID-19-related issues contributed to null findings in the study. In this study, among patients with moderate-risk to high-risk CKD, a multifaceted electronic health record-based population health management intervention resulted in more exposure days to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers but did not reduce risk of CKD progression or hypertension control vs usual care. ClinicalTrials.gov Identifier: NCT03832595.

SGLT2 inhibitors in diabetic and non-diabetic kidney transplant recipients: current knowledge and expectations.

The beneficial effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown recently in numerous randomized controlled trials (RCT) and systematic reviews. According to KDIGO guidelines, SGLT2i currently represent a first choice for diabetic patients with chronic kidney disease (CKD). In addition, a recent meta-analysis of 13 large led by the 'SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium' (SMART-C) provided solid evidence of SGLT2i beneficial effects in CKD or in patients with heart failure, with and without diabetes. Collectively, the patients treated with SGLT2i had a decreased risk of CKD progression, acute kidney injury (AKI), end-stage kidney disease (ESKD) or death from heart failure. Whether these cardio-renal benefits should be extrapolated to kidney transplant recipients (KTR) needs to be assessed in further studies. In this article, we report recent data accumulated so far in the literature, looking at the efficacy and safety of SGLT2i in diabetic and non-diabetic KTR. We found encouraging data regarding the use of SGLT2i in KTR with diabetes. These agents appeared to be safe, and they reduced body weight and blood pressure in this group of patients. Potential effects on kidney graft function and survival are yet to be investigated.