T Follicular Helper Cells in Tertiary Lymphoid Structure Contribute to Renal Fibrosis by IL-21.

Tertiary lymphoid structure (TLS) represents lymphocyte clusters in non-lymphoid organs. The formation and maintenance of TLS are dependent on follicular helper T (TFH) cells. However, the role of TFH cells during renal TLS formation and the renal fibrotic process has not been comprehensively elucidated in chronic kidney disease. Here, we detected the circulating TFH cells from 57 IgAN patients and found that the frequency of TFH cells was increased in IgA nephropathy patients with renal TLS and also increased in renal tissues from the ischemic-reperfusion-injury (IRI)-induced TLS model. The inducible T-cell co-stimulator (ICOS) is one of the surface marker molecules of TFH. Remarkably, the application of an ICOS-neutralizing antibody effectively prevented the upregulation of TFH cells and expression of its canonical functional mediator IL-21, and also reduced renal TLS formation and renal fibrosis in IRI mice in vivo. In the study of this mechanism, we found that recombinant IL-21 could directly promote renal fibrosis and the expression of p65. Furthermore, BAY 11-7085, a p65 selective inhibitor, could effectively alleviate the profibrotic effect induced by IL-21 stimulation. Our results together suggested that TFH cells contribute to TLS formation and renal fibrosis by IL-21. Targeting the ICOS-signaling pathway network could reduce TFH cell infiltration and alleviate renal fibrosis.

Relation Between Dietary Carotenoid Intake, Serum Concentration, and Mortality Risk of CKD Patients Among US Adults: National Health and Nutrition Examination Survey 2001-2014.

Background: Current evidence on the relationship between carotenoids and chronic kidney disease (CKD) patients are limited and controversial. Methods: Data were obtained from the Nutrition and Health Examination Survey (NHANES) database and the NHANES Linked Mortality File, both from a nationally representative sample. Dietary intake was assessed through 24-h dietary recall, and information was available both on dietary and serum α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and lutein/zeaxanthin (combined) through the NHANES cycles used. We used multivariable Cox proportional hazards regression models to estimate the risk for all-cause mortality associated with carotene intakes and serum levels, adjusting for potential confounding factors. Results: Of the 6,095 CKD participants, 1,924 subjects died (mean follow-up time, 8.1 years). After eliminating all the confounding factors, we found that high levels of total carotene (HR = 0.85, 95% CI, 0.75-0.97, P = 0.011) intakes at baseline were significantly associated with a lower risk of death. And the serum concentrations of carotenoid were also showing that a-carotene (HR = 0.77, 95%CI, 0.65-0.92, P = 0.002), beta-cryptoxanthin (HR = 0.83, 95%CI, 0.70-0.98, P = 0.019), lycopene (HR = 0.77, 95% CI, 0.65-0.91, P = 0.002), and lutein + zeaxanthin (HR = 0.82, 95% CI, 0.70-0.96, P = 0.002) was significantly associated with decreased all-cause mortality of CKD patients. The associations remained similar in the sensitivity analyses. Conclusion: Findings suggest that high-level carotene dietary intake and the serum concentration were associated with a lower risk of mortality in the CKD population.

Sugar-sweetened beverage consumption and mortality of chronic kidney disease: results from the US National Health and Nutrition Examination Survey, 1999-2014.

Background: The relationship between intake of sugar-sweetened beverages (SSBs) and the risk of death in patients with chronic kidney disease (CKD) is unclear. We evaluated the association between SSB intake and subsequent overall mortality in CKD patients. Methods: We included data from 3996 CKD patients who participated in the 1999-2014 National Health and Nutrition Examination Survey (NHANES). SSB intake was assessed by a 24-h dietary recall, grouped as none, >0 to <1 serving/day, 1 to <2 servings/day and ≥2 servings/day. After adjusting for demographic variables, lifestyle, diet and comorbidities, Cox proportional risk regressions were applied to analyze the associations between the daily intake of SSBs as well as added sugar from beverages and all-cause mortality. Results: In the whole research population, the median age at baseline was 67 years, 22% were Black and 54% were female. A total of 42% had stage 3 CKD. During an average follow-up period of 8.3 years, a sum of 1137 (28%) deaths from all causes was recorded. The confounder-adjusted risk of mortality was associated with an increase of 1 serving/day of SSBs, with all-cause mortality of 1.18 [95% confidence interval (95% CI)1.08-1.28], and intakes of increased 20-g added sugar/1000 kcal of total energy per day were associated with all-cause mortality of 1.14 (1.05-1.24). Equivalently substituting 1 serving/day of SSBs with unsweetened coffee [HR (95% CI) 0.82 (0.74-0.91)], unsweetened tea [HR (95% CI) 0.86 (0.76-0.98)], plain water [HR (95% CI) 0.79 (0.71-0.88)], or non- or low-fat milk [HR (95% CI) 0.75 (0.60-0.93)] were related to a 14-25% reduced risk of all-cause mortality. Conclusion: Findings suggest that in the CKD population, increased SSB intake was associated with a higher risk of mortality and indicated a stratified association with dose. Plain water and unsweetened coffee/tea might be possible alternatives for SSBs to avert untimely deaths.

Low-Carbohydrate-Diet Score and Mortality in Adults With and Without Chronic Kidney Disease: Results From the Third National Health and Nutrition Examination Survey.

OBJECTIVE: The long-term safety of consuming low-carbohydrate diets (LCDs) remains controversial. As high protein and high fat might accelerate chronic kidney disease (CKD) progression, the impact of LCD on mortality might be different in subjects with CKD and subjects without CKD. Therefore, the objective of this study was to assess the association of LCD with mortality among individuals with and without CKD. METHODS: Data from 1158 subjects with CKD and 9523 subjects without CKD in the Third National Health and Nutrition Examination Survey were analyzed. The LCD score was calculated based on a 24-hour dietary recall interview. Mortality was from baseline until 31 December 2015. Cox proportional hazards regression models were fitted to estimate multivariable-adjusted hazard ratios and 95% confidence intervals. RESULTS: During the median follow-up of 24 years, 751 (65%) deaths and 2624 (28%) deaths were recorded in the CKD group and the non-CKD group, respectively. The multivariable-adjusted hazard ratio for all-cause mortality comparing the highest versus lowest quarters of LCD score was 1.51 (95% confidence interval, 1.01-2.25, P for trend = 0.045) in the CKD group. However, there were no association between the LCD score and all-cause mortality in the non-CKD group. CONCLUSIONS: The LCD scores were found significantly positively associated with all-cause mortality in adults with CKD, but not in adults without CKD.

Dietary Omega-3 Fatty Acid Intake and Mortality in CKD Population: A 1999-2014 NHANES Analysis.

INTRODUCTION: High risk of early death, especially contributed to cardiovascular disease, exists in patients who have chronic kidney disease (CKD). And the burden of cardiovascular disease is able to be lightened by an increase in omega-3 polyunsaturated fatty acid (omega-3 PUFA). A diet high in omega-3 PUFA in the general population is protective, although it is inconclusive about its beneficial role in the CKD population. METHODS: From the 1999 to 2014 National Health and Nutrition Examination Surveys (NHANES), we can collect 2,990 participants who suffered from CKD, who were classified into 4 groups: <0.86, 0.87-1.30, 1.31-1.92, and 1.93-9.65 g/day based on NHANES 24-h dietary recall questionnaire dietary omega-3 PUFA. Moreover, their mortality details were available to be obtained by linking NHANES to the National Death Index. The associations between dietary omega-3 PUFA and mortality were evaluated by constructing multivariable Cox proportional hazards models. RESULTS: Over 8 years of a median follow-up, 864 deaths were recorded. The adjusted hazard ratios (95% confidence interval) for all-cause mortality of the diseased people with CKD in the 2nd (0.87-1.30 g/day), 3rd (0.87-1.30 g/day), and 4th (1.93-9.65 g/day) quartiles of dietary omega-3 PUFA were 0.94 (0.72, 1.23), 0.74 (0.54, 1.02), and 0.67 (0.48, 0.93), respectively, versus those with the lowest quartile of dietary omega-3 PUFA intake (<0.86 g/day) (p for trend = 0.011). CONCLUSION: There may be a inverse relation of dietary omega-3 PUFA intake and all-cause mortality in patients with CKD. Therefore, an increase of dietary omega-3 PUFA may be encouraged to be used clinically in patients with CKD.

Effect of Marital Status on Depression and Mortality among Patients with Chronic Kidney Disease from National Health and Nutrition Examination Survey 2005-2014.

BACKGROUND: The relationship between marital status and CKD is rarely studied. We aimed to explore the effect of marital status on the depression and mortality of patients with CKD. METHODS: The data sources came from the NHANES database during 2005-2014 and 3,865 participants were included in this study. We used logistic regression models to examine the relationship between marital status and depression of CKD patients. The Cox proportional hazard models were used to evaluate the association between marital status and mortality of CKD patients. RESULTS: In terms of depression in CKD patients, unmarried patients had a worse situation than married patients. Meanwhile, after adjusting the covariables, unmarried patients had increased risk of depression (OR = 1.26, 95% CI: 1.01-1.57) compared with married CKD patients, especially in males (OR = 1.45, 95% CI: 1.02-2.06) and patients with more than college education level (OR = 12.4, 95% CI: 3.75-41.02). There was a significant relationship between marital status and mortality of general CKD patients (HR = 1.36, 95% CI: 1.17-1.58). Moreover, marriage showed a protective effect against death among male patients, patients with school graduate or less and more than college educational level, patients with high income, and patients in different estimated glomerular filtration rate groups. CONCLUSIONS: The use of large numbers of participants has revealed the effect of marital status on CKD patients. Unmarried ones had a higher risk of depression than married ones among CKD patients. Meanwhile, the risk of death was higher in unmarried ones than married ones among CKD patients in this study.

Risk Factors and Outcomes of Acute Kidney Injury in Critically Ill Patients with Coronavirus Disease 2019.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has emerged as a major global health threat with a great number of deaths worldwide. Acute kidney injury (AKI) is a common complication in patients admitted to the intensive care unit. We aimed to assess the incidence, risk factors and in-hospital outcomes of AKI in COVID-19 patients admitted to the intensive care unit. METHODS: We conducted a retrospective observational study in the intensive care unit of Tongji Hospital, which was assigned responsibility for the treatments of severe COVID-19 patients by the Wuhan government. AKI was defined and staged based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Mild AKI was defined as stage 1, and severe AKI was defined as stage 2 or stage 3. Logistic regression analysis was used to evaluate AKI risk factors, and Cox proportional hazards model was used to assess the association between AKI and in-hospital mortality. RESULTS: A total of 119 patients with COVID-19 were included in our study. The median patient age was 70 years (interquartile range, 59-77) and 61.3% were male. Fifty-one (42.8%) patients developed AKI during hospitalization, corresponding to 14.3% in stage 1, 28.6% in stage 2 and 18.5% in stage 3, respectively. Compared to patients without AKI, patients with AKI had a higher proportion of mechanical ventilation mortality and higher in-hospital mortality. A total of 97.1% of patients with severe AKI received mechanical ventilation and in-hospital mortality was up to 79.4%. Severe AKI was independently associated with high in-hospital mortality (OR: 1.82; 95% CI: 1.06-3.13). Logistic regression analysis demonstrated that high serum interleukin-8 (OR: 4.21; 95% CI: 1.23-14.38), interleukin-10 (OR: 3.32; 95% CI: 1.04-10.59) and interleukin-2 receptor (OR: 4.50; 95% CI: 0.73-6.78) were risk factors for severe AKI development. CONCLUSIONS: Severe AKI was associated with high in-hospital mortality, and inflammatory response may play a role in AKI development in critically ill patients with COVID-19.

Recovery of new-onset kidney disease in COVID-19 patients discharged from hospital.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has emerged as a major global health threat with a great number of deaths worldwide. Despite abundant data on that many COVID-19 patients also displayed kidney disease, there is limited information available about the recovery of kidney disease after discharge. METHODS: Retrospective and prospective cohort study to patients with new-onset kidney disease during the COVID-19 hospitalization, admitted between January 28 to February 26, 2020. The median follow-up was 4 months after discharge. The follow-up patients were divided into the recovery group and non-recovery group. Descriptive statistics and between-groups comparison were used. RESULTS: In total, 143 discharged patients with new-onset kidney disease during the COVID-19 hospitalization were included. Patients had a median age was 64 (IQR, 51-70) years, and 59.4% of patients were men. During 4-months median follow-up, 91% (130 of 143) patients recovered from kidney disease, and 9% (13 of 143) patients haven't recovered. The median age of patients in the non-recovery group was 72 years, which was significantly higher than the median age of 62 years in the recovery group. Discharge serum creatinine was significantly higher in the non-recovery group than in the recovery group. CONCLUSIONS: Most of the new-onset kidney diseases during hospitalization of COVID-19 patients recovered 4 months after discharge. We recommend that COVID-19 patients with new-onset kidney disease be followed after discharge to assess kidney recovery, especially elderly patients or patients with high discharge creatinine.

Tertiary lymphoid organs are associated with the progression of kidney damage and regulated by interleukin-17A.

Background: Tertiary lymphoid organs (TLOs) occur after multiple chronic kidney injuries. interleukin-17A (IL-17A) has been reported to associate with the development of TLOs in inflammatory diseases. However, regulation of the renal TLOs and its clinical significance to the pathogenesis of chronic kidney injury are unknown. Methods: To evaluate the clinical significance and regulation of renal TLOs, we analyzed the progression of patients with kidney damage based on the existence and absence of TLOs in a larger multicenter cohort. We also blocked the recruitment of lymphocyte cells into the kidney by FTY720 (fingolimod) in vivo. Besides, we used aged IL-17A genetic knocked out mice and IL-17A-neutralizing antibody to explore the role of IL-17A in renal TLOs formation. Results: We demonstrated that renal TLOs of IgA nephropathy patients were associated with disease severity and were independent risk factors for renal progression after adjustment for age, sex, mean arterial pressure, proteinuria and, baseline eGFR and MEST-C score, especially in the early stage. Plasma levels of TLO-related chemokines CXCL13, CCL19, and CCL21 were higher in patients with renal TLOs. Inhibiting the formation of renal TLOs by FTY720 could reduce the intrarenal inflammation and fibrosis, and early intervention was found to be more effective. IL-17A was increased in renal TLOs models, and genetic depletion of IL-17A or treatment with anti-IL-17A antibody resulted in a marked reduction of the TLOs formation as well as alleviation of renal inflammation and fibrosis. Conclusion: These results indicate that TLOs are associated with the progression of kidney damage and regulated by IL-17A and may be effective targets for the treatment of kidney damage.

Leisure-Time Physical Activity and Mortality in CKD: A 1999-2012 NHANES Analysis.

BACKGROUND: For patients with CKD, evidence on the optimal dose of physical activity and possible harm with excessive exercise is limited. This study aimed to analyze the dose-response association between leisure-time physical activity (LTPA) and mortality in those with CKD and explore the optimal dose or possible harm associated with increased levels of LTPA. METHODS: 4,604 participants with CKD from the 1999 to 2012 National Health and Nutrition Examination Surveys with linked mortality data obtained through 2015 were classified into 6 groups: 0, 1-149, 150-299, 300-599, 600-899, and ≥900 min/week based on the total duration of the self-reported LTPA. Multivariable-adjusted Cox proportional hazards models were used to examine dose-response associations between LTPA and mortality. RESULTS: During the median follow-up of 114 months, 1,449 (31%) all-cause deaths were recorded. Compared to the inactive group (0 min/week), we observed a 22% lower risk of all-cause mortality (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.63-0.97) among participants who performed 1-149 min per week for LTPA. The corresponding HRs and 95% CIs for all-cause mortality for 150-299 and 300-599 min/week of LTPA were 0.79 (0.64-0.97) and 0.74 (0.56-0.98). The benefit appeared to reach a threshold of a 43% (HR, 0.57; 95% CI, 0.36-0.91) lower risk of all-cause mortality among individuals performing 600-899 min/week for LTPA. Importantly, for ≥900 min/week of LTPA, the continued benefits were observed (HR, 0.62; 95% CI, 0.44-0.87). CONCLUSION: LTPA was associated with lower mortality in those with CKD. The optimal dose was observed at the LTPA level of approximately 600-899 min/week, and there were still benefits rather than the excess risk with LTPA levels as high as ≥900 min/week. Therefore, clinicians should encourage inactive CKD patients to perform LTPA and do not need to discourage CKD patients who already adhere to long-term physical activity.

The Incidence, Risk Factors, and Prognosis of Acute Kidney Injury in Adult Patients with Coronavirus Disease 2019.

BACKGROUND AND OBJECTIVES: Since December 2019, coronavirus disease 2019 (COVID-19) outbreak occurred and has rapidly spread worldwide. However, little information is available about the AKI in COVID-19. We aimed to evaluate the incidence, risk factors, and prognosis of AKI in adult patients with COVID-19. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective cohort study of 1392 patients with COVID-19 admitted to a tertiary teaching hospital. Clinical characteristics and laboratory data were extracted from electronic hospitalization and laboratory databases. AKI was defined and staged according to the 2012 Kidney Disease: Improving Global Outcomes criteria. Risk factors for AKI and the association of AKI with in-hospital mortality were assessed. RESULTS: A total of 7% (99 of 1392) of patients developed AKI during hospitalization, 40% (40 of 99) of which occurred within 1 week of admission. Factors associated with a higher risk of AKI include severe disease (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.37 to 3.67), higher baseline serum creatinine (OR, 2.19; 95% CI, 1.17 to 4.11), lymphopenia (OR, 1.99; 95% CI, 1.12 to 3.53), and elevated D-dimer level (OR, 2.68; 95% CI, 1.07 to 6.70). The in-hospital mortality in patients with AKI stage 1, stage 2, and stage 3 was 62%, 77%, and 80%, respectively. AKI was associated with in-hospital mortality even after adjustment for confounders (OR, 5.12; 95% CI, 2.70 to 9.72). CONCLUSIONS: AKI is uncommon but carries high in-hospital mortality in patients with COVID-19.