The Impact of Obesity on Kidney Disease: Observational Cohort Study Analyzing 14,492 Kidney Biopsy Cases.

BACKGROUND: The obesity epidemic is associated with the emergence of new kidney diseases including obesity-related glomerulopathy (ORG) and metabolic syndrome-associated disorders. However, the effects of obesity on prevalence and outcome of biopsy-proven kidney disease are not well known. METHODS: We analyzed 14,492 kidney biopsies in 18 hospitals from 1979 to 2018 in Korea. Obesity was defined as a body mass index value of ≥ 30 kg/m². RESULTS: The most common disease was IgA nephropathy (IgAN) in both obese and non-obese participants (33.7% vs. 38.9%). Obesity was associated with a higher risk of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy (HT-N) (odds ratio [OR], 1.72, 95% confidence interval [CI], 1.37-2.17; OR, 1.96, 95% CI, 1.21-3.19) and a lower risk of IgAN (OR, 0.74, 95% CI, 0.62-0.88). During the median follow up of 93.1 ± 88.7 months, obesity increased the risk of end-stage kidney disease (ESKD) in patients with IgAN (relative risk [RR], 1.49, 95% CI, 1.01-2.20) and lupus nephritis (LN) (RR, 3.43, 95% CI, 1.36-8.67). Of 947 obese individuals, ORG was detected in 298 (31.5%), and 230 participants had other kidney diseases, most commonly, IgAN (40.9%) followed by diabetic nephropathy (15.2%). Participants with ORG, when combined with other renal diseases, showed higher risks for developing ESKD compared to those with ORG alone (RR, 2.48, 95% CI, 1.09-5.64). CONCLUSION: Obesity is associated with an increased risk of FSGS and HT-N, and also increase the ESKD risk in IgAN and LN patients. ORG in obese participants may have favorable renal outcomes if it occurs alone without any other renal disease.

Waist-hip ratio measured by bioelectrical impedance analysis as a valuable predictor of chronic kidney disease development.

Obesity is a major health problem worldwide and is associated with chronic kidney disease (CKD). Body mass index (BMI) is a common method of diagnosing obesity, but there are concerns about its accuracy and ability to measure body composition. This study evaluated the risk of CKD development in a middle-aged population in association with various body composition metrics. From a prospective cohort of 10,030 middle-aged adults, we enrolled 6727 for whom baseline and follow-up data were available. We collected data pertaining to participants' BMI, manually measured waist-hip ratio (WHR), and various measurements of bioelectrical impedance analysis (BIA), including total body fat content, muscle content, and calculated WHR, and classified the participants into quintiles accordingly. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 in follow-up laboratory tests. While an increase in BMI, WHR, and total body fat were associated with an elevated risk of CKD, an increase in total body muscle decreased the risk. Among the body composition metrics, WHR measured by BIA had the highest predictive value for CKD (C-statistics: 0.615). In addition, participants who were "healthy overweight, (defined as low WHR but high BMI), exhibited a 62% lower risk of developing CKD compared to those with "normal-weight obesity," (defined as high WHR despite a normal BMI). In conclusion, we suggest that central obesity measured by BIA is a more accurate indicator than BMI for predicting the development of CKD.

Changes in Mortality According to Creatinine/Cystatin C Ratio in Chronic Kidney Disease and Non-chronic Kidney Disease Patients.

Background: Serum creatinine and cystatin C are not only good indicators of renal function but have also been confirmed to be related to disease prognosis and mortality in various diseases via creatinine/cystatin C ratio (CCR). However, although they are biomarkers of renal function, there is no study regarding renal impairment as a confounding variable in the relationship between CCR and all-cause mortality. Methods: Patients who had simultaneous measurements of serum creatinine and cystatin C between 2003 and 2020 were enrolled. The patients with chronic kidney disease (CKD) were defined as having an estimated glomerular filtration rate (eGFR) CKD-EPI Cr-Cystatin C < 60 ml/min/1.73 m2. CCR was calculated by dividing the serum creatinine level by the cystatin C level measured on the same day. The main outcome assessed was all-cause mortality according to CCR in CKD or non-CKD groups. Results: Among the 8,680 patients in whom creatinine and cystatin C levels were measured simultaneously, 4,301 were included in the CKD group, and 4,379 were included in the non-CKD group, respectively. CCR was 1.4 ± 0.6 in total participants. The non-CKD group showed higher mean CCR, (1.5 ± 0.7 vs. 1.3 ± 0.5) as well as a wider distribution of CCR (p < 0.001) when compared to the CKD group. In non-CKD group, 1st, 4th and 5th quintiles of CCR significantly increased the all-cause mortality risk compared to 2nd quintile of CCR, suggesting U-shaped mortality risk according to CCR in non-CKD. On the other hand, in CKD group, the risk of all-cause mortality linearly increased and 5th quintile of CCR showed 1.82 times risk of mortality compared to 2nd quintile of CCR. In the subgroup analysis of mortality by age and sex, the mortality difference according to CCR were diminished in old age and female sex subgroups. Conclusion: We discovered a U-shaped relationship between mortality and CCR levels in normal renal function, and an increased risk of mortality in CKD with elevated CCR.

Impact of acute kidney injury on long-term adverse outcomes in obstructive uropathy.

Obstructive uropathy is known to be associated with acute kidney injury (AKI). This study aimed to investigate the etiologies, clinical characteristics, consequences and also assess the impact of AKI on long-term outcomes. This multicenter, retrospective study of 1683 patients with obstructive uropathy who underwent percutaneous nephrostomy (PCN) analyzed clinical characteristics, outcomes including progression to end-stage kidney disease (ESKD), overall mortality, and the impact of AKI on long-term outcomes. Obstructive uropathy in adults was most commonly caused by malignancy, urolithiasis, and other causes. AKI was present in 78% of the patients and was independently associated with preexisting chronic kidney disease (CKD). Short-term recovery was achieved in 56.78% after the relief of obstruction. ESKD progression rate was 4.4% in urolithiasis and 6.8% in other causes and older age, preexisting CKD, and stage 3 AKI were independent factors of progression. The mortality rate (34%) was highly attributed to malignant obstruction (52%) stage 3 AKI was also an independent predictor of mortality in non-malignant obstruction. AKI is a frequent complication of adult obstructive uropathy. AKI negatively affects long-term kidney outcomes and survival in non-malignant obstructions. A better understanding of the epidemiology and prognostic factors is needed for adult obstructive uropathy.

The beneficial effects of menopausal hormone therapy on renal survival in postmenopausal Korean women from a nationwide health survey.

Several studies have demonstrated the nephroprotective effects of estrogen on renal damage. In light of the inconsistent results of previous findings, this study aims to evaluate the in-depth role of menopausal hormone therapy (MHT) on the development of end stage renal disease (ESRD). 3,109,506 Korean adult women who had undergone a medical examination in 2009 (index year) were initially identified for inclusion in this study. We excluded subjects had not experienced menopause naturally, had data missing for at least one variable, and were diagnosed with ESRD within 1 year from the index year. MHT data was obtained from self-reporting questionnaires and the primary outcome was the development of ESRD from the index year until December 31, 2018. A final total of 1,460,311 subjects were included in this study. The participants were divided into four groups according to the duration of MHT; no history of MHT, MHT < 2 years, 2 ≤ MHT < 5 years, MHT ≥ 5 years. During the 9-year study period, a total of 4905 participants developed ESRD. The participants who had a history of MHT use were found to have a 30% reduced risk of developing ESRD. Results from the subgroup analyses were similar to that of the primary study. The findings in this study demonstrate the beneficial effects of MHT on the development of ESRD in postmenopausal women. Based on results, our study may offer suggestions for further studies to investigate the therapeutic options on kidney disease.

Impact of water consumption on renal function in the general population: a cross-sectional analysis of KNHANES data (2008-2017).

BACKGROUND: The renoprotective effect of water intake remains unclear. We aimed to investigate the relationship between water intake and renal impairment in the Korean general population, focusing on individual differences in body fluid distribution and risk of chronic dehydration. METHODS: We conducted a cross-sectional analysis of the 2008-2017 Korea National Health and Nutrition Examination Survey (KNHANES). Adult participants who had body weight and serum creatinine data and had answered 24-h recall nutritional survey were included. Four water intake groups were defined by daily total water intake per body weight: lowest (< 20 mL/kg/day), low-moderate (20-29.9 mL/kg/day), high-moderate (30-49.9 mL/kg/day), and highest (≥ 50 mL/kg/day). We assessed the risk of renal impairment (estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2) according to water intake. RESULTS: In total of 50,113 participants, 3.9% had renal impairment. The risk of renal impairment gradually decreased as water intake increased. After adjustment of sodium intake, the trend of renoprotective effect was remained in low-moderate and high-moderate water intake group compared to low intake group, whereas no significant impact was observed with the highest water intake due to concurrent intake of high sodium. In subgroup analysis, the renoprotective effect of water intake was significant in the participants with elderly, male and daily sodium intake over 2 g/day. CONCLUSIONS: High daily water intake is renoprotective. Our data may provide an important basis for determining the amount of water intake needed to prevent renal impairment, considering variations in body weight, body composition and risk of chronic dehydration.

Associations between Cell-Free Mitochondrial DNA and Inflammation, and Their Clinical Implications for Patients on Hemodialysis: A Prospective Multicenter Cohort Study.

BACKGROUND: Cell-free mitochondrial DNA (cf-mtDNA) has recently been in the spotlight as an endogenously produced danger molecule that can potentially elicit inflammation. However, its clinical and prognostic implications are uncertain in patients undergoing hemodialysis. METHODS: We examined the association of baseline cf-mtDNA categorized as tertiles with health-related quality of life (HRQOL), inflammatory cytokines, and mortality in a multicenter prospective cohort of 334 patients on hemodialysis. To better understand cf-mtDNA-mediated inflammation, we measured cytokine production after in vitro stimulation of bone marrow-derived macrophages (BMDMs) with mtDNA. RESULTS: The higher cf-mtDNA tertile had a longer dialysis vintage, a greater comorbidity burden, and increased levels of inflammatory markers, including high-sensitivity-C-reactive protein, tumor necrosis factor-alpha, CXCL16, and osteoprotegerin. In particular, mtDNA augmented inflammatory cytokine release from BMDMs by lipopolysaccharide, the levels of which are reported to be increased in hemodialysis patients. Although the patients with higher levels of cf-mtDNA generally had lower (poorer) scores for HRQOL, cf-mtDNA was not associated with all-cause mortality in hemodialysis patients. CONCLUSION: cf-mtDNA was correlated with poor clinical status and modestly associated with impaired quality of life in patients on hemodialysis. In proinflammatory milieu in end-stage renal disease, these associations may be attributed to the boosting effects of cf-mtDNA on inflammation.

Long-term Renal Outcome of Biopsy-proven Acute Tubular Necrosis and Acute Interstitial Nephritis.

BACKGROUND: Although emerging evidence suggest acute kidney injury (AKI) progress to chronic kidney disease (CKD), long-term renal outcome of AKI still remains unclear. Acute tubular necrosis (ATN) is the most common cause of AKI due to ischemia, toxin or sepsis. Acute interstitial nephritis (AIN), caused by drugs or autoimmune diseases is also increasingly recognized as an important cause of AKI. Unlike glomerular diseases, AKI is usually diagnosed in the clinical context without kidney biopsies, and lack of histology might contribute to this uncertainty. METHODS: Among 8,769 biopsy series, 253 adults who were histologically diagnosed with ATN and AIN from 1982 to 2018 at five university hospitals were included. Demographic and pathological features that are associated with the development of end stage renal disease (ESRD) were also examined. RESULTS: Rate of non-recovery of renal function at 6 month was significantly higher in the AIN (ATN vs AIN 49.3 vs 69.4%, P = 0.007) with a 2.71-fold higher risk of non- recovery compared to ATN (95% confidence interval [CI], 1.20-6.47). During the mean follow up of 76.5 ± 91.9 months, ESRD developed in 39.4% of patients with AIN, and 21.5% patients of ATN. The risk of ESRD was significantly higher in AIN (23.05; 95% CI, 2.42-219.53) and also in ATN (12.14; 95% CI, 1.19-24.24) compared to control with non-specific pathology. Older age, female gender, renal function at the time of biopsy and at 6 months, proteinuria and pathological features including interstitial inflammation and fibrosis, tubulitis, vascular lesion were significantly associated with progression to ESRD. CONCLUSION: Our study demonstrated that patients with biopsy proven ATN and AIN are at high risk of developing ESRD. AIN showed higher rate of non-renal recovery at 6 month than ATN.

Dipstick proteinuria and cancer incidence: a nationwide population-based study.

BACKGROUND: The association between proteinuria and malignancy has been frequently reported, but the issue is matter of controversy. Thus, in order to shed light on the association, we evaluated proteinuria as a risk factor for malignancy using the dataset from the Korean National Health Insurance System (NHIS). METHODS: The subjects had undergone a medical examination in 2009 (index year) among the entire Korean adult population. From a pool of 10,505,818 participants, we excluded subjects who were younger than 19 years (15,327), had a previous diagnosis of cancer (152,095), had missing data for at least one variable (544,508), and were diagnosed with cancer within 1 year from the index year (79,501). Proteinuria was examined by a single dipstick urinalysis. RESULTS: A total of 9,714,387 subjects were included in this study and tracked until December 31, 2017. The participants were divided into three groups; no (95.2%), trace (2.3%), and overt (2.5%) proteinuria. Over the duration of this study, we observed that overt proteinuria was associated with an increased risk of cancer development (all cancers) (adjusted HR 1.154, 95% CI 1.134-1.173) and the long-term risk of cancer incidence increased proportionally according to the changes in proteinuria over a four-year period. LIMITATIONS: Our study population consisted of Korean adults. Therefore, the results of this study may not be generalized to other ethnicities. CONCLUSIONS: We found a significant relationship between proteinuria and the risk of overall and site-specific cancer development. Further studies are needed to find an explanation of these findings.

Serum Uric Acid is Associated with Renal Prognosis of Lupus Nephritis in Women but not in Men.

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus. Early intervention in lupus nephritis improves prognosis. There is an association between hyperuricemia and lupus nephritis; nevertheless, the sex-specific role of uric acid in lupus nephritis remains unclear. We retrospectively analyzed 578 patients diagnosed with LN by renal biopsy. We determine the relationship of serum uric acid to progression of LN using Kaplan-Meier survival analyses and Cox proportional hazards models. The primary end point was LN progression defined as the initiation of dialysis or kidney transplantation. Men had higher mean serum uric acid levels than did women. Every 1 mg/dL increase in baseline uric acid level increased the risk of LN progression by 15.1%. The serum uric acid level was an independent risk factor for LN progression in women (hazard ratio [HR], 1.158; confidence interval [CI], 1.018-1.317; p = 0.028) but not in men (HR, 1.499; CI, 0.964-2.331; p = 0.072). Sensitivity analysis involving serum uric acid terciles generated consistent and robust results. Serum uric acid level was an independent risk factor for LN progression in women but not in men.

The role of nuclear factor erythroid-2-related factor 2 expression in radiocontrast-induced nephropathy.

Radiocontrast-induced nephropathy (CIN) is the third most common cause of acute renal failure. The pathophysiology of CIN is related to tubular injury caused by oxidative stress, and nuclear factor erythroid-2-related factor 2 (Nrf2) is critical in coordinating intracellular antioxidative processes. We thus investigated the role of Nrf2 in CIN. CIN was established in mice and in NRK-52E cells via iohexol administration according to the protocols of previous studies. To determine the role of Nrf2 in CIN, Nrf2 expression was reduced in vivo using Nrf2 knockout (KO) mice (B6.129 × 1-Nfe2 l2tm1Ywk/J) and in vitro with siRNA treatment targeting Nrf2. Increased Nrf2 expression was observed after iohexol treatment both in vivo and in vitro. Serum creatinine at 24 h after iohexol injection was significantly higher in KO mice than in wild-type (WT) mice. Histologic examination showed that iohexol-induced tubular vacuolization and structural disruption were aggravated in Nrf2 KO mice. Significant increases in apoptosis and F4/80(+) inflammatory cell infiltration were demonstrated in KO mice compared to WT mice. In addition, the increase in reactive oxygen species after iohexol treatment was augmented by Nrf2 inhibition both in vivo and in vitro. Nrf2 may be implicated in the pathogenesis of CIN via the modulation of antioxidant, anti-apoptotic, and anti-inflammatory processes.

Resveratrol Ameliorates Contrast Induced Nephropathy Through the Activation of SIRT1-PGC-1α-Foxo1 Signaling in Mice.

BACKGROUND/AIMS: SIRT1 activation promotes the resistance of renal tubular cells to oxidative stress, and resveratrol is known as a SIRT1 activator. METHODS: Resveratrol was injected intraperitoneally with iohexol for 24 hours. NRK-52E cells were pretreated with resveratrol for 24 hours and then exposed to iohexol for 3 hours. Renal function was measured by serum creatinine and cell survival was assessed by MTT assay. We investigated whether resveratrol attenuates oxidative stress and apoptosis in contrast-induced nephropathy (CIN). RESULTS: Serum creatinine and tubular injury increased significantly after iohexol treatment, and resveratrol co-treatment attenuated the renal injury. Cell survival decreased after iohexol exposure and resveratrol reduced cell death induced by iohexol. Resveratrol was accompanied with the activation of SIRT1 and PGC-1α and dephosphorylation of FoxO1 in mice with CIN. SIRT1 and PGC-1α expression were decreased by iohexol, and increased significantly in resveratrol-pretreated cells. These processes resulted in reduction of oxidative stress and apoptosis both in vivo and in vitro experiments. Resveratrol decreased inflammatory cell infiltration induced by iohexol in mice with CIN. SIRT1 inhibition using siRNA in tubular cells accentuated the decrease of cell viability by iohexol. CONCLUSION: Resveratrol attenuated CIN by modulating renal oxidative stress and apoptosis through activation of SIRT1-PGC-1α-FoxO1 signaling.

Pre-Stage Acute Kidney Injury Can Predict Mortality and Medical Costs in Hospitalized Patients.

The significance of minimal increases in serum creatinine below the levels indicative of the acute kidney injury (AKI) stage is not well established. We aimed to investigate the influence of pre-stage AKI (pre-AKI) on clinical outcomes. We enrolled a total of 21,261 patients who were admitted to the Seoul National University Bundang Hospital from January 1, 2013 to December 31, 2013. Pre-AKI was defined as a 25-50% increase in peak serum creatinine levels from baseline levels during the hospital stay. In total, 5.4% of the patients had pre-AKI during admission. The patients with pre-AKI were predominantly female (55.0%) and had a lower body weight and lower baseline levels of serum creatinine (0.63 ± 0.18 mg/dl) than the patients with AKI and the patients without AKI (P < 0.001). The patients with pre-AKI had a higher prevalence of diabetes mellitus (25.1%) and malignancy (32.6%). The adjusted hazard ratio of in-hospital mortality for pre-AKI was 2.112 [95% confidence interval (CI), 1.143 to 3.903]. In addition, patients with pre-AKI had an increased length of stay (7.7 ± 9.7 days in patients without AKI, 11.4 ± 11.4 days in patients with pre-AKI, P < 0.001) and increased medical costs (4,061 ± 4,318 USD in patients without AKI, 4,966 ± 5,099 USD in patients with pre-AKI, P < 0.001) during admission. The adjusted hazard ratio of all-cause mortality for pre-AKI during the follow-up period of 2.0 ± 0.6 years was 1.473 (95% CI, 1.228 to 1.684). Although the adjusted hazard ratio of pre-AKI for overall mortality was not significant among the patients admitted to the surgery department or who underwent surgery, pre-AKI was significantly associated with mortality among the non-surgical patients (adjusted HR 1.542 [95% CI, 1.330 to 1.787]) and the patients admitted to the medical department (adjusted HR 1.384 [95% CI, 1.153 to 1.662]). Pre-AKI is associated with increased mortality, longer hospital stay, and increased medical costs during admission. More attention should be paid to the clinical significance of pre-AKI.

Frailty as a Predictor of Acute Kidney Injury in Hospitalized Elderly Patients: A Single Center, Retrospective Cohort Study.

BACKGROUND: Elderly patients have an increased risk for acute kidney injury (AKI). However, few studies have reported on predictors for AKI in geriatric patients. Therefore, we aimed at determining the effect of frailty as a predictor of AKI. METHODS: We retrospectively enrolled 533 hospitalized elderly patients (aged ≥ 65 years) who had their creatinine levels measured (≥ 1 measurement) during admission for a period of 1 year (2013) and conducted a comprehensive geriatric assessment (CGA) within 1 year before the index hospitalization. We examined five variables (activity of daily living [ADL] and instrumental ADL dependence, dementia, nutrition, and polypharmacy) from CGA. We categorized the patients into 3 groups according to the tertile of aggregate frailty scores: Group 1, score 1-2; Group 2, score 3-4; Group 3, score 5-8). RESULTS: Fifty-four patients (10.1%) developed AKI (median duration, 4 days). The frailest group (Group 3) showed an increased risk of AKI as compared to Group 1, (hazard ratio [HR] = 3.536, P = 0.002). We found that discriminatory accuracy for AKI improved with the addition of the tertile of aggregate frailty score to covariates (area under the receiver operator characteristics curves [AUROC] 0.641, AUROC 0.739, P = 0.004). Forty-six patients (8.6%) were transferred to nursing facilities and 477 patients (89.5%) were discharged home. The overall 90-day and 1-year mortality for elderly inpatients were 7.9% and 26.3%. The frailest group also demonstrated an increased risk of discharge to nursing facilities, and 90-day and 1-year mortality as compared to Group 1, independent of AKI severity (nursing facilities: odd ratio = 4.843, P = 0.002; 90-day mortality: HR = 6.555, P = 0.002; 1-year mortality: HR = 3.249, P = 0.001). CONCLUSIONS: We found that frailty may independently predict the development of AKI and adverse outcomes in geriatric inpatients.

Glomerular Immune Deposits Are Predictive of Poor Long-Term Outcome in Patients with Adult Biopsy-Proven Minimal Change Disease: A Cohort Study in Korea.

BACKGROUND AND OBJECTIVES: There has been little published information on risk factors for poor long-term outcome in adult biopsy-proven minimal change disease (MCD). METHODS: Data from sixty-three adult, biopsy-proven primary MCD patients treated at a tertiary university hospital between 2003 and 2013 were analyzed. Baseline clinical and pathologic factors were assessed for the associations with composite outcome of creatinine doubling, end stage renal disease, or all-cause mortality. RESULTS: During a median (interquartile) 5.0 (2.8-5.0) years, the composite outcome occurred in 11.1% (7/63) of patients. The rate of glomerular immune deposits was 23.8% (15/63). Patients with glomerular immune deposits showed a significantly lower urine protein creatinine ratio than those without deposits (P = 0.033). The rate of non-responders was significantly higher in patients with glomerular immune deposits than in those without deposits (P = 0.033). In patients with deposits, 26.7% (4/15) developed the composite outcome, while only 6.3% (3/48) developed the composite outcome among those without deposits (P = 0.049). In multivariate Cox proportional hazards regression analysis, the presence of glomerular immune deposits was the only factor associated with development of the composite outcome (hazard ratio: 2.310, 95% confidence interval: 1.031-98.579, P = 0.047). CONCLUSION: Glomerular immune deposits were associated with increased risk of a composite outcome in adult MCD patients. The higher rate of non-responders in patients with deposits might be related to the poor outcome. Future study is needed.

Glomerular Hypertrophy Is a Risk Factor for Relapse in Minimal Change Disease Patients.

BACKGROUND/AIMS: Patients with minimal change disease (MCD) have a high relapse rate, which results in many complications. Identifying the risk factors for relapse is crucial, but little is known about these factors. Therefore, we performed the current study to determine the factors related to relapse in this patient population. METHODS: We retrospectively analyzed 51 adult patients with biopsy-proven primary MCD treated between 2003 and 2013. The demographic, physiologic, laboratory and therapeutic data were gathered from the electronic medical records database. Lesions of the glomerulus, tubulointerstitium and vasculature were analyzed for associations with relapse. RESULTS: During a median 50.9 months, 96.1% (49 of 51) of patients had achieved complete remission, and the rest ultimately achieved at least partial remission. A total of 56.9% (29 of 51) patients experienced at least 1 episode of relapse after the first remission. Patients with relapse had a higher rate of glomerular hypertrophy (GH; 34.5%) than those without relapse (9.1%; p < 0.05). After adjusting for confounders, GH was associated with increased odds of relapse (OR 15.992; 95% CI 1.537-166.362; p = 0.02). In a subgroup analysis according to median age, sex and tubulointerstitial (TI) lesions, the association between GH and relapse was evident only in men and in the group with TI lesions. CONCLUSION: GH is associated with relapse in adult patients with MCD, particularly in men and in those with TI lesions. Frequent monitoring and early intervention are needed in these groups. Future large prospective cohort studies are needed to confirm the study results.

Effects of acute kidney injury and chronic kidney disease on long-term mortality after coronary artery bypass grafting.

BACKGROUND: Both acute kidney injury (AKI) and chronic kidney disease (CKD) are important issues in patients undergoing coronary artery bypass grafting (CABG), particularly with regard to mortality. However, their synergistic or discrete effects on long-term mortality remain unresolved. METHODS: A total of 1,899 patients undergoing CABG were retrospectively analyzed. The adjusted hazard ratios for all-cause mortality were calculated after stratifying the timeframes. To evaluate the synergistic effects between AKI and CKD, the relative excess risk due to interaction was applied. RESULTS: The presence of AKI, CKD, or both increased the hazard ratios for mortality, compared with the absence of both: AKI alone, 1.84 (1.464-2.319); CKD alone, 2.46 (1.735-3.478); and AKI and CKD together, 3.21 (2.301-4.488). However, the relationships with mortality were different between AKI and CKD, according to the timeframes: AKI primarily affected early mortality, particularly within 3 years, whereas CKD had a relatively constant effect on both the early and late periods. When the parameters from the relative excess risk due to interaction were obtained, there was a synergistic additive effect on early mortality between AKI and CKD. CONCLUSIONS: The relationships with mortality after CABG were different between AKI and CKD. However, their effects were not exclusive but synergistic.

Bilirubin activates transcription of HIF-1α in human proximal tubular cells cultured in the physiologic oxygen content.

The expression of hypoxia-inducible factor (HIF) is influenced by reactive oxygen species (ROS). Effect of bilirubin on HIF-1 expression in proximal tubular cells was investigated under physiological oxygen concentration, which is relative hypoxic condition mimicking oxygen content in the medulla of renal tissue. The human kidney (HK2) cells were cultured in 5% oxygen with or without bilirubin. HIF-1α protein expression was increased by bilirubin treatment at 0.01-0.2 mg/dL concentration. The messenger RNA expression of HIF-1α was increased by 1.69±0.05 folds in the cells cultured with 0.1 mg/dL bilirubin, compared to the control cells. The inhibitors of PI3K/mTOR, PI3K/AKT, and ERK 1/2 pathways did not attenuate increased HIF-1α expression by bilirubin. HIF-1α expression decreased by 10 µM exogenous hydrogen peroxide (H2O2); scavenger of ROS with or without bilirubin in the HK2 cells increased HIF-1α concentration more than that in the cells without bilirubin. Exogenous H2O2 decreased the phosphorylation of P70S6 kinase, which was completely reversed by bilirubin treatment. Knockdown of NOX4 gene by small interfering RNA (siRNA) increased HIF-1α mRNA expression. In coonclusion, bilirubin enhances HIF-1α transcription as well as the up-regulation of HIF-1α protein translation through the attenuation of ROS and subunits of NADPH oxidase.

Effect of bilirubin on triglyceride synthesis in streptozotocin-induced diabetic nephropathy.

We aimed to elucidate the effect of bilirubin on dyslipidemia and nephropathy in a diabetes mellitus (DM) type I animal model. Sprague-Dawley rats were separated into control, DM, and bilirubin-treated DM (Bil) groups. The Bil group was injected intraperitoneally with 60 mg/kg bilirubin 3 times per week and hepatoma cells were cultured with bilirubin at a concentration of 0.3 mg/dL. The Bil group showed lower serum creatinine levels 5 weeks after diabetes onset. Bilirubin treatment also decreased the amount of mesangial matrix, lowered the expression of renal collagen IV and transforming growth factor (TGF)-ß1, and reduced the level of apoptosis in the kidney, compared to the DM group. These changes were accompanied by decreased tissue levels of hydrogen superoxide and NADPH oxidase subunit proteins. Bilirubin decreased serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), free fatty acids, and triglycerides (TGs), as well as the TG content in the liver tissues. Bilirubin suppressed protein expression of LXRα, SREBP-1, SCD-1, and FAS, factors involved in TG synthesis that were elevated in the livers of DM rats and hepatoma cells under high-glucose conditions. In conclusion, bilirubin attenuates renal dysfunction and dyslipidemia in diabetes by suppressing LXRα and SREBP-1 expression and oxidative stress.

Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney.

BACKGROUND: The inhibition of dipeptidyl peptidase (DPP) IV shows protective effects on tissue injury of the heart, lung, and kidney. Forkhead box O (FoxO) transcriptional factors regulate cellular differentiation, growth, survival, the cell cycle, metabolism, and oxidative stress. The aims of this study were to investigate whether the DPP IV inhibitor sitagliptin could attenuate kidney injury and to evaluate the status of FoxO3a signaling in the rat remnant kidney model. METHODS: Rats were received two-step surgery of 5/6 renal mass reduction and fed on an oral dose of 200 mg/kg/day sitagliptin for 8 weeks. Before and after the administration of sitagliptin, physiologic parameters were measured. After 8 weeks of treatment, the kidneys were harvested. RESULTS: The sitagliptin treatment attenuated renal dysfunction. A histological evaluation revealed that glomerulosclerosis and tubulointerstitial injury were significantly decreased by sitagliptin. Sitagliptin decreased DPP IV activity and increased the renal expression of glucagon-like peptide-1 receptor (GLP-1R). The subtotal nephrectomy led to the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and FoxO3a phosphorylation, whereas sitagliptin treatment reversed these changes, resulting in PI3K-Akt pathway inactivation and FoxO3a dephosphorylation. The renal expression of catalase was increased and the phosphorylation of c-Jun N-terminal kinase (JNK) was decreased by sitagliptin. Sitagliptin treatment reduced apoptosis by decreasing cleaved caspase-3 and -9 and Bax levels and decreased macrophage infiltration. CONCLUSIONS: In rat remnant kidneys, DPP IV inhibitor attenuated renal dysfunction and structural damage. A reduction of apoptosis, inflammation and an increase of antioxidant could be suggested as a renoprotective mechanism together with the activation of FoxO3a signaling. Therefore, DPP IV inhibitors might provide a promising approach for treating CKD, but their application in clinical practice remains to be investigated.