Framingham risk score is a useful indicator of posttransplant cardiovascular events and survival among Korean kidney transplant recipients: a nationwide, prospective cohort study.

Background: Cardiovascular disease is an important risk factor for mortality among kidney transplant recipients. In this study, we aimed to investigate the association between cardiovascular risk score at kidney transplantation and long-term outcomes of patients. Methods: In this prospective, observational cohort study, we enrolled kidney transplant recipients who participated in the Korean Organ Transplantation Registry and underwent transplantation between April 2014 and December 2019. The cardiovascular risk status of kidney transplant recipients was assessed using the Framingham risk score. All-cause mortality, major adverse cardiovascular events, allograft failure, estimated glomerular filtration rates (eGFRs), and composite outcomes were evaluated after kidney transplantation. Results: Of the 4,682 kidney transplant recipients, 96 died during 30.7 ± 19.1 months of follow-up. The Kaplan-Meier survival analysis results showed that high Framingham risk scores were associated with all-cause mortality, major adverse cardiovascular events, and composite outcomes. According to the multivariable Cox analysis, high Framingham risk scores were associated with an increased risk of mortality (hazard ratio [HR], 3.20; 95% confidence interval [CI], 1.30-7.91), major adverse cardiovascular events (HR, 8.43; 95% CI, 2.41-29.52), and composite outcomes (HR, 2.05; 95% CI, 1.19-3.46). The eGFRs after transplantation were significantly higher among patients in the low Framingham risk score group (p < 0.001). However, Framingham risk scores were not associated with graft loss or rapid decline in eGFRs. Conclusion: The Framingham risk score is a useful indicator of cardiovascular events, mortality, and kidney function after kidney transplantation.

Synergistic effect of periodontitis and C-reactive protein levels on mortality: NHANES 2001-2004.

Periodontitis is associated with elevated C-reactive protein (CRP) levels. Although the coexistence of periodontitis and elevated CRP levels may heighten the risk of mortality, previous studies have not confirmed their synergistic effect. Understanding this interaction is crucial for identifying potential interventions to reduce mortality risk in individuals with periodontitis. This study aimed to assess the synergistic effects of periodontitis and elevated CRP levels on mortality in 7,938 adult individuals who participated in the National Health and Nutrition Examination Study 2001-2004. The association of periodontitis status and CRP levels with mortality was assessed using a survey-weighted Cox model. The interactive effect was estimated; the synergistic effect of CRP levels and periodontitis status on mortality was assessed using the relative excess risk due to interaction (RERI). Periodontitis was diagnosed in 1,065 (13.4%) participants. Compared with the participants without periodontitis and possessing CRP levels of ≤ 0.5 mg/dL, those with periodontitis (hazard ratio [HR], 1.38) or CRP levels of > 0.5 mg/dL (HR 1.23) had higher HRs. The participants with both periodontitis and CRP levels of > 0.5 mg/dL had the highest HR of 2.01. The additive scale interactive effect of the periodontal status and CRP levels, measured using RERI 0.41 (-0.07, 0.95), was positive and nearly significant in the total population. The synergy between the periodontal status and CRP levels was more prominent in the participants aged ≥60 years than that in younger individuals. Periodontitis with high CRP levels may indicate a high mortality rate, indicating the importance of active monitoring and intensive management of periodontitis and inflammatory markers.

Antioxidative effects of molybdenum and its association with reduced prevalence of hyperuricemia in the adult population.

The relationship between molybdenum and kidney-related disease outcomes, including hyperuricemia, is not well investigated. This study aims to determine whether molybdenum and its antioxidative property are associated with systemic inflammation and kidney-related disease parameters including hyperuricemia. Urinary molybdenum's epidemiological relationship to hyperuricemia and kidney-disease related outcomes was evaluated in 15,370 adult participants in the National Health and Nutrition Examination Survey (NHANES) collected between 1999 and 2016. Individuals' urinary molybdenum levels were corrected to their urinary creatinine concentrations. The association between urinary molybdenum-to-creatinine ratio and kidney-disease related outcomes were assessed by multivariable linear and logistic regression analyses, adjusting for covariates including age, sex, ethnicity, diabetes mellitus, hypertension, body mass index, and estimated glomerular filtration rate. Antimony and tungsten were used as control trace metals. Experimentally, HK-2 cell was used to assess molybdenum's antioxidative properties. HK-2 cells were challenged with H2O2-induced oxidative stress. Oxidative stress was measured using a fluorescent microplate assay for reactive oxygen species (ROS) and antioxidation levels were assessed by measuring the expression of manganese superoxide dismutase. In the adult NHANES population, urinary molybdenum-to-creatinine ratio was significantly associated with decreased serum uric acid (ß, -0.119; 95% CI, -0.148 to -0.090) concentrations, and decreased prevalence of hyperuricemia (OR, 0.73; 95% CI, 0.64-0.83) and gout (OR, 0.71; 95% CI, 0.52-0.94). Higher urinary molybdenum levels were associated with lower levels of systemic oxidative stress (gamma-glutamyltransferase levels; ß, -0.052; 95% CI, -0.067 to -0.037) and inflammation (C-reactive protein levels; ß, -0.184; 95% CI, -0.220 to -0.148). In HK-2 cells under H2O2-induced oxidative stress, molybdenum upregulated manganese superoxide dismutase expression and decreased oxidative stress. Urinary molybdenum levels are associated with decreased prevalence of hyperuricemia and gout in adult population. Molybdenum's antioxidative properties might have acted as an important mechanism for the reduction of systemic inflammation, ROS, and uric acid levels.

Impact of hyperuricemia on CKD risk beyond genetic predisposition in a population-based cohort study.

The bidirectional effect of hyperuricemia on chronic kidney disease (CKD) underscores the importance of hyperuricemia as a risk factor for CKD. We evaluated the effect of hyperuricemia on the presence and development of CKD after considering genetic background by calculating polygenic risk scores (PRSs). We employed genome-wide association study summary statistics-excluding the United Kingdom Biobank (UKB) datasets among published CKD Gen Consortium papers-to calculate the PRSs for CKD in white background subjects. To validate PRS performance, we divided the UKB into two datasets to validate and test the data. We used logistic regression analysis to evaluate the association between hyperuricemia and CKD, and performed Kaplan-Meier survival analysis exclusively for subjects with available follow-up data. In total, 438,253 clinical data and 4,307,940 single nucleotide polymorphisms from 459,155 samples were included. We observed a significant positive association between PRS and CKD and the presence and development of CKD. Hyperuricemia significantly increased CKD risk (adjusted odds ratio 1.55, 95% confidence interval 1.48-1.61). The impact of hyperuricemia on CKD was maintained irrespective of PRS range. In addition, negative interaction between hyperuricemia and PRS for CKD was found. Survival analysis indicates that the presence of hyperuricemia significantly increased the risk of CKD development. The PRS for CKD thoroughly reflects the risk of CKD development. Hyperuricemia is a significant indicator of CKD risk, even after incorporating the genetic risk score for CKD. Irrespective of genetic risk, patients with a prospective risk of developing CKD require uric acid monitoring and management.

Surviving the cold: Assessing long-term outcomes among Korean CKD patients exposed to low perceived temperature during winter.

Perceived temperature (PT), which encompasses meteorological factors such as wind speed, cloud cover, and humidity, reflects the actual effect of temperature on the human body. However, limited data exist on the health implications of prolonged exposure to low temperatures during winter in individuals with chronic kidney disease (CKD). We investigated the association between winter PT and long-term outcomes among CKD patients. A total of 32,870 CKD patients from three tertiary hospitals in Seoul were enrolled in this retrospective study (2001-2018). PT was calculated using Staiger's equation, integrating temperature data from 29 automated weather stations across Seoul, along with dew point temperature, wind velocity, and cloud cover data. Kriging interpolation was utilized to estimate PT values at the patients' locations. Overall mortality and major adverse cardiovascular events (MACEs) were assessed using a time-varying Cox proportional hazards model. Additionally, the Cox regression model evaluated PT corresponding to temperature thresholds for cold surge watches or warnings. Over a median follow-up of 6.14 ± 3.96 years, 6147 deaths (18.7%) were recorded. We found that as the average or minimum PT and Ta decreased by 1 °C, the risk of overall mortality significantly increased. In multivariable analyses, the hazard ratio (HR) for the average PT was 1.049 (95% confidence interval [CI] 1.028-1.071), and that for the minimum PT was 1.038 (CI 1.027-1.052). Furthermore, a cold surge warning at a PT of -25.63 °C indicated an HR of 1.837 (CI 1.764-1.914) and a C-index of 0.792. The increased risk of mortality was more pronounced in patients with low or middle socioeconomic statuses. For MACEs, lower average and minimum PT and Ta were associated with an increased risk, following a similar trend to overall mortality, although not all results reached statistical significance. These findings emphasize the importance of targeted public health policies to mitigate risks among vulnerable CKD patients.

Risk of mortality and cause of death according to kidney function parameters: a nationwide observational study in Korea.

BACKGROUND: Further study is warranted to determine the association between estimated glomerular filtration rate (eGFR) or albuminuria and the risk of death from diverse causes. METHODS: We screened >10 million general health screening examinees who received health examinations conducted in 2009 using the claims database of Korea. After the exclusion of those previously diagnosed with renal failure and those with missing data, 9,917,838 individuals with available baseline kidney function measurements were included. The primary outcome was mortality and cause-specific death between 2009 and 2019 identified through death certificates based on the diagnostic codes of International Classification of Diseases, 10th revision. Multivariable Cox regression analysis adjusted for various clinicodemographic and social characteristics was used to assess mortality risk. RESULTS: The hazard ratio of death was significantly high in both the eGFR <60 mL/min/1.73 m2 and in the eGFR ≥120 mL/ min/1.73 m2 groups in univariable and multivariable regression analyses when compared to those within the reference range (eGFR of 90-120 mL/min/1.73 m2). The results were similar for death by cardiovascular, cancer, infection, endocrine, respiratory, and digestive causes. We also found that albuminuria was associated with higher risk of death regardless of eGFR range, and those in the higher categories of dipstick albuminuria showed higher risk. CONCLUSION: We reconfirmed the significant association between eGFR, albuminuria, and mortality. Healthcare providers should keep in mind that albuminuria and decreased eGFR as well as kidney hyperfiltration are independent predictors of mortality.

Associations of MRI-derived kidney volume, kidney function, body composition and physical performance in ≈38 000 UK Biobank participants: a population-based observational study.

Background: Kidney volume is used as a predictive and therapeutic marker for several clinical conditions. However, there is a lack of large-scale studies examining the relationship between kidney volume and various clinicodemographic factors, including kidney function, body composition and physical performance. Methods: In this observational study, MRI-derived kidney volume measurements from 38 526 UK Biobank participants were analysed. Major kidney volume-related measures included body surface area (BSA)-adjusted total kidney volume (TKV) and the difference in bilateral kidneys. Multivariable-adjusted linear regression and cubic spline analyses were used to explore the association between kidney volume-related measures and clinicodemographic factors. Cox or logistic regression was used to identify the risks of death, non-kidney cancer, myocardial infarction, ischaemic stroke and chronic kidney disease (CKD). Results: The median of BSA-adjusted TKV and the difference in kidney volume were 141.9 ml/m2 [interquartile range (IQR) 128.1-156.9] and 1.08-fold (IQR 1.04-1.15), respectively. Higher BSA-adjusted TKV was significantly associated with higher estimated glomerular filtration rate {eGFR; ß = 0.43 [95% confidence interval (CI) 0.42-0.44]; P < .001}, greater muscle volume [ß = 0.50 (95% CI 0.48-0.51); P < .001] and greater mean handgrip strength [ß = 0.15 (95% CI 0.13-0.16); P < .001] but lower visceral adipose tissue volume [VAT; ß = -0.09 (95% CI -0.11 to -0.07); P < .001] in adjusted models. A greater difference in bilateral kidney volumes was associated with lower eGFR, muscle volume and physical performance but with higher proteinuria and VAT. Higher BSA-adjusted TKV was significantly associated with a reduced risk of CKD [odds ratio (OR) 0.7 (95% CI 0.63-0.77); P < .001], while a greater difference in kidney volume was significantly associated with an increased risk of CKD [OR 1.13 (95% CI 1.07-1.20); P < .001]. Conclusion: Higher BSA-adjusted TKV and lower differences in bilateral kidney volumes are associated with higher kidney function, muscle volume and physical performance and a reduced risk of CKD.

Association between dyslipidemia and the risk of incident chronic kidney disease affected by genetic susceptibility: Polygenic risk score analysis.

BACKGROUND: The effect of dyslipidemia on kidney disease outcomes has been inconclusive, and it requires further clarification. Therefore, we aimed to investigate the effects of genetic factors on the association between dyslipidemia and the risk of chronic kidney disease (CKD) using polygenic risk score (PRS). METHODS: We analyzed data from 373,523 participants from the UK Biobank aged 40-69 years with no history of CKD. Baseline data included plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride, as well as genome-wide genotype data for PRS. Our primary outcome, incident CKD, was defined as a composite of estimated glomerular filtration rate < 60 ml/min/1.73 m2 and CKD diagnosis according to International Classification of Disease-10 codes. The effects of the association between lipid levels and PRS on incident CKD were assessed using the Cox proportional hazards model. To investigate the effect of this association, we introduced multiplicative interaction terms into a multivariate analysis model and performed subgroup analysis stratified by PRS tertiles. RESULTS: In total, 4,424 participants developed CKD. In the multivariable analysis, PRS was significantly predictive of the risk of incident CKD as both a continuous variable and a categorized variable. In addition, lower total cholesterol, LDL-C, HDL-C, and higher triglyceride levels were significantly associated with the risk of incident CKD. There were interactions between triglycerides and intermediate and high PRS, and the interactions were inversely associated with the risk of incident CKD. CONCLUSIONS: This study showed that PRS presented significant predictive power for incident CKD and individuals in the low-PRS group had a higher risk of triglyceride-related incident CKD.

Antibiotic-induced intestinal microbiota depletion can attenuate the acute kidney injury to chronic kidney disease transition via NADPH oxidase 2 and trimethylamine-N-oxide inhibition.

Intestinal microbiota and their metabolites affect systemic inflammation and kidney disease outcomes. Here, we investigated the key metabolites associated with the acute kidney injury (AKI)-to chronic kidney disease (CKD) transition and the effect of antibiotic-induced microbiota depletion (AIMD) on this transition. In 61 patients with AKI, 59 plasma metabolites were assessed to determine the risk of AKI-to-CKD transition. An AKI-to-CKD transition murine model was established four weeks after unilateral ischemia-reperfusion injury (IRI) to determine the effects of AIMD on the gut microbiome, metabolites, and pathological responses related to CKD transition. Human proximal tubular epithelial cells were challenged with CKD transition-related metabolites, and inhibitory effects of NADPH oxidase 2 (NOX2) signals were tested. Based on clinical metabolomics, plasma trimethylamine N-oxide (TMAO) was associated with a significantly increased risk for AKI-to-CKD transition [adjusted odds ratio 4.389 (95% confidence interval 1.106-17.416)]. In vivo, AIMD inhibited a unilateral IRI-induced increase in TMAO, along with a decrease in apoptosis, inflammation, and fibrosis. The expression of NOX2 and oxidative stress decreased after AIMD. In vitro, TMAO induced fibrosis with NOX2 activation and oxidative stress. NOX2 inhibition successfully attenuated apoptosis, inflammation, and fibrosis with suppression of G2/M arrest. NOX2 inhibition (in vivo) showed improvement in pathological changes with a decrease in oxidative stress without changes in TMAO levels. Thus, TMAO is a key metabolite associated with the AKI-to-CKD transition, and NOX2 activation was identified as a key regulator of TMAO-related AKI-to-CKD transition both in vivo and in vitro.

The estimated mediating roles of anemia-related variables in the association between kidney function and mortality: a National Health and Nutrition Examination Survey (NHANES) study.

Anemia is a common complication of chronic kidney disease (CKD), impacting long-term outcomes such as mortality and morbidity. Analyzing NHANES data from 1999 through 2016 for adults aged ≥ 20 years, we assessed the mediating effects of anemia biomarkers (hemoglobin, hematocrit, red cell distribution width [RDW], and mean corpuscular hemoglobin concentration [MCHC]) on CKD-related outcomes by using hazard ratios from a biomarker-adjusted model. Of 44,099 participants, 7463 experienced all-cause death. Cox proportional hazard models revealed a higher all-cause mortality risk in the > 45 years and CKD groups than in the early CKD group. Hemoglobin, hematocrit and MCHC were inversely related to all-cause mortality; RDW was related to mortality. Single mediation analysis showed greater mediating effects of anemia indicators on CKD and mortality in the elderly (> 65 years) population than those in the general population. In the multimediation analysis, the combined mediating effect of anemia was higher in the CKD population than in the general population. This study showed a proportional increase in the mediating effect of anemia with CKD stage, suggesting potential therapeutic avenues. However, further exploration of other mediating factors on kidney outcomes is necessary.

Kidney Health Plan 2033 in Korea: bridging the gap between the present and the future.

In response to the increase in the prevalence of chronic kidney disease (CKD) in Korea, the growth of patients requiring renal replacement therapy and the subsequent increase in medical costs, the rapid expansion of patients with end-stage kidney disease (ESKD), and the decrease in patients receiving home therapy, including peritoneal dialysis, the Korean Society of Nephrology has proclaimed the new policy, Kidney Health Plan 2033 (KHP 2033). KHP 2033 would serve as a milestone to bridge the current issues to a future solution by directing the prevention and progression of CKD and ESKD, particularly diabetic kidney disease, and increasing the proportion of home therapy, thereby reducing the socioeconomic burden of kidney disease and improving the quality of life. Here, we provide the background for the necessity of KHP 2033, as well as the contents of KHP 2033, and enlighten the Korean Society of Nephrology's future goals. Together with patients, healthcare providers, academic societies, and national policymakers, we need to move forward with goal-oriented drive and leadership to achieve these goals.

Long-term exposure to high perceived temperature and risk of mortality among patients with chronic kidney disease.

Health risks due to climate change are emerging, particularly from high-temperature exposure. The perceived temperature is an equivalent temperature based on the complete heat budget model of the human body. Therefore, we aimed to analyze the effect of perceived temperature on overall mortality among patients with chronic kidney disease. In total, 32,870 patients with chronic kidney disease in Seoul participated in this retrospective study (2001-2018) at three medical centers. The perceived temperature during the summer season was calculated using meteorological factors, including the air temperature near the automated weather station, dew point temperature, wind velocity, and total cloud amount. We assessed the association between perceived temperature using Kriging spatial interpolation and mortality in patients with CKD in the time-varying Cox proportional hazards model that was adjusted for sex, age, body mass index, hypertension, diabetes mellitus, estimated glomerular filtration rate, smoking, alcohol consumption, and educational level. During the 6.14 ± 3.96 years of follow-up, 3863 deaths were recorded. In multivariable analysis, the average level of perceived temperature and maximum level of perceived temperature demonstrated an increased risk of overall mortality among patients with chronic kidney disease. The concordance index for mortality of perceived temperature was higher than temperature, discomfort index, and heat index. When stratified by age, diabetes mellitus, and estimated glomerular filtration rate, patients with chronic kidney disease with young age (age <65 years) showed higher hazard ratio for mortality (interaction P = 0.049). Moreover, the risk of death in the winter and spring seasons was more significant compared to that of the summer and autumn seasons. Therefore, long-term exposure to high perceived temperature during summer increases the risk of mortality among patients with chronic kidney disease.

Long-term ozone exposure and mortality in patients with chronic kidney disease: a large cohort study.

BACKGROUND: Epidemiologic studies on the effects of long-term exposure to ozone (O3) have shown inconclusive results. It is unclear whether to O3 has an effect on chronic kidney disease (CKD). We investigated the effects of O3 on mortality and renal outcome in CKD. METHODS: We included 61,073 participants and applied Cox proportional hazards models to examine the effects of ozone on the risk of end-stage renal disease (ESRD) and mortality in a two-pollutants model adjusted for socioeconomic status. We calculated the concentration of ozone exposure one year before enrollment and used inverse distance weighting (IDW) for interpolation, where the exposure was evenly distributed. RESULTS: In the single pollutant model, O3 was significantly associated with an increased risk of ESRD and all-cause mortality. Based on the O3 concentration from IDW interpolation, this moving O3 average was significantly associated with an increased risk of ESRD and all-cause mortality. In a two-pollutants model, even after we adjusted for other measured pollutants, nitrogen dioxide did not attenuate the result for O3. The hazard ratio (HR) value for the district-level assessment is 1.025 with a 95% confidence interval (CI) of 1.014-1.035, while for the point-level assessment, the HR value is 1.04 with a 95% CI of 1.035-1.045. The impact of ozone on ESRD, hazard ratio (HR) values are, 1.049(95%CI: 1.044-1.054) at the district unit and 1.04 (95%CI: 1.031-1.05) at the individual address of the exposure assessment. The ozone hazard ratio for all-cause mortality was 1.012 (95% confidence interval: 1.008-1.017) for administrative districts and 1.04 (95% confidence interval: 1.031-1.05) for individual addresses. CONCLUSIONS: This study suggests that long-term ambient O3 increases the risk of ESRD and mortality in CKD. The strategy to decrease O3 emissions will substantially benefit health and the environment.

Primary sclerosing cholangitis causally affects kidney function decline: A Mendelian randomization study.

BACKGROUND AND AIM: The causal linkage between primary sclerosing cholangitis (PSC) and kidney function is unexplored despite their potential for long-term detrimental effects on kidney function. METHODS: Two-sample summary-level Mendelian randomization (MR) study was conducted to identify the association between PSC and kidney function. The genetic variants were extracted from the PSC-specific multi-trait analyzed genome-wide association study (GWAS) of European ancestry. Summary-level data for kidney function traits, including estimated glomerular filtration rate (eGFR), annual eGFR decline, and chronic kidney disease (CKD), were obtained from the CKDGen consortium. Multiplicative random-effects inverse-variance weighted (MR-IVW), and a series of pleiotropy-robust analyses were performed to investigate the causal effects and ascertain their robustness. RESULTS: Significant causal associations between genetically predicted PSC and kidney function traits were identified. Genetically predicted PSC was associated with decreased log-transformed eGFR (MR-IVW; beta = -0.41%; standard error [SE] = 0.02%; P < 0.001), increased rate of annual eGFR decline (MR-IVW; beta = 2.43%; SE = 0.18%; P < 0.001), and higher risk of CKD (MR-IVW; odds ratio = 1.07; 95% confidence interval = 1.06-1.08; P < 0.001). The main findings were supported by pleiotropy-robust analysis, including MR-Egger with bootstrapped error and weighted median. CONCLUSIONS: Our study demonstrates that genetically predicted PSC is causally associated with kidney function impairment. Further studies are warranted to identify the underlying mechanisms.

Periostin deficiency attenuates kidney fibrosis in diabetic nephropathy by improving pancreatic ß-cell dysfunction and reducing kidney EMT.

Diabetic nephropathy (DN) is associated with kidney fibrosis. A previous study revealed that periostin (POSTN) contributes to kidney fibrosis. This study examined the role of POSTN in DN. The urinary concentrations of POSTN and TNC increased according to the severity of DN in human samples. Streptozotocin (STZ) was administered after unilateral nephrectomy (UNXSTZ) to induce DN in wild-type and Postn-null mice. Four experimental groups were generated: wild-typeham (WT Sham), wild-type UNXSTZ (WT STZ), Postn-null Sham (KO Sham), and Postn-null UNXSTZ (KO STZ). After 20 weeks, the KO STZ group had lower levels of urine albumin excretion, glomerular sclerosis, and interstitial fibrosis than those of the WT STZ group. Additionally, the KO STZ group had lower expression of fibrosis markers, including TNC. The KO STZ group showed better glucose regulation than the WT STZ model. Furthermore, the KO STZ group exhibited significantly preserved pancreatic islet integrity and insulin expression. HK-2 cells were used to observe the aggravation of fibrosis caused by POSTN under TGF-ß conditions. We stimulated INS-1 cells with streptozotocin and evaluated the viability of these cells. The anti-POSTN antibody treatment of INS-1 cells with streptozotocin resulted in higher cell viability than that with treatment with streptozotocin alone. The absence of POSTN in DN contributes to renal fibrosis alleviation by improving pancreatic ß-cell function. Additionally, there is an association between POSTN and TNC.

Impact of decreased levels of total CO2 on in-hospital mortality in patients with COVID-19.

Decreased total CO2 (tCO2) is significantly associated with all-cause mortality in critically ill patients. Because of a lack of data to evaluate the impact of tCO2 in patients with COVID-19, we assessed the impact of tCO2 on all-cause mortality in this study. We retrospectively reviewed the data of hospitalized patients with COVID-19 in two Korean referral hospitals between February 2020 and September 2021. The primary outcome was in-hospital mortality. We assessed the impact of tCO2 as a continuous variable on mortality using the Cox-proportional hazard model. In addition, we evaluated the relative factors associated with tCO2 ≤ 22 mmol/L using logistic regression analysis. In 4,423 patients included, the mean tCO2 was 24.8 ± 3.0 mmol/L, and 17.9% of patients with tCO2 ≤ 22 mmol/L. An increase in mmol/L of tCO2 decreased the risk of all-cause mortality by 4.8% after adjustment for age, sex, comorbidities, and laboratory values. Based on 22 mmol/L of tCO2, the risk of mortality was 1.7 times higher than that in patients with lower tCO2. This result was maintained in the analysis using a cutoff value of tCO2 24 mmol/L. Higher white blood cell count; lower hemoglobin, serum calcium, and eGFR; and higher uric acid, and aspartate aminotransferase were significantly associated with a tCO2 value ≤ 22 mmol/L. Decreased tCO2 significantly increased the risk of all-cause mortality in patients with COVID-19. Monitoring of tCO2 could be a good indicator to predict prognosis and it needs to be appropriately managed in patients with specific conditions.

Revisiting metformin therapy for the mitigation of diabetic foot ulcer in patients with diabetic kidney disease from real-world evidence.

Diabetic foot ulcer and diabetic kidney disease are diabetes-related chronic vascular complications that strongly correlate with high morbidity and mortality. Although metformin potentially confers a wound-healing advantage, no well-established clinical evidence supports the benefit of metformin for diabetic foot ulcer. Thus, this study investigated the effect of metformin on diabetic foot ulcer from a large diabetic kidney disease cohort for the first time. This retrospective cohort study enrolled 10 832 patients who visited the nephrology department more than twice at two South Korean tertiary-referral centers between 2001 and 2016. The primary outcome was diabetic foot ulcer events; secondary outcomes included hospitalization, amputation, a composite of amputation or vascular intervention, and Wagner Grade ≥ 3. Multivariate Cox analysis and propensity score matching (PSM) were used to balance baseline intergroup differences between metformin users and non-users. In total, 4748 patients were metformin users, and 6084 patients were metformin non-users. Over a follow-up period of 117.5 ± 66.9 months, the diabetic foot ulcer incidence was 5.2%. After PSM, metformin users showed a lower incidence of diabetic foot ulcer events than metformin non-users (adjusted hazard ratio 0.41; p < 0.001). In a sensitivity analysis of 563 patients with diabetic foot ulcer, metformin usage was associated with lower severity in all four secondary outcomes: hospitalization (adjusted hazard ratio 0.33; p < 0.001); amputation (adjusted hazard ratio 0.44; p = 0.001); composite of amputation or vascular intervention (adjusted hazard ratio 0.47; p < 0.001); and Wagner Grade ≥ 3 (adjusted hazard ratio 0.39; p < 0.001). In conclusion, metformin therapy in patients with diabetic kidney disease can lower diabetic foot ulcer incidence and progression.

Causal Effect of Chondroitin, Glucosamine, Vitamin, and Mineral Intake on Kidney Function: A Mendelian Randomization Study.

The causal effects of chondroitin, glucosamine, and vitamin/mineral supplement intake on kidney function remain unknown, despite being commonly used. We conducted a two-sample summary-level Mendelian randomization (MR) analysis to test for causal associations between regular dietary supplement intake and kidney function. Genetic instruments for chondroitin, glucosamine, and vitamin/mineral supplement intake were obtained from a genome-wide association study of European ancestry. Summary statistics for the log-transformed estimated glomerular filtration rate (log-eGFR) were provided by the CKDGen consortium. The multiplicative random-effects inverse-variance weighted method showed that genetically predicted chondroitin and glucosamine intake was causally associated with a lower eGFR (chondroitin, eGFR change beta = -0.113%, standard error (SE) = 0.03%, p-value = 2 × 10-4; glucosamine, eGFR change beta = -0.240%, SE = 0.035%, p-value = 6 × 10-12). However, a genetically predicted vitamin/mineral supplement intake was associated with a higher eGFR (eGFR change beta = 1.426%, SE = 0.136%, p-value = 1 × 10-25). Validation analyses and pleiotropy-robust MR results for chondroitin and vitamin/mineral supplement intake supported the main results. Our MR study suggests a potential causal effect of chondroitin and glucosamine intake on kidney function. Therefore, clinicians should carefully monitor their long-term effects.

Urine myo-inositol as a novel prognostic biomarker for diabetic kidney disease: a targeted metabolomics study using nuclear magnetic resonance.

BACKGROUND: As a leading cause of chronic kidney disease, clinical demand for noninvasive biomarkers of diabetic kidney disease (DKD) beyond proteinuria is increasing. Metabolomics is a popular method to identify mechanisms and biomarkers. We investigated urinary targeted metabolomics in DKD patients. METHODS: We conducted a targeted metabolomics study of 26 urinary metabolites in consecutive patients with DKD stage 1 to 5 (n = 208) and healthy controls (n = 26). The relationships between estimated glomerular filtration rate (eGFR) or urine protein-creatinine ratio (UPCR) and metabolites were evaluated. Multivariate Cox analysis was used to estimate relationships between urinary metabolites and the target outcome, end-stage renal disease (ESRD). C statistics and time-dependent receiver operating characteristics (ROC) were used to assess diagnostic validity. RESULTS: During a median 4.5 years of follow-up, 103 patients (44.0%) progressed to ESRD and 65 (27.8%) died. The median fold changes of nine metabolites belonged to monosaccharide and tricarboxylic acid (TCA) cycle metabolites tended to increase with DKD stage. Myo-inositol, choline, and citrates were correlated with eGFR and choline, while mannose and myo-inositol were correlated with UPCR. Elevated urinary monosaccharide and TCA cycle metabolites showed associations with increased morality and ESRD progression. The predictive power of ESRD progression was high, in the order of choline, myo-inositol, and citrate. Although urinary metabolites alone were less predictive than serum creatinine or UPCR, myo-inositol had additive effect with serum creatinine and UPCR. In time-dependent ROC, myo-inositol was more predictive than UPCR of 1-year ESRD progression prediction. CONCLUSION: Myo-inositol can be used as an additive biomarker of ESRD progression in DKD.

Comparison of the performance of currently used estimated glomerular filtration rate equations with 24-hour urine creatinine clearance: sample analysis of randomised controlled trial participants.

OBJECTIVE: There are several equations for estimating the glomerular filtration rate (GFR), and each method has its limitations. We compared various estimated GFR (eGFR) equations with 24 hours urine creatinine clearance (24u-CCr). DESIGN: Sample analysis of randomised controlled trial participants. SETTING AND PARTICIPANTS: We compared the mean 24u-CCr values measured 2-3 times for 211 patients with eGFR values calculated using the following equations: isotope dilution mass spectrometry-Modification of Diet in Renal Disease (IDMS-MDRD) equation, Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, equations for Koreans (KOR-IDMS-MDRD and KOR-CKD-EPI) and full age spectrum equation. OUTCOME MEASURES: Performance of various creatinine-based eGFR equations, including those with Korean coefficients, compared with the results of the 24u-CCr. RESULTS: IDMS-MDRD showed the best overall correlation with the 24u-CCr (R=0.949, p<0.001), and KOR-CKD-EPI showed the best agreement in terms of the intraclass correlation coefficient (ICC, 0.969, 95% CI 0.959 to 0.976, p<0.001). In subgroup analysis, IDMS-MDRD-GFR showed the highest ICCs in CKD stages 1 and 3 (ICC 0.872 in stage 1 and 0.927 in CKD stage 3, all p<0.001). KOR-CKD-EPI showed the highest ICC in CKD stage 2 (ICC 0.854, p<0.001). Overall, the accuracy of CKD-EPI (2021) was the highest at P15 (15%) and P30 (30%) (P15: 65.4 and P30: 97.6). In addition, CKD-EPI (2021) showed the highest P30 accuracy in CKD stage 1 (98.7), whereas KOR-IDMS-MDRD showed the highest P30 accuracy in CKD stages 2 and 3 (98.8 and 98.2, respectively). CONCLUSIONS: The IDMS-MDRD equation showed the best correlation and overall good agreement with the 24u-CCr; however, the accuracy was low. The most accurate measurements were obtained using the CKD-EPI (2021) equation in CKD stage 1 and the KOR-IDMS-MDRD equation in CKD stages 2-3; nevertheless, the CKD-EPI (2021) equation showed the best overall accuracy. TRIAL REGISTRATION NUMBER: NCT01552954.