Sex and the Relationship Between Cardiometabolic Risk Factors and Estimated GFR Decline: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Females have a higher prevalence of chronic kidney disease (CKD) than males but are less likely to be treated with kidney replacement therapy (KRT). We studied the interaction between sex and the association of cardiometabolic risk factors for the decline in kidney function over time. STUDY DESIGN: A population-based cohort study. SETTING & PARTICIPANTS: 1,127,731 adults living in Wales, United Kingdom, within the Secure Anonymised Information Linkage Databank. EXPOSURE: Sex and risk factors including age, estimated glomerular filtration rate (eGFR), cardiometabolic conditions, smoking, and socioeconomic deprivation. These risk factors were defined using primary care records. OUTCOME: The yearly declines in eGFR and the risk of incident kidney failure defined as long-term KRT and/or sustained eGFR<15mL/min/1.73m2. ANALYTICAL APPROACH: Linear mixed effects models and Cox proportional hazards analysis. RESULTS: The average decline in eGFR at age≤73 years was equal in males and females. After age 73 years, eGFR decline was faster in males than females, particularly for males with heart failure (males-1.22mL/min/1.73m2 per year [95% CI, -1.25 to-1.20] vs females-0.87mL/min/1.73m2 per year [95% CI, -0.89 to-0.85]) and current smokers (males-1.58mL/min/1.73m2 per year [95% CI, -1.60 to-1.55] vs females-1.27mL/min/1.73m2 per year [95% CI, -1.29 to-1.25]). Socioeconomic deprivation was one of the most impactful risk factors on eGFR decline among females aged>73 years, whereas cardiometabolic risk factors were more important among males. Older females at baseline were less likely to develop incident kidney failure than older males (P for age<0.001). LIMITATIONS: Study of people who were almost exclusively White and who had blood laboratory test data. Reliance on creatinine-based eGFR. Albuminuria and body mass index data were incomplete. CONCLUSIONS: The eGFR decline was faster in males than in females, especially in the setting of heart failure and smoking. Socioeconomic deprivation was an important risk factor associated with eGFR decline, particularly for females. further work is required to explore less well-recognized risk factors, but these findings may inform clinical management strategies of CKD overall and within sex-specific groups. PLAIN-LANGUAGE SUMMARY: Kidney function is known to decline at a faster rate among males than females. This study incorporated blood laboratory test results from the routine care of 1.1 million adults living in the United Kingdom and found that the decline in kidney function associated with risk factors varied by sex. Before and at the age of 73 years, the decline in kidney function was similar between males and females. After age 73, cardiometabolic risk factors were associated with faster decline in kidney function among males than females, specifically heart failure and smoking. Socioeconomic deprivation was also associated with the decline in kidney function for both sexes, but it was a stronger risk factor among females. These findings may inform the management of kidney disease overall and within sex-specific groups.

Glycated haemoglobin variability and risk of renal function decline in type 2 diabetes mellitus: An updated systematic review and meta-analysis.

OBJECTIVE: To assess the association between glycated haemoglobin (HbA1c) variability and risk of renal function decline in type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: A comprehensive search was carried out in PubMed, Embase, Web of Science and the Cochrane Library (until 12 March 2024). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines were followed for this meta-analysis. HbA1c variability was presented as indices of the standard deviation (SD), coefficient of variation (CV), HbA1c variability score (HVS) and haemoglobin glycation index (HGI). This meta-analysis was performed using random-effect models. RESULTS: Eighteen studies met the objectives of this meta-analysis. The analyses showed positive associations between HbA1c variability and kidney function decline, with hazard ratio (HR) 1.26 (95% confidence interval [CI] 1.15-1.38) for high versus low SD groups, HR 1.47 (95% CI 1.30-1.65) for CV groups, HR 1.32 (95% CI 1.10-1.57) for HVS groups and HR 1.53 (95% CI 1.05-2.23) for HGI groups. In addition, each 1% increase in SD and CV was linked to kidney function decline, with HR 1.26 (95% CI 1.17-1.35), and 1.13 (95% CI 1.03-1.23), respectively. Also, each 1-SD increase in SD of HbA1c was associated with deterioration in renal function, with HR 1.17 (95% CI 1.07-1.29). CONCLUSIONS: The four HbA1c variability indicators were all positively associated with renal function decline progression; therefore, HbA1c variability might play an important and promising role in guiding glycaemic control targets and predicting kidney function decline progression in T2DM.

Air quality and kidney health: Assessing the effects of PM10, PM2.5, CO, and NO2 on renal function in primary glomerulonephritis.

BACKGROUND: While extensive studies have elucidated the relationships between exposure to air pollution and chronic diseases, such as cardiovascular disorders and diabetes, the intricate effects on specific kidney diseases, notably primary glomerulonephritis (GN)-an immune-mediated kidney ailment-are less well understood. Considering the escalating incidence of GN and conspicuous lack of investigative focus on its association with air quality, investigation is dedicated to examining the long-term effects of air pollutants on renal function in individuals diagnosed with primary GN. METHODS: This retrospective cohort analysis was conducted on 1394 primary GN patients who were diagnosed at Seoul National University Bundang Hospital and Seoul National University Hospital. Utilizing time-varying Cox regression and linear mixed models (LMM), we examined the effect of yearly average air pollution levels on renal function deterioration (RFD) and change in estimated glomerular filtration rate (eGFR). In this context, RFD is defined as sustained eGFR of less than 60 mL/min per 1.73 m2. RESULTS: During a mean observation period of 5.1 years, 350 participants developed RFD. Significantly, elevated interquartile range (IQR) levels of air pollutants-including PM10 (particles ≤10 micrometers, HR 1.389, 95 % CI 1.2-1.606), PM2.5 (particles ≤2.5 micrometers, HR 1.353, 95 % CI 1.162-1.575), CO (carbon monoxide, HR 1.264, 95 % CI 1.102-1.451), and NO2 (nitrogen dioxide, HR 1.179, 95 % CI 1.021-1.361)-were significantly associated with an increased risk of RFD, after factoring in demographic and health variables. Moreover, exposure to PM10 and PM2.5 was associated with decreased eGFR. CONCLUSIONS: This study demonstrates a substantial link between air pollution exposure and renal function impairment in primary GN, accentuating the significance of environmental determinants in the pathology of immune-mediated kidney diseases.

Inverse Association Between Baseline Plasma Selenium Concentrations and Risks of Renal Function Decline in Hypertensive Adults.

BACKGROUND: The kidney has the highest level of selenium (Se) in the body, but the role of plasma Se in chronic kidney disease is uncertain. OBJECTIVE: We aimed to investigate the longitudinal association between baseline plasma Se and renal function decline in adults with hypertension and to explore possible effect modifiers. METHODS: This was a post hoc analysis of 935 men and women with hypertension aged 40 to 75 years from a folic-acid intervention trial (the China Stroke Primary Prevention Trial) in China. The baseline plasma Se was analyzed both as a continuous variable and as tertiles. The primary outcome was a rapid decline in renal function, defined as a mean decline in the estimated glomerular filtration rate of ≥ 5 mL/(min × 1.73 m2) per year. RESULTS: The median follow-up duration from baseline to outcome was 4.4 years. After multivariate adjustment, there was an inverse association between plasma Se and a rapid decline in renal function (per 10-unit increment; OR: 0.85; 95% CI: 0.73, 0.99). When the baseline plasma Se was assessed as tertiles, compared to the lowest tertile (<74.5 µg/L), a lower trend of the primary outcome was found in the second tertile (74.5 to < 89.4 µg/L; OR: 0.60; 95% CI: 0.34, 1.07) and the highest tertile (89.4 to <150 µg/L; OR: 0.42; 95% CI: 0.22, 0.80; Ptrend = 0.006). Furthermore, the Se-renal association was more pronounced among participants with folic acid treatment or with a higher baseline folate concentration (both Pinteraction values < 0.05). CONCLUSIONS: In this sample of Chinese adults with hypertension, baseline plasma Se concentrations were inversely associated with the risk of renal function decline. The China Stroke Primary Prevention Trial was registered at clinicaltrials.gov as NCT00794885.

Tumor necrosis factor-alpha mediates the negative association between telomere length and kidney dysfunction.

Aim/hypothesis: The relationship between peripheral blood leukocyte telomere length (LTL) and kidney dysfunction, especially in people with hypertension, remains unclear. No clinical study has explored the role of inflammation and oxidative stress in the relationship between LTL and kidney dysfunction. Therefore, we examined the relationship between baseline LTL and albuminuria progression and/or rapid renal function decline in Chinese patients with or without hypertension and investigated whether inflammation and oxidative stress played a mediating role in this relationship. Methods: We conducted a prospective study including 262 patients in a 7-year follow-up period from 2014 to 2021. Data on LTL, inflammation, oxidative markers, renal function, and urine protein levels were assessed. Kidney dysfunction was defined as either albuminuria progression, rapid decline in renal function, or the composite endpoint (albuminuria progression and rapid decline in renal function). Logistic regression and simple mediation models were used for the analysis. Results: In this cohort (mean age, 54.3±9.7 years; follow-up period, 5.9±1.1 years), 42(16.0%), 21(8.0%), and 59(22.5%) patients developed albuminuria progression, rapid eGFR decline, and the composite endpoint of kidney dysfunction, respectively. Logistic regression analysis showed that each standard deviation decrease of baseline LTL and the lower quartile (Q) of baseline LTL were significantly correlated with an increased risk of rapid decline in renal function (OR=1.83 [95% CI 1.07, 3.27] per 1SD, P=0.03; OR=7.57 [95% CI 1.25, 145.88] for Q1 vs. Q4, P for trend=0.031); and the composite endpoint of kidney dysfunction (OR=1.37 [95% CI 0.97, 1.96] per 1SD, borderline positive P=0.072; OR=2.96[95% CI 1.15, 8.2] for Q1 vs. Q4, P for trend=0.036). The mediating analysis showed that tumor necrosis factor (TNF)-a partly mediated the relationship between LTL and rapid decline in renal function (direct effect: ß=0.046 95%CI [0.006, 0.090],P=0.02; indirect effect: ß=0.013 95%CI [0.003, 0.020]), and the mediating proportion was 22.4%.In subgroup analyses, LTL was inversely associated with rapid decline in renal function or the composite endpoint of kidney dysfunction only in patients with hypertension (OR=49.07[3.72,211.12] vs.1.32[0.69,2.58] per 1SD, P for interaction=0.045;OR=3.10 [1.48, 7.52] vs.1.08[0.92,1.63] per 1SD, P for interaction=0.036). Conclusion: Baseline LTL could independently predict kidney dysfunction at follow-up, especially in participants with hypertension. TNF-a partially mediated the negative association between LTL and kidney dysfunction.

The level of serum albumin is associated with renal prognosis and renal function decline in patients with chronic kidney disease.

OBJECTIVE: The study's purpose is to explore the link of serum albumin on renal progression in patients with chronic kidney disease (CKD). METHODS: This study was a secondary analysis of a prospective cohort study in which a total of 954 participants were non-selectively and consecutively collected from the research of CKD-ROUTE in Japan between November 2010 and December 2011. We evaluated the association between baseline ALB and renal prognosis (initiation of dialysis or 50% decline in eGFR from baseline) and renal function decline (annual eGFR decline) using the Cox proportional-hazards and linear regression models, respectively. We performed a number of sensitivity analyses to ensure the validity of the results. In addition, we performed subgroup analyses. RESULTS: The included patients had a mean age of (66.86 ± 13.41) years, and 522 (69.23%) were male. The mean baseline ALB and eGFR were (3.89 ± 0.59) g/dL and (33.43 ± 17.97) ml/min/1.73 m2. The annual decline in eGFR was 2.65 mL/min/1.73 m2/year. 218 (28.9%) individuals experienced renal prognosis during a median follow-up period of 36.0 months. The baseline ALB was inversely linked with renal prognosis (HR = 0.61, 95%CI: 0.45, 0.81) and renal function decline (ß = -1.41, 95%CI: -2.11, -0.72) after controlling for covariates. The renal prognosis and ALB had a non-linear connection, with ALB's inflection point occurring at 4.3 g/dL. Effect sizes (HR) were 0.42 (0.32, 0.56) and 6.11 (0.98, 38.22) on the left and right sides of the inflection point, respectively. There was also a non-linear relationship between ALB and renal function decline, and the inflection point of ALB was 4.1 g/dL. The effect sizes(ß) on the left and right sides of the inflection point were -2.79(-3.62, -1.96) and 0.02 (-1.97, 1.84), respectively. CONCLUSION: This study shows a negative and non-linear association between ALB and renal function decline as well as renal prognosis in Japanese CKD patients. When ALB is lower than 4.1 g/dL, ALB decline was closely related to poor renal prognosis and renal function decline. From a therapeutic point of view, reducing the decline in ALB makes sense for delaying CKD progression.

Longitudinal TNFR1 and TNFR2 and Kidney Outcomes: Results from AASK and VA NEPHRON-D.

BACKGROUND: Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied. METHODS: We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m2, respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function. RESULTS: There were 129 ESKD events over a median of 7.0 years in AASK (n=418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D (n=754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively. CONCLUSIONS: Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function.

Sex Differences in Age-Related Loss of Kidney Function.

BACKGROUND: CKD is more prevalent in women, but more men receive kidney replacement therapy for kidney failure. This apparent contradiction is not well understood. METHODS: We investigated sex differences in the loss of kidney function and whether any sex disparities could be explained by comorbidity or CKD risk factors. In the Renal Iohexol Clearance Survey (RENIS) in northern Europe, we recruited 1837 persons (53% women, aged 50-62 years) representative of the general population and without self-reported diabetes, CKD, or cardiovascular disease. Participants' GFR was measured by plasma iohexol clearance in 2007-2009 (n=1627), 2013-2015 (n=1324), and 2018-2020 (n=1384). At each study visit, healthy persons were defined as having no major chronic diseases or risk factors for CKD. We used generalized additive mixed models to assess age- and sex-specific GFR decline rates. RESULTS: Women had a lower GFR than men at baseline (mean [SD], 90.0 [14.0] versus 98.0 [13.7] ml/min per 1.73 m2; P<0.001). The mean GFR change rate was -0.96 (95% confidence interval [CI], -0.88 to -1.04) ml/min per 1.73 m2 per year in women and -1.20 (95% confidence interval [CI], -1.12 to -1.28) in men. Although the relationship between age and GFR was very close to linear in women, it was curvilinear in men, with steeper GFR slopes at older ages (nonlinear effect; P<0.001). Healthy persons had a slower GFR decline, but health status did not explain the sex difference in the GFR decline. CONCLUSION: Among middle-aged and elderly individuals in the general population, decline in the mean GFR in women was slower than in men, independent of health status.

Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure and has few treatment options. Metformin is well tolerated and safe in other patient populations. The primary objective of this clinical trial was to determine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. STUDY DESIGN: Prospective randomized controlled double-blind clinical trial. SETTING & PARTICIPANTS: 51 adults aged 30-60 years with ADPKD, without diabetes, and an estimated glomerular filtration rate (eGFR) 50-80 mL/min/1.73 m2. EXPOSURE: Metformin (maximum dose 2,000 mg/d) or placebo for 12 months. OUTCOME: Coprimary end points were the percentage of participants in each group prescribed at the end of the 12-month period: (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. RESULTS: The participants' mean age was 48 ± 8 (SD) years, and eGFR was 70 ± 14 mL/min/1.73 m2. The metformin group had no cases of lactic acidosis, and there was 1 episode of mild hypoglycemia in each group. Participants in the metformin group reported more adverse symptoms, mostly related to the gastrointestinal tract. Eleven of 22 metformin-treated participants (50%) completed the treatment phase on the full dose compared with 23 of 23 in the placebo group (100%). In the metformin group, 82% of participants tolerated at least 50% of the dose, compared with 100% in the placebo group. In exploratory analyses, changes in htTKV or eGFR were not significantly different between the groups. LIMITATIONS: Short study duration. CONCLUSIONS: We found that 50% or more of the maximal metformin dose was safe and well tolerated over 12 months in patients with ADPKD. Safety of other preparations of metformin as well as its efficacy should be tested in future clinical trials. FUNDING: Government and philanthropic grants (NIDDK and the Zell Foundation). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02903511.

External validation of the Palacios' equation: a simple and accurate tool to estimate the new baseline renal function after renal cancer surgery.

PURPOSE: To externally validate the Palacios' equation estimating the new baseline glomerular filtration rate (NB-GFR) after partial or radical-nephrectomy (PN, RN) for Renal cancer carcinoma (RCC). MATERIALS AND METHODS: Our research group recently published two studies that investigated the association between renal function and cancer-specific survival in RCC. The first one included 3457 patients undergone RN or PN for a cT1-2 RCC coming from five high-volume centers; the second one considered 1767 patients undergone RN or PN for a cT1-4 RCC in a single high-volume center. From such datasets, available complete patients' data were used to calculate the predicted NB-GFR through the Palacios' equation: predicted NB-GFR = 35.03 + 0.65 ∙ preoperative GFR - 18.19 ∙ (if radical nephrectomy) - 0.25 ∙ age + 2.83 ∙ (if tumor size > 7 cm) - 2.09 ∙ (if diabetes). The observed NB-GFR was calculated by the CKD-EPI equation on serum creatinine at 3-12 months after surgery. Concordance between observed and predicted NB-GFR was evaluated by Lin's concordance correlation coefficient and Bland-Altman analysis. RESULTS: 2419 patients were included (1210, cohort #1; 1219, cohort #2). The median observed NB-GFR value in cohorts #1 and #2 was 73.0 ml/min/1.73 m2 (IQR 56.1-90.1) and 64.2 ml/min/1.73 m2 (IQR 49.6-83); the median predicted NB-GFR was 71.1 ml/min/1.73 m2 (IQR 58-81.5) and 62.6 ml/min/1.73m2 (IQR 47.9-75.9). The concordance line showed a slope of 0.80 and 0.86, and an intercept at 11.02 and 5.41 ml/min/1.73 m2 in the cohort#1 and #2, respectively. The Palacio's equation moderately over-estimated and under-estimated NB-GFR, for values below and above the cut-off of 50 ml/min/1.73 m2 and 35 ml/min/1.73m2 in cohort#1 and #2. The Lin's concordance correlation coefficient was 0.79 (95% CI 0.77-0.81) and 0.83 (95% CI 0.82-0.85). CONCLUSIONS: We confirm the predictive performances of Palacios' equation, supporting its utilization in clinical practice.

A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease.

BACKGROUND: Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking. METHODS: A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death. RESULTS: When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively. CONCLUSIONS: The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.

Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy.

BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). RESULTS: During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. CONCLUSIONS: Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.

Risks of AKI and Major Adverse Clinical Outcomes in Patients with Severe Acute Respiratory Syndrome or Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) are closely related. The effect of AKI on the clinical outcomes of these two conditions is unclear. METHODS: This retrospective, territory-wide cohort study used an electronic public healthcare database in Hong Kong to identify patients with SARS or COVID-19 by diagnosis codes, virologic results, or both. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. RESULTS: We identified 1670 patients with SARS and 1040 patients with COVID-19 (median ages, 41 versus 35 years, respectively). Among patients with SARS, 26% met the primary endpoint versus 5.3% of those with COVID-19. Diabetes mellitus, abnormal liver function, and AKI were factors significantly associated with the primary endpoint among patients with either SARS or COVID-19. Among patients with SARS, 7.9%, 2.1%, and 3.7% developed stage 1, stage 2, and stage 3 AKI, respectively; among those with COVID-19, 6.6%, 0.4%, and 1.1% developed stage 1, stage 2, and stage 3 AKI, respectively. In both groups, factors significantly associated with AKI included diabetes mellitus and hypertension. Among patients with AKI, those with COVID-19 had a lower rate of major adverse clinical outcomes versus patients with SARS. Renal function recovery usually occurred within 30 days after an initial AKI event. CONCLUSIONS: AKI rates were higher among patients with SARS than those with COVID-19. AKI was associated with major adverse clinical outcomes for both diseases. Patients with diabetes mellitus and abnormal liver function were also at risk of developing severe consequences after SARS and COVID-19 infection.

Increased Body Fat and Organic Acid Anions Production Are Associated with Larger Kidney Size in ADPKD.

Background and Objectives: A high body mass index (BMI) is associated with the progression of autosomal dominant polycystic kidney disease (ADPKD). However, body fat (BF), which is another adiposity marker, has not yet been studied. Excessive weight may promote elevation in the endogenous synthesis of organic acid (OA) anions. Accordingly, we aimed to investigate the possible association of the aforementioned markers with kidney volume and renal function in patients with ADPKD. Materials and Methods: We conducted a retrospective cohort study of adult ADPKD outpatients involving clinical, serum, and urinary laboratorial data and body composition assessments retrieved from their medical records. BF was estimated by skinfold thickness (mm) on the non-dominant arm and was considered as normal or high for each sex. Total kidney volume (TKV) and height-adjusted volume (htTKV) were measured by magnetic resonance imaging. The annual estimated glomerular filtration rate (eGFR) slope was analyzed during a median follow-up time of 6 (5.0-7.0) years to calculate rapid progression (decline in renal function ≥2.5 mL/min/year over 5 years). Results: A total of 104 patients were included (41.9 ± 11.9 years old, 38.5% men), with 62.5% of the patients classified as high BF. The High BF group presented higher levels of OA, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), 24 h urinary sodium (UNa), and htTKV, and lower eGFR than those with a normal BF. In the multivariate linear regression, the associated variables with TKV were high BF, OA and BMI (std. ß 0.47, p < 0.05; std. ß 0.36, p = 0.001; std. ß 0.25, p = 0.01, respectively). In the binary logistic regression, when adjusted for potential confounders, UNa was the only parameter associated with an increased risk of eGFR decline ≥2.5 mL/min/year (OR 1.02, 95% CI 1.01-1.03, p = 0.02). Conclusions: Increased body fat and endogenous production of organic acid anions are associated with larger kidney size in ADPKD but not with a decline in renal function.

Changes in GFR and Albuminuria in Routine Clinical Practice and the Risk of Kidney Disease Progression.

RATIONALE & OBJECTIVE: Changes in urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used separately as alternative kidney disease outcomes in randomized trials. We tested the hypothesis that combined changes in UACR and eGFR predict advanced kidney disease better than either alone. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 91,319 primary care patients assembled from the Clinical Practice Research Datalink in the United Kingdom between 2000 and 2015. EXPOSURES: Changes in UACR and eGFR (categorized as ≥30% increase, stable, or ≥30% decrease), alone and in combination, over a 3-year period. OUTCOMES: The primary outcome was advanced CKD (sustained eGFR <30 mL/min/1.73 m2); secondary outcomes included kidney failure, cardiovascular disease, and all-cause mortality. ANALYTICAL APPROACH: Multivariable Cox regression with bias from missing values assessed using multiple imputation; discrimination statistics compared across exposure groups. RESULTS: 91,319 individuals were studied, with a mean eGFR of 72.6 mL/min/1.73 m2 and median UACR of 9.7 mg/g; 70,957 (77.7%) had diabetes. During a median follow-up of 2.9 years, 2,541 people progressed to advanced CKD. Compared with stable values, hazard ratios for a ≥30% increase in UACR and ≥30% decrease in eGFR were 1.78 (95% CI, 1.59-1.98) and 7.53 (95% CI, 6.70-8.45), respectively, for the outcome of advanced CKD. Compared with stable values of both, the hazard ratio for the combination of an increase in UACR and a decrease in eGFR was 15.15 (95% CI, 12.43-18.46) for the outcome of advanced CKD. The combination of changes in UACR and eGFR predicted kidney outcomes better than either alone. LIMITATIONS: Selection bias, relatively small proportion of individuals without diabetes, and very few kidney failure events. CONCLUSIONS: In a large-scale general population, the combination of an increase in UACR and a decrease in eGFR was strongly associated with the risk of advanced CKD. Further assessment of combined changes in UACR and eGFR as an alternative outcome for kidney failure in trials of CKD progression is warranted.

Incidence and predictors of early and delayed renal function decline after aortic aneurysm repair in the Vascular Quality Initiative database.

BACKGROUND: Postoperative acute kidney injury (AKI) may complicate both open and endovascular aortic aneurysm repair (EVAR) and is associated with substantial morbidity, mortality, and health care expense. We aim to evaluate the incidence of postoperative AKI and factors associated with its occurrence and the effects of postoperative AKI on long-term renal function and mortality after open and EVAR in the Society for Vascular Surgery Vascular Quality Initiative registry. METHODS: Elective aneurysm cases were identified including thoracic endovascular aortic aneurysm repair (TEVAR) and complex endovascular aortic aneurysm repair (cEVAR), infrarenal endovascular repair (EVAR) and infrarenal open repair (OAR) from 2003 to 2019. The preoperative estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula and stratified based on chronic kidney disease (CKD) grades. Postoperative AKI was defined per the Vascular Quality Initiative definition as a creatinine increase of 0.5 mg/dL or if postoperative dialysis was required. Patients on preprocedural hemodialysis and those with previous renal transplant were excluded. Demographics and procedural factors were evaluated for predicting in-hospital postoperative AKI (all approaches) and at 9 to 21 months of long-term follow-up (EVAR only) using logistic regression modeling. RESULTS: We identified a total of 2813 cEVAR, 2995 TEVAR, 39,945 EVAR, and 8143 OAR patients. Of those, postoperative AKI occurred in 377 cEVAR (13.5%), 199 TEVAR (6.7%), 1099 EVAR (2.8%), and 1249 OAR (15.5%). Risk factors for postoperative AKI across all groups were worse preoperative eGFR, total number of blood transfusions, perioperative anemia, reinterventions, and postoperative respiratory complications. Additional procedure-specific risk factors of postoperative AKI were preoperative hemoglobin of less than 10 and contrast volume of 125 to 150 mL, hypertension, a low ejection fraction, and a history of percutaneous revascularization for EVAR; for both EVAR/cEVAR, renal artery coverage was a risk factor, whereas for OAR, male sex, non-White race, hypertension, suprarenal aortic cross-clamp, and increased renal ischemic time were risk factors. Among 8133 EVAR patients with long-term follow-up, a decrease in kidney function occurred in 56.7% of patients with postoperative AKI vs 19.9% without postoperative AKI (P < .001). The following risk factors were associated with a decrease in renal function at long-term follow-up: postoperative AKI, a preoperative eGFR of less than 90, and hypertension. A preoperative hemoglobin of greater than 12 was protective. Postoperative AKI was associated with significantly lower survival compared with no postoperative AKI across all procedures (log rank <0.001). CONCLUSIONS: Postoperative AKI occurs more often in patients with worse preoperative renal function, lower preoperative hemoglobin, and in open surgeries with inter-renal or suprarenal cross-clamping. Importantly, postoperative AKI is associated with increased mortality across all types of aortic repair. Given the long-term impact of postoperative AKI on outcomes for all aortic repairs and the limitations of current insensitive functional indices, there is a need to seek more sensitive indicators of decreases in early renal structural in this population.

Renal function decline in older men and women with advanced chronic kidney disease-results from the EQUAL study.

INTRODUCTION: Understanding the mechanisms underlying the differences in renal decline between men and women may improve sex-specific clinical monitoring and management. To this end, we aimed to compare the slope of renal function decline in older men and women in chronic kidney disease (CKD) Stages 4 and 5, taking into account informative censoring related to the sex-specific risks of mortality and dialysis initiation. METHODS: The European QUALity Study on treatment in advanced CKD (EQUAL) study is an observational prospective cohort study in Stages 4 and 5 CKD patients ≥65 years not on dialysis. Data on clinical and demographic patient characteristics were collected between April 2012 and December 2018. Estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation. eGFR trajectory by sex was modelled using linear mixed models, and joint models were applied to deal with informative censoring. RESULTS: We included 7801 eGFR measurements in 1682 patients over a total of 2911 years of follow-up. Renal function declined by 14.0% [95% confidence interval (CI) 12.9-15.1%] on average each year. Renal function declined faster in men (16.2%/year, 95% CI 15.9-17.1%) compared with women (9.6%/year, 95% CI 6.3-12.1%), which remained largely unchanged after accounting for various mediators and for informative censoring due to mortality and dialysis initiation. Diabetes was identified as an important determinant of renal decline specifically in women. CONCLUSION: In conclusion, renal function declines faster in men compared with women, which remained similar after adjustment for mediators and despite a higher risk of informative censoring in men. We demonstrate a disproportional negative impact of diabetes specifically in women.

Urinary excretion of epidermal growth factor and rapid loss of kidney function.

BACKGROUND: Lower urinary excretion of the kidney tubule-specific biomarker epidermal growth factor (uEGF) is associated with increased risk of renal function [glomerular filtration rate (GFR)] loss in diabetes and in patients with established chronic kidney disease (CKD). We investigated whether uEGF is associated with rapid GFR decline or incident CKD in the general population. METHODS: Subjects without CKD or diabetes were recruited from the general population in Tromso, Norway [Renal Iohexol Clearance Survey (RENIS); N = 1249] and Groningen, the Netherlands [Prevention of REnal and Vascular END-stage disease (PREVEND); N = 4534], with a median follow-up of 5.6 and 7.4 years, respectively. GFR was measured by iohexol clearance in the RENIS and estimated using the CKD Epidemiology Collaboration creatinine-cystatin C equation in the PREVEND study. Rapid GFR decline was defined as an annual GFR loss >3.0 mL/min/1.73 m2 and in sensitivity analyses as subjects with the 10% steepest GFR slope within each cohort. RESULTS: Lower baseline uEGF excretion was associated with rapid GFR loss in both cohorts {RENIS, odds ratio [OR] per 1 µg/mmol lower uEGF 1.42 [95% confidence interval (CI) 1.06-1.91], P = 0.02; PREVEND, OR 1.29 [95% CI 1.10-1.53], P < 0.01}, adjusted for baseline GFR, albumin:creatinine ratio and conventional CKD risk factors. Similar results were obtained using the outcome of the 10% steepest GFR slope in each cohort. Lower uEGF levels were associated with incident CKD in the combined analysis of both cohorts. CONCLUSIONS: Lower uEGF levels are associated with increased risk of rapid GFR loss and incident CKD in the general population. This finding, together with previous findings in CKD and high-risk populations, supports that uEGF may serve as a broadly applicable biomarker representing the tubular component of the current glomerulus-centric clinical risk assessment system.

GFR in Healthy Aging: an Individual Participant Data Meta-Analysis of Iohexol Clearance in European Population-Based Cohorts.

BACKGROUND: Population mean GFR is lower in older age, but it is unknown whether healthy aging is associated with preserved rather than lower GFR in some individuals. METHODS: We investigated the cross-sectional association between measured GFR, age, and health in persons aged 50-97 years in the general population through a meta-analysis of iohexol clearance measurements in three large European population-based cohorts. We defined a healthy person as having no major chronic disease or risk factors for CKD and all others as unhealthy. We used a generalized additive model to study GFR distribution by age according to health status. RESULTS: There were 935 (22%) GFR measurements in persons who were healthy and 3274 (78%) in persons who were unhealthy. The mean GFR was lower in older age by -0.72 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], -0.96 to -0.48) for men who were healthy versus -1.03 ml/min per 1.73 m2 per year (95% CI, -1.25 to -0.80) for men who were unhealthy, and by -0.92 ml/min per 1.73 m2 per year (95% CI, -1.14 to -0.70) for women who were healthy versus -1.22 ml/min per 1.73 m2 per year (95% CI, -1.43 to -1.02) for women who were unhealthy. For healthy and unhealthy people of both sexes, both the 97.5th and 2.5th GFR percentiles exhibited a negative linear association with age. CONCLUSIONS: Healthy aging is associated with a higher mean GFR compared with unhealthy aging. However, both the mean and 97.5 percentiles of the GFR distribution are lower in older persons who are healthy than in middle-aged persons who are healthy. This suggests that healthy aging is not associated with preserved GFR in old age.

Effect of Vitamin B12 Levels on the Association Between Folic Acid Treatment and CKD Progression: A Post Hoc Analysis of a Folic Acid Interventional Trial.

RATIONALE & OBJECTIVE: In populations with folic acid fortification or supplementation, the main nutritional determinant of total homocysteine levels is vitamin B12 (B12) status. We aimed to evaluate the modifying effect of B12 levels on the association between folic acid treatment and chronic kidney disease (CKD) progression. STUDY DESIGN: A post hoc analysis of an interventional trial. SETTING & PARTICIPANTS: This is a post hoc analysis of 1,374 hypertensive adults with mild to moderate CKD and B12 measurements at baseline from the kidney disease substudy of the China Stroke Primary Prevention Trial (CSPPT), conducted in 20 communities in Jiangsu province in China, a region with low folate consumption. INTERVENTIONS: Assignments to a double-blinded daily treatment of enalapril, 10mg, and folic acid, 0.8mg; or enalapril, 10mg, alone. OUTCOMES: The primary outcome was progression of CKD (defined as a decrease in estimated glomerular filtration rate [eGFR] ≥ 30% and to a level of<60mL/min/1.73m2 if baseline eGFR was≥60mL/min/1.73m2; or a decrease in eGFR≥50% if baseline eGFR was<60mL/min/1.73m2; or kidney failure). RESULTS: Mean baseline eGFR in this study was 86.1±20.5 (SD) mL/min/1.73m2. Median treatment duration was 4.4 years. Among participants with higher baseline B12 levels (≥248pmol/L), compared to enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of the primary outcome (OR, 0.17; 95% CI, 0.07-0.40). However, among those with baseline B12 levels<248pmol/L (metabolic B12 deficiency), there was no significant group difference in the primary outcome (OR, 1.21; 95% CI, 0.51-2.85). The interaction between B12 level and folic acid treatment was significant (P = 0.001). LIMITATIONS: The analysis is post hoc and event rate is low. CONCLUSIONS: Folic acid treatment was associated with a greater reduction in the odds of CKD progression among patients with mild to moderate CKD and higher B12 levels. FUNDING: Government funding (National Key Research and Development Program of China).