Higher sclerostin is associated with pulmonary hypertension in pre-dialysis end-stage kidney disease patients: a cross-sectional prospective observational cohort study.

BACKGROUND: Pulmonary hypertension (PH) is a complication of chronic kidney disease (CKD) that contributes to mortality. Sclerostin, a SOST gene product that reduces osteoblastic bone formation by inhibiting Wnt/ß-catenin signaling, is involved in arterial stiffness and CKD-bone mineral disease, but scanty evidence to PH. This study explored the relationship between sclerostin and PH in CKD 5, pre-dialysis end-stage kidney disease (ESKD) patients. METHODS: This cross-sectional prospective observational cohort study included 44 pre-dialysis ESKD patients between May 2011 and May 2015. Circulating sclerostin levels were measured using an enzyme-linked immunosorbent assay. PH was defined as an estimated pulmonary artery systolic pressure > 35 mmHg on echocardiography. RESULTS: Patients with higher sclerostin levels ≥ 218.18pmol/L had echocardiographic structural cardiac abnormalities, especially PH (P < 0.01). On multivariate logistic analysis, sclerostin over 218.19pmol/L was significantly associated with PH (odds ratio [OR], 41.14; 95% confidence interval [CI], 4.53-373.89, P < 0.01), but multivariate Cox regression analysis showed the systemic vascular calcification score over 1 point (Hazard ratio [HR] 11.49 95% CI 2.48-53.14, P = 0.002) and PH ([HR] 5.47, 95% CI 1.30-23.06, P = 0.02) were risk factors for all-cause mortality in pre-dialysis ESKD patients. CONCLUSIONS: Serum sclerostin and PH have a positive correlation in predialysis ESKD patients. The higher systemic vascular calcification score and PH have an association to increase all-cause mortality in pre-dialysis ESKD patients.

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.

Altered gut microbiome plays an important role in AKI to CKD transition in aged mice.

Introduction: This study investigated the role of renal-intestinal crosstalk in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) in elderly individuals. Methods: Using young and aged mice, we induced bilateral ischemia-reperfusion injury (IRI) and compared intestinal and kidney inflammation over 28 days. To determine the role of the microbiome in gut-kidney crosstalk, we analyzed the microbiome of fecal samples of the young vs. aged mice and examined the effects of probiotic supplementation. Results: In the post-IRI recovery phase, prolonged intestinal and renal inflammation along with dysbiosis were evident in aged vs. younger mice that was associated with severe renal dysfunction and fibrosis progression in aged mice. Probiotic supplementation with Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI alleviated intestinal inflammation but not intestinal leakage, characterized by decreased inflammatory cytokine levels and decreased infiltration of macrophages, neutrophils, and Th17 cells. This was associated with improved M1-dominant renal inflammation and ultimately improved renal function and fibrosis, suggesting that renal-intestinal crosstalk in aged mice contributes to the transition from AKI to CKD. Discussion: Our study findings suggest that exacerbation of chronic inflammation through the gut-kidney axis might be an important mechanism in the transition from AKI to CKD in the elderly.

Smoking amplifies the risk of albuminuria in individuals with high sodium intake: the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2011 and 2014-2018.

Background: Smoking and sodium intake (SI) have been evaluated as risk factors for kidney disease; however, the data are inconsistent. We assessed the association between SI and cotinine-verified smoking status and the risk of albuminuria. Methods: An observational study using the Korea National Health and Nutrition Examination Survey (2008-2011 and 2014-2018) was performed. We included 37,410 adults with an estimated glomerular filtration rate of ≥60 mL/min/1.73 m2 . The smoking status was assumed based on the urine cotinine/creatinine ratio (Ucot/Ucrea). SI was estimated from spot urine sodium using the Kawasaki formula. Results: Ucot/Ucrea levels were significantly higher in current smokers (920.22 ± 9.00 ng/mg) than in ex-smokers and nonsmokers (48.31 ± 2.47 and 23.84 ± 1.30 ng/mg) (p < 0.001). Ucot/Ucrea levels were significantly higher in second-hand smokers than in participants without a history of smoking (p < 0.001). Ucot/ Ucrea levels were positively associated with SI (p for trend < 0.001). Smoking status was not associated with albuminuria. SI had a linear relationship with albuminuria (p < 0.001). In groups with the highest Ucot/Ucrea levels, the highest SI quartile indicated a significantly higher risk of albuminuria than that in the lowest quartile (risk ratio, 2.22; 95% confidence interval, 1.26-3.92; p = 0.006). The risk of albuminuria was not significant in groups with the lowest and middle tertile adjusted for multiple risk factors. Conclusion: Smokers consume higher dietary sodium and dietary SI was positively related to the risk of albuminuria. Smoking is not associated with albuminuria as a single factor. The risk of albuminuria is the higher in participants with smoking and high SI.

Mechanisms of Piperacillin/Tazobactam Nephrotoxicity: Piperacillin/Tazobactam-Induced Direct Tubular Damage in Mice.

Piperacillin/tazobactam (PT) is one of the most commonly prescribed antibiotics for critically ill patients in intensive care. PT has been reported to cause direct nephrotoxicity; however, the underlying mechanisms remain unknown. We investigated the mechanisms underlying PT nephrotoxicity using a mouse model. The kidneys and sera were collected 24 h after PT injection. Serum blood urea nitrogen (BUN), creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and renal pathologies, including inflammation, oxidative stress, mitochondrial damage, and apoptosis, were examined. Serum BUN, creatinine, and NGAL levels significantly increased in PT-treated mice. We observed increased IGFBP7, KIM-1, and NGAL expression in kidney tubules. Markers of oxidative stress, including 8-OHdG and superoxide dismutase, also showed a significant increase, accompanied by mitochondrial damage and apoptosis. The decrease in the acyl-coA oxidase 2 and Bcl2/Bax ratio also supports that PT induces mitochondrial injury. An in vitro study using HK-2 cells also demonstrated mitochondrial membrane potential loss, indicating that PT induces mitochondrial damage. PT appears to exert direct nephrotoxicity, which is associated with oxidative stress and mitochondrial damage in the kidney tubular cells. Given that PT alone or in combination with vancomycin is the most commonly prescribed antibiotic in patients at high risk of acute kidney injury, caution should be exercised.

Role of the Circadian Clock and Effect of Time-Restricted Feeding in Adenine-Induced Chronic Kidney Disease.

Most physiological functions exhibit circadian rhythmicity that is partly regulated by the molecular circadian clock. Herein, we investigated the relationship between the circadian clock and chronic kidney disease (CKD). The role of the clock gene in adenine-induced CKD and the mechanisms of interaction were investigated in mice in which Bmal1, the master regulator of the clock gene, was knocked out, and Bmal1 knockout (KO) tubule cells. We also determined whether the renoprotective effect of time-restricted feeding (TRF), a dietary strategy to enhance circadian rhythm, is clock gene-dependent. The mice with CKD showed altered expression of the core clock genes with a loss of diurnal variations in renal functions and key tubular transporter gene expression. Bmal1 KO mice developed more severe fibrosis, and transcriptome profiling followed by gene ontology analysis suggested that genes associated with the cell cycle, inflammation, and fatty acid oxidation pathways were significantly affected in the mutant mice. Tubule-specific deletion of BMAL1 in HK-2 cells by CRISPR/Cas9 led to upregulation of p21 and tumor necrosis α and exacerbated epithelial-mesenchymal transition-related gene expression upon transforming growth factor ß stimulation. Finally, TRF in the mice with CKD partially restored the disrupted oscillation of the kidney clock genes, accompanied by improved cell cycle arrest and inflammation, leading to decreased fibrosis. However, the renoprotective effect of TRF was abolished in Bmal1 KO mice, suggesting that TRF is partially dependent on the clock gene. Our data demonstrate that the molecular clock system plays an important role in CKD via cell cycle regulation and inflammation. Understanding the role of the circadian clock in kidney diseases can be a new research field for developing novel therapeutic targets.

A Case Report of Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination and Heparin Use During Hemodialysis.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but life-threatening complication. VITT strongly mimics heparin-induced thrombocytopenia (HIT) and shares clinical features. Heparin is commonly used to prevent coagulation during hemodialysis. Therefore, nephrologists might encounter patients needing dialysis with a history of heparin exposure who developed thrombotic thrombocytopenia after vaccination. A 70-year-old male presented with acute kidney injury and altered mental status due to lithium intoxication. He needed consecutive hemodialysis using heparin. Deep vein thrombosis of left lower extremity and accompanying severe thrombocytopenia of 15,000/µL on 24 days after vaccination and at the same time, nine days after heparin use. Anti-platelet factor 4 antibody test was positive. Anticoagulation with apixaban and intravenous immunoglobulin (IVIG) infusion resolved swelling of his left calf and thrombocytopenia. There were no definitive diagnostic tools capable of differentiating between VITT and HIT in this patient. Although VITT and HIT share treatment with IVIG and non-heparin anticoagulation, distinguishing between VITT and HIT will make it possible to establish a follow-up vaccination plan in a person who has had a thrombocytopenic thrombotic event. Further research is needed to develop the tools to make a clear distinction between the clinical syndromes.

The effect of periodontitis on recipient outcomes after kidney transplantation.

BACKGROUND: Recent several reports have demonstrated that periodontitis is prevalent and adversely affects the survival in patients with chronic kidney disease (CKD) or end-stage kidney disease. However, its impact on transplant outcomes remains uncertain. METHODS: This retrospective cohort study included 136 and 167 patients, respectively, who underwent living donor kidney transplantation (KT) at Seoul National University Hospital from July 2012 to August 2016 and Korea University Hospital from April 2008 to October 2018. We divided patients into three groups according to stages of periodontitis based on a new classification system. RESULTS: Patients with severe periodontitis were older, had a higher prevalence of diabetes, a higher body mass index and C-reactive protein level, a lower cardiac output, and were more likely to be smokers, indicating its association with chronic systemic inflammation. After KT, stage IV periodontitis was independently associated with a lower incidence of acute T cell-mediated rejection, suggesting the possible effect of periodontitis on immune function. However, 1-year and 3-year estimated glomerular filtration rates were not different. Among the KT recipients followed up more than 3 years, new-onset cardiovascular disease occurred in nine patients, and coronary artery disease occurred more frequently in patients with stage IV periodontitis. However, diabetes was the independent predictor of new-onset coronary artery disease in multivariate logistic regression analysis. CONCLUSION: Our findings showed that periodontitis might be an important player in determining posttransplant outcomes in recipients. Further interventional trials to test whether treating periodontitis could modify transplant outcome are needed.

The effect of probiotic supplementation on systemic inflammation in dialysis patients.

BACKGROUND: Emerging evidence suggests that intestinal dysbiosis contributes to systemic inflammation and cardiovascular diseases in dialysis patients. The purpose of this study was to evaluate the effects of probiotic supplementation on various inflammatory parameters in hemodialysis (HD) patients. METHODS: Twenty-two patients with maintenance HD were enrolled. These patients were treated twice a day with 2.0 ×1010 colony forming units of a combination of Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI for 3 months. The microbiome and fecal short-chain fatty acids (SCFAs) were analyzed. The percentages of CD14+ CD16+ proinflammatory monocytes and CD4+ CD25+ regulatory T-cells (Tregs) before and after probiotic supplementation were determined by flow cytometry. Serum levels of calprotectin and cytokine responses upon lipopolysaccharide (LPS) challenge were compared before and after probiotic supplementation. RESULTS: Fecal SCFAs increased significantly after probiotic supplementation. Serum levels of calprotectin and interleukin 6 upon LPS stimulation significantly decreased. The anti-inflammatory effects of probiotics were associated with a significant increase in the percentage of CD4+ CD25+ Tregs (3.5% vs. 8.6%, p < 0.05) and also with a decrease of CD14+ CD16+ proinflammatory monocytes (310/ mm2 vs. 194/mm2 , p < 0.05). CONCLUSION: Probiotic supplementation reduced systemic inflammatory responses in HD patients and this effect was associated with an increase in Tregs and a decrease in proinflammatory monocytes. Hence, targeting intestinal dysbiosis might be a novel strategy for decreasing inflammation and cardiovascular risks in HD patients.

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.

Probiotics partially attenuate the severity of acute kidney injury through an immunomodulatory effect.

BACKGROUND: A healthy microbiome helps maintain the gut barrier and mucosal immune tolerance. Previously, we demonstrated that acute kidney injury (AKI) provoked dysbiosis, gut inflammation, and increased permeability. Here, we investigated the renoprotective effects of the probiotic Bifidobacterium bifidum BGN4 and the underlying mechanisms thereof. METHODS: C57BL/6 mice were subjected to bilateral renal ischemia-reperfusion injury (IRI) or sham operation. In the probiotic-treated group, BGN4 was administered by gavage once daily, starting 2 weeks before injury. RESULTS: Administration of BGN4 significantly increased gut microbiome diversity and prevented expansion of the Enterobacteriaceae and Bacteroidetes that were the hallmarks of AKI-induced dysbiosis. Further, BGN4 administration also significantly reduced other IRI-induced changes in the colon microenvironment, including effects on permeability, apoptosis of colon epithelial cells, and neutrophil and proinflammatory macrophage infiltration. Mononuclear cells co-cultured with BGN4 expressed significantly increased proportions of CD103+/CD11c+ and CD4+ CD25+ Treg cells, suggesting a direct immunomodulatory effect. BGN4 induced Treg expansion in colon, mesenteric lymph nodes (MNL), and kidney. BGN4 also reduced CX3CR1intermediateLy6Chigh monocyte infiltration and interleukin (IL)-17A suppression in the small intestine, which may have attenuated AKI severity, kidney IL-6 messenger RNA expression, and AKI-induced liver injury. CONCLUSION: Prior supplementation with BGN4 significantly attenuated the severity of IRI and secondary liver injury. This renoprotective effect was associated with increased Foxp3 and reduced IL-17A expression in the colon, MNL, and kidney, suggesting that BGN4-induced immunomodulation might contribute to its renoprotective effects. Probiotics may therefore be a promising strategy to reduce AKI severity and/or remote organ injury.

Impact of changes in waist-to-hip ratio after kidney transplantation on cardiovascular outcomes.

Recently, waist to hip ratio (WHR) has been reported to be a better indicator of predicting cardiovascular outcomes than body mass index (BMI). We evaluated the effects of pre or post-transplant changes of WHR or BMI on the new onset cardiovascular diseases (CVD) in recipients of kidney transplantation (KT). A total of 572 patients were enrolled from a multicenter observational cohort (KNOW-KT). Measurement of WHR and BMI was done at pre-KT, first and last visit year after KT, and the changes of these parameters and their effect on the incident CVD were analyzed. During the median follow up period of 32.73 ± 15.26 months, the new onset CVD developed in 31 out of 572 patients. The older age, diabetes mellitus and increase of WHR from pre KT or previous follow up year were found to be independent factors predicting the new onset CVD in these patients. However, baseline BMI, WHR prior to KT did not predict the incident CVD. The new metabolic burden, presented as increase of WHR in KT patients has a critical impact on the development of new onset CVD. Strategies to prevent the metabolic burden after KT might improve cardiovascular outcomes and patient's survival.

The effect of baseline serum uric acid on chronic kidney disease in normotensive, normoglycemic, and non-obese individuals: A health checkup cohort study.

INTRODUCTION: The independent role of serum uric acid (SUA) on kidney disease is controversial due to its association with metabolic syndrome. The objective of this study was to investigate the association of baseline SUA with development of chronic kidney disease and eGFR decline in normotensive, normoglycemic and non-obese individuals during follow up period. MATERIALS AND METHODS: We included non-hypertensitive, non-diabetic, and non-obese 13,133 adults with estimated glomerular filtration rate (eGFR) ≥ 60ml/min/1.73m2 who had a voluntary health check-up during 2004-2017. RESULTS: SUA was positively related to adjusted means of systolic blood pressure (SBP), triglyceride, body mass index, and body fat percent. SUA was inversely associated with high density lipoprotein HDL (P for trend ≤0.001). SUA was an independent risk factor for the development of diabetes, hypertension, and obesity. During 45.0 [24.0-76.0] months of median follow up, the highest quartiles of SUA showed significant risks of 30% eGFR decline compared than the lowest quartile (RR:3.701; 95% CI: 1.504-9.108). The highest quartile had a 2.2 fold (95% CI: 1.182-4.177) increase in risk for incident chronic kidney disease (CKD). CONCLUSIONS: SUA is an independent risk factor for the development of diabetes, hypertension, and obesity in the healthy population. High SUA is associated with increased risk of CKD development and eGFR decline in participants with intact renal function.

The Effect of Statins on Mortality of Patients With Chronic Kidney Disease Based on Data of the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) and Korea National Health Insurance Claims Database.

The role of statins in chronic kidney disease (CKD) has been extensively evaluated, but it remains controversial in specific population such as dialysis-dependent CKD. This study examined the effect of statins on mortality in CKD patients using two large databases. In data from the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) from two hospitals, CKD was defined as an estimated glomerular filtration rate < 60 mL/min/m2; we compared survival between patients with or without statin treatment. As a sensitivity analysis, the results were validated with the Korea National Health Insurance (KNHI) claims database. In the analysis of CDM datasets, statin users showed significantly lower risks of all-cause and cardiovascular mortality in both hospitals, compared to non-users. Similar results were observed in CKD patients from the KNHI claims database. Lower mortality in the statin group was consistently evident in all subgroup analyses, including patients on dialysis and low-risk young patients. In conclusion, we found that statins were associated with lower mortality in CKD patients, regardless of dialysis status or other risk factors.

Renal hyperfiltration as a risk factor for chronic kidney disease: A health checkup cohort study.

INTRODUCTION: Renal hyperfiltration (RHF) has been found to be an independent predictor of adverse cardiovascular outcome. However, it remains uncertain whether it is precursor of chronic kidney disease (CKD) in a healthy population. MATERIALS AND METHODS: To determine relative risks and identify the predictor of incident proteinuria and decline of estimated glomerular filtration rate (eGFR) in subjects with RHF. A total of 55,992 subjects aged ≥20 years who underwent health check-up during 2004-2017 were included. Among them, 16,946 subjects who completed at least two health checkups were analyzed. RESULTS: A total of 949 (5.6%) subjects developed proteinuria and 98 (0.6%) subjects showed ≥ 30% of eGFR decline. The risk of incident proteinuria was significantly higher in those with RHF (RR: 1.644; 95% CI: 1.064-2.541). Those with RHF showed 8.720 fold (95% CI: 4.205-18.081) increased risk for ≥30% decline. ESR, CRP, and monocyte count showed reversed J shaped curve according to the increase of eGFR. The adjusted mean of monocyte count was significantly higher in participants with eGFR ≥90ml/min/1.73m2 or < 60ml/min/1.73m2 compared to that in patients with eGFR 75-89ml/min/1.73m2. Compared to subjects with the lowest tertile of monocyte and no RHF, those with the highest tertile of monocyte count in the RHF group had 3.314-fold (95% CI: 1.893-5.802) higher risk of incident proteinuria and 3.822-fold (95% CI, 1.327-11.006) risk of 30% eGFR decline. CONCLUSIONS: RHF had significantly increased risk of developing proteinuria and CKD in healthy subjects. Higher monocyte count might be used as a predictor of CKD in subjects with RHF.

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.

Intestinal microbiota control acute kidney injury severity by immune modulation.

Intestinal microbiota impacts the host immune system and influences the outcomes of chronic diseases. However, it remains uncertain whether acute kidney injury (AKI) impacts intestinal microbiota or vice versa. To determine this, we investigated the mechanistic link between AKI, microbiota, and immune response in ischemia/reperfusion injury. Microbiota alteration and its biological consequences after ischemia/reperfusion injury were examined and the effect of dysbiotic microbiota on the outcome of AKI was also assessed by colonizing germ-free mice with post-AKI microbiota. The role of Th17, Th1, Tregs cells and macrophage polarization in mediating the renoprotective effect of antibiotic induced microbiota depletion in ischemia/reperfusion injury was also determined. Increase of Enterobacteriacea, decrease of Lactobacilli, and Ruminococacceae were found to be the hallmarks of ischemia/reperfusion injury induced dysbiosis and were associated with a decreased levels of short-chain fatty acids, intestinal inflammation and leaky gut. Colonizing germ-free mice with post-AKI microbiota worsened ischemia/reperfusion injury severity with exaggerated inflammation in recipient mice compared to colonizing with microbiota from sham operated mice. Microbiota depletion by oral antibiotics protected against ischemia/reperfusion injury. This renoprotective effect was associated with reduced Th 17, Th 1 response along with expansion of regulatory T cells, and M2 macrophages. Our study demonstrated a unique bidirectional relationship between the kidney and the intestine during AKI. Intestinal dysbiosis, inflammation and leaky gut are consequences of AKI but they also represent an important modifier determining post-AKI severity. Thus, targeting the intestinal microbiota might provide a novel therapeutic strategy in AKI.

Pathogens of peritoneal dialysis peritonitis: Trends from a single-center experience over 15 years.

BACKGROUND: Concerns are increasing about the emergence of pathogens with antibiotic resistance in peritoneal dialysis (PD) peritonitis. We investigated the current pathogen trends and risk factors in PD peritonitis. METHODS: We conducted a retrospective study analyzing data from 643 patients who maintained PD over 3 months between January 2001 and December 2015. The isolated pathogens from PD peritonitis were compared between period A (2001-2008) and period B (2009-2015). RESULTS: Among 643 PD patients, 252 patients experienced one or more episodes of PD peritonitis (total 308 episodes) during the median follow-up of 66 months. In both periods, gram-positive bacteria were the dominant pathogens (22.2% vs. 53.8%, P < 0.01). Gram-negative bacteria showed an increasing tendency in period B, but without statistical significance (17.0% vs. 23.7%, P = 0.15). The culture-negative rate was improved from 57% in period A to 18% in period B (P < 0.01). There was no increase in the prevalence of resistant pathogens such as methicillin-resistant Staphylococcus epidermidis (MRSE), Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli between periods A and B. Preserved residual renal function was associated with a lower risk of PD peritonitis (odds ratio, 0.53; 95% confidence interval, 0.31-0.88; P = 0.01). CONCLUSION: Over the past two decades, the pathogens of PD peritonitis have not significantly changed in Korea. Gram-positive organisms remained dominant, with S. epidermidis being the most common pathogen. Resistant bacteria such as MRSE, MRSA, ESBL-producing Gram-negative bacilli did not increase, but should be monitored.

M2 macrophages predict worse long-term outcomes in human acute tubular necrosis.

Although macrophages are important players in the injury/repair processes in animal models of acute kidney injury (AKI), their roles in human AKI remains uncertain owing to a paucity of human biopsy studies. We investigated the role of macrophages in 72 cases of biopsy-proven acute tubular necrosis (ATN) and six cases of healthy kidney. Macrophages were identified by CD68 and CD163 immunohistochemistry and analyzed for their effect on renal outcomes. CD163+ M2 macrophages outnumbered CD68+ cells in the healthy kidneys, suggesting that CD163+ macrophages are resident macrophages. The infiltration of both subtypes of macrophages increased significantly in ATN. The density of the CD68+ macrophages was significantly higher in advanced-stage AKI, whereas CD163+ M2 macrophages was not. Eighty percent of patients exhibited renal functional recovery during follow-up. Older age and a higher density of CD163+ macrophages predicted non-recovery, whereas the AKI stage, tubular injury score, and density of CD68+ cells did not. The density of CD163+ M2 macrophages was an independent predictor of low eGFR at 3 months in advanced-stage AKI. This is the first human study demonstrating the possible role of macrophages in the injury and repair phases of AKI.

Efficacy and Safety of CKD-11101 (Proposed Biosimilar of Darbepoetin-Alfa) Compared with Darbepoetin-Alfa in Patients on Hemodialysis: A Randomized, Double-Blinded, Parallel-Group Phase III Study.

BACKGROUND: Darbepoetin-alfa is an erythropoiesis-stimulating agent (ESA) with a long elimination half-life that achieves better hemoglobin (Hb) stability than short-acting ESAs. OBJECTIVE: We aimed to evaluate the efficacy and safety of intravenous CKD-11101 (a biosimilar of darbepoetin-alfa) compared with those of darbepoetin-alfa in hemodialysis patients. METHODS: The study was performed in 24 centers in Korea between June 2015 and June 2017. The study subjects were randomized in a double-blind manner. The follow-up duration was 24 weeks, which consisted of 20 weeks of maintenance and 4 weeks of evaluation period. All patients underwent a stabilization period to achieve a target baseline Hb of 10-12 g/dL before randomization. Following randomization, patients received darbepoetin-alfa or CKD-11101 weekly or biweekly. RESULTS: A total of 403 patients were randomized into two groups, and a total of 325 patients (80.6%) completed the investigation. The differences between the two groups in terms of change in the average Hb level from baseline to evaluation were not significant. The average administered dose of ESA was similar between the groups. There was no difference in the proportion of patients who maintained the target Hb during the evaluation period [60.4% vs. 66.2% in the CKD-11101 and darbepoetin-alfa groups, respectively (p = 0.3038)]. In addition, the safety analysis, consisting of adverse events and adverse drug reactions, showed comparable results between the two groups. CONCLUSION: The changes in the level of Hb, dose of erythropoietin, and achievement rate of the target Hb during the study period were comparable between the groups. CKD-11101 has an equivalent efficacy and safety compared with darbepoetin-alfa in patients undergoing hemodialysis.