PGC-1α inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis

Background: NOD-like receptor, pyrin domain containing protein 3 (NLRP3) contributes to inflammation, cell death, and fibrosis in kidney disease. The NLRP3 inflammasome is activated by mitochondrial damage. However, it is unknown whether peroxisomal proliferator-γ coactivator-1α (PGC-1α), a key mitochondrial biogenesis regulator, can modulate NLRP3 inflammasome pathway. Here, I demonstrated that PGC-1α inhibits activation of NLRP3 inflammasome via preserving mitochondrial viability during kidney injury. Methods: Primary renal tubular epithelial cells (RTECs) were isolated from C57BL/6 mice. The NLRP3 inflammasome pathway, mitochondrial dynamics and morphology, oxidative stress levels, and cell injury markers were examined in RTECs treated with TGF-β1 alone, TGF-β1+PGC-1α activators (metformin and 5-aminoimidazole-4-carboxamide ribonucleotide [AICAR]) or PGC-1α plasmid, and TGF-β1+small interfering-PGC-1α. For animal study, adenine-fed mice and unilateral ureteral obstruction (UUO) mice were treated with PGC-1α activator. Results: In vitro, TGF-β1 treatment to RTECs suppressed the expression levels of PGC-1α and mitochondrial dynamic-related genes. In addition, the NLRP3 inflammasome pathway was activated and the expression levels of fibrotic and apoptotic cell death markers were increased. The indirect and direct expression of PGC-1α with the activators and the plasmid improved mitochondrial dynamics and morphology and attenuated the NLRP3 inflammasome pathway and cell injury. In contrast, these changes were accentuated by PGC-1α knock-down. The oxidative stress levels, which are inducers of the NLRP3 inflammasome after mitochondrial damage, were increased and the expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), which is regulated by PGC-1α and also known as a negative regulator of NLRP3 inflammasome, was decreased by TGF-β1 and PGC-1α knock-down. However, restoration of PGC-1α significantly reversed these alterations. In vivo, adenine- and UUO-induced kidney injury models resulted in decreased expression levels of PGC-1α, TNFAIP3, and mitochondrial dynamics. In addition, the expression levels of oxidative stress, NLRP3 inflammasome pathway, and kidney fibrosis were increased in these mice. However, these changes were significantly reversed by treatment of PGC-1α activator. Conclusion: This study demonstrated that kidney injury was ameliorated by PGC-1α-induced inactivation of the NLRP3 inflammasome via modulation of mitochondrial viability and dynamics.open박

The interactive effects of input and output on managing fluid balance in patients with acute kidney injury requiring continuous renal replacement therapy

BACKGROUND: The interactive effect of cumulative input and output on achieving optimal fluid balance has not been well elucidated in patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT). This study evaluated the interrelation of fluid components with mortality in patients with AKI requiring CRRT. METHODS: This is a retrospective observational study conducted with a total of 258 patients who were treated with CRRT due to AKI between 2016 and 2018 in the intensive care unit of Ewha Womans University Mokdong Hospital. The amounts of fluid input and output were assessed at 24-h and 72-h from the initiation of CRRT. The study endpoints were 7- and 28-day all-cause mortality. RESULTS: The mean patient age was 64.7 ± 15.8 years, and 165 (64.0%) patients were male. During the follow-up, 7- and 28-day mortalities were observed in 120 (46.5%) and 157 (60.9%) cases. The patients were stratified into two groups (28-day survivors vs. non-survivors), and the cumulative fluid balances (CFBs) at 24 h and 72 h were significantly higher in the 28-day non-survivors compared with the survivors. The increase in 24-h and 72-h CFB was significantly associated with an increase in 7- and 28-day mortality risks. To examine the interactive effect of cumulative input or output on the impact of CFB on mortality, we also stratified patients into three groups based on the tertile of 24-h and 72-h cumulative input or output. The increases in 24-h and 72-h CFBs were still significantly related to the increases in 7-day and 28-day mortality, irrespective of the cumulative input. However, we did not find significant associations between increase in 24-h and 72-h CFB and increase in mortality risk in the groups according to cumulative output tertile. CONCLUSIONS: The impact of cumulative fluid balance on mortality might be more dependent on cumulative output. The physicians need to decrease the cumulative fluid balance of CRRT patients as much as possible and consider increasing patient removal.ope

The Impact of Comorbidity Burden on The Association between Vascular Access Type and Clinical Outcomes among Elderly Patients Undergoing Hemodialysis

The optimal vascular access type for elderly hemodialysis patients is controversial. We evaluated the impact of comorbidity burden on the association between vascular access type and mortality risk among 23,100 hemodialysis patients aged ≥65 years from the Korean Society of Nephrology End-Stage Renal Disease registry data. Subjects were stratified into tertiles according to the simplified Charlson comorbidity index (sCCI), and the survival and hospitalization rates were compared with respect to vascular access type: arteriovenous fistula (AVF), arteriovenous graft (AVG), and central venous catheter (CVC). Among all tertiles of sCCI, CVC use showed highest risk of mortality than AVF use. In the lowest to middle tertile, no difference was observed in survival rates between the use of AVF and AVG. However, in the highest tertile, AVG use showed higher risk of mortality than AVF use. When subjects were classified according to a combination of sCCI tertile and access type (AVF vs. AVG), patients with the highest CCI with AVG showed 1.75-folded increased risk of mortality than those with the lowest sCCI with AVF. Hospitalization rates due to access malfunction were highest in patients with CVC in all sCCI tertiles. In the highest tertile, patients with AVG showed increased rates of hospitalization compared to those with AVF due to access malfunction. However, hospitalization rates due to access infection were highest in patients with AVG in all tertiles. The use of AVF may be of benefit and switching to AVF should be considered in elderly hemodialysis patients with a high burden of comorbidity.ope

Korean Society of Nephrology 2022 recommendations on controversial issues in diagnosis and management of hyponatremia

The Korean Society for Electrolyte and Blood Pressure Research, in collaboration with the Korean Society of Nephrology, has published a clinical practice guideline (CPG) document for hyponatremia treatment. The document is based on an extensive evidence-based review of the diagnosis, evaluation, and treatment of hyponatremia with the multidisciplinary participation of representative experts in hyponatremia with methodologist support for guideline development. This CPG consists of 12 recommendations (two for diagnosis, eight for treatment, and two for special situations) based on eight detailed topics and nine key questions. Each recommendation begins with statements graded by the strength of the recommendations and the quality of the evidence. Each statement is followed by rationale supporting the recommendations. The committee issued conditional recommendations in favor of rapid intermittent bolus administration of hypertonic saline in severe hyponatremia, the use of vasopressin receptor antagonists in heart failure with hypervolemic hyponatremia, and syndrome of inappropriate antidiuresis with moderate to severe hyponatremia, the individualization of desmopressin use, and strong recommendation on the administration of isotonic fluids as maintenance fluid therapy in hospitalized pediatric patients. We hope that this CPG will provide useful recommendations in practice, with the aim of providing clinical support for shared decision-making to improve patient outcomes.ope

Korean Society of Nephrology 2022 recommendations on controversial issues in diagnosis and management of hyponatremia

The Korean Society for Electrolyte and Blood Pressure Research, in collaboration with the Korean Society of Nephrology, has published a clinical practice guideline (CPG) document for hyponatremia treatment. The document is based on an extensive evidence-based review of the diagnosis, evaluation, and treatment of hyponatremia with the multidisciplinary participation of representative experts in hyponatremia with methodologist support for guideline development. This CPG consists of 12 recommendations (two for diagnosis, eight for treatment, and two for special situations) based on eight detailed topics and nine key questions. Each recommendation begins with statements graded by the strength of the recommendations and the quality of the evidence. Each statement is followed by rationale supporting the recommendations. The committee issued conditional recommendations in favor of rapid intermittent bolus administration of hypertonic saline in severe hyponatremia, the use of vasopressin receptor antagonists in heart failure with hypervolemic hyponatremia, and syndrome of inappropriate antidiuresis with moderate to severe hyponatremia, the individualization of desmopressin use, and strong recommendation on the administration of isotonic fluids as maintenance fluid therapy in hospitalized pediatric patients. We hope that this CPG will provide useful recommendations in practice, with the aim of providing clinical support for shared decision-making to improve patient outcomes.ope

Characterization of IgA Deposition in the Kidney of Patients with IgA Nephropathy and Minimal Change

Approximately 5% of patients with IgA nephropathy (IgAN) exhibit mild mesangial lesions with acute onset nephrotic syndrome and diffuse foot process effacement representative of minimal change disease (MCD). It is not clear whether these unusual cases of IgAN with MCD (IgAN-MCD) are variant types of IgAN or coincidental deposition of IgA in patients with MCD. In a retrospective multicenter cohort study of 18 hospitals in Korea, we analyzed 46 patients with IgAN-MCD. Patients with endocapillary proliferation, segmental sclerosis, and crescent were excluded, and the clinical features and prognosis of IgAN-MCD were compared with those of pure MCD. In addition, we performed galactose-deficient IgA1 (KM55) staining to characterize IgAN-MCD. Among the 21,697 patients with glomerulonephritis enrolled in the database, 46 patients (0.21%) were diagnosed with IgAN-MCD, and 1610 patients (7.4%) with pure MCD. The 46 patients with IgAN-MCD accounted for 0.6% of primary IgAN patients (n= 7584). There was no difference in prognosis between patients with IgAN-MCD and those with only MCD. IgA and KM55 showed double positivity in all patients with IgAN-MCD (n= 4) or primary IgAN (n= 5) under double immunofluorescent staining. However, in four patients with lupus nephritis, mesangial IgA was deposited, but galactose-deficient-IgA1 (Gd-IgA1) was not. These findings suggest that IgAN-MCD is a dual glomerulopathy in which MCD was superimposed on possibly indolent IgAN. We confirmed by KM55 staining that IgAN-MCD is true IgAN, enabling better characterizations of the disease. Furthermore, IgAN-MCD shows a good prognosis when treated according to the usual MCD treatment modality.ope

Pulse pressure and the risk of renal hyperfiltration in young adults: Results from Korea National Health and Nutrition Examination Survey (2010-2019)

Background: High pulse pressure (PP) is associated with increased risk of decline of kidney function. However, little is known about the association between PP and RHF in young adults. This study aimed to evaluate the association between PP and RHF in healthy young adults. Methods: Data were retrieved from the Korea National Health and Nutrition Examination Survey from 2010 to 2019. A total of 10,365 participants aged 19-39 years with no hypertension and normal kidney function were analyzed. RHF was defined as logarithm transformed estimated glomerular filtration rate (eGFR) with residuals >90th percentile after adjustment for sex, logarithm transformed age, weight, and height. Participants were divided into tertile based on PP levels. Results: The prevalence of RHF was higher in higher PP tertile group (6.6, 10.5, and 12.7% in T1, T2, and T3; P for trend < 0.001). In multivariable logistic regression analyses, the risk for RHF was increased in higher PP tertiles compared to the lowest tertile [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.19-1.69 in T2; OR, 1.44; 95% CI, 1.20-1.73 in T3]. When PP levels were treated as continuous variable, the risk of RHF was increased 2.36 per 1.0 increase of PP (P < 0.001). In subgroup analyses stratified sex, histories of diabetes or dyslipidemia, and isolated systolic hypertension or isolated diastolic hypertension, there were no significant interactions with PP for the risk for RHF, suggesting that high PP was associated with increased risk of RHF regardless of subgroups. However, the subgroup with BMI showed significant interaction with PP for the risk of RHF, indicating that participants with BMI ≥ 25 kg/m2 were at higher risk of RHF with increasing PP levels than those with BMI < 25 kg/m2 (OR, 1.89; 95% CI, 1.25-2.87 in BMI < 25 kg/m2; OR, 3.16; 95% CI, 1.74-5.73 in BMI ≥ 25 kg/m2; P for interaction = 0.01). Conclusion: High PP is associated with an increased risk of RHF in healthy young adults and this association is prominent in obese young adults. The assessment of PP and associated RHF may give benefit to early detect the potential risk of CKD development in young adults.ope

Skin Sodium and Blood Pressure Regulation

Hypertension is a major public health concern due to its high prevalence and increased risk of cardiovascular disease and mortality. Complex traits resulting from both genetic and environmental factors affect the development of hypertension. Among environmental factors, a high salt diet is an important cause for hypertension. Humans show a heterogeneous blood pressure (BP) response to sodium intake. Although the precise mechanisms for the association between salt sensitivity and hypertension have not been fully elucidated, renal sodium handling has been considered to play a pivotal role. However, this conventional view has recently been challenged in that a third compartment, namely, skin may have a role in the regulation of sodium homeostasis. Skin is comprised of a significant portion of interstitium, which is a major extracellular fluid compartment, and its complex capillary network regulates body temperature and skin perfusion. Growing evidence indicates that local regulatory action of cutaneous blood flow as well as salt and water metabolism is associated with systemic BP control. Previous experimental studies have shown that dietary salt loading resulted in nonosmotic sodium accumulation via glycosaminoglycans and lymphatics embedded in the skin that were mediated by several endogenous factors and attenuated an increase in BP. Studies in humans have also suggested that the skin serves as a buffer system for sodium storage and that skin sodium contributes to salt sensitivity and hypertension. Thus, skin sodium storage provides the possibility of being an additional buffering system in response to salt loading and concomitant BP changes in humans.ope

Removal of large middle molecules via haemodialysis with medium cut-off membranes at lower blood flow rates: an observational prospective study

BACKGROUND: Online haemodiafiltration (OL-HDF) may improve middle molecular clearance in contrast to conventional haemodialysis (HD). However, OL-HDF requires higher convective flows and cannot sufficiently remove large middle molecules. This study evaluated the efficacy of a medium cut-off (MCO) dialyser in removing large middle molecular uraemic toxins and compared it with that of conventional high-flux (HF) dialysers in HD and predilution OL-HDF. METHODS: Six clinically stable HD patients without residual renal function were investigated. Dialyser and treatment efficacies were examined during a single midweek treatment in three consecutive periods: 1) conventional HD using an HF dialyser, 2) OL-HDF using the same HF dialyser, and 3) conventional HD using an MCO dialyser. Treatment efficacy was assessed by calculating the reduction ratio (RR) for β2-microglobulin (β2M), myoglobin, κ and λ free light chains (FLCs), and fibroblast growth factor (FGF)-23 and measuring clearance for FLCs. RESULTS: All three treatments showed comparable RRs for urea, phosphate, creatinine, and uric acid. MCO HD showed greater RRs for myoglobin and λFLC than did HF HD and predilution OL-HDF (myoglobin: 63.1 ± 5.3% vs. 43.5 ± 8.9% and 49.8 ± 7.3%; λFLC: 43.2 ± 5.6% vs. 26.8 ± 4.4% and 33.0 ± 9.2%, respectively; P <  0.001). Conversely, predilution OL-HDF showed the greatest RR for β2M, whereas MCO HD and HF HD showed comparable RRs for β2M (predilution OL-HDF vs. MCO HD: 80.1 ± 4.9% vs. 72.6 ± 3.8%, P = 0.01). There was no significant difference among MCO HD, HF HD, and predilution OL-HDF in the RRs for κFLC (63.2 ± 6.0%, 53.6 ± 15.5%, and 61.5 ± 7.0%, respectively; P = 0.37), and FGF-23 (55.5 ± 20.3%, 34.6 ± 13.1%, and 35.8 ± 23.2%, respectively; P = 0.13). Notably, MCO HD showed improved clearances for FLCs when compared to HF HD or OL-HDF. CONCLUSIONS: MCO HD showed significantly greater RR of large middle molecules and achieved improved clearance for FLCs than conventional HD and OL-HDF, without the need for large convection volumes or high blood flow rates. This would pose as an advantage for elderly HD patients with poor vascular access and HD patients without access to OL-HDF. TRIAL REGISTRATION: Clinical Research Information Service (CRIS): KCT 0003009. The trial was prospectively registered on the 21 Jul 2018.ope

Cumulative fluid balance and mortality in elderly patients with acute kidney injury requiring continuous renal-replacement therapy: a multicenter prospective cohort study

Background: The effect of fluid balance on outcomes in elderly patients with acute kidney injury (AKI) requiring continuous renal-replacement therapy (CRRT) is not explained well. We investigated outcomes according to cumulative fluid balance (CFB) in elderly patients with AKI undergoing CRRT. Methods: A total of 607 patients aged 65 years or older who started CRRT due to AKI were enrolled and stratified into two groups (fluid overload [FO] vs. no fluid overload [NFO]) based on the median CFB value for 72 hours before CRRT initiation. Propensity score-matching analysis was performed. Results: The median age of included patients was 73.0 years and 60.0% of the population was male. The median 72-hour CFB value was 2,839.0 mL. The overall cumulative survival and 28-day survival rates were lower in the FO group than in the NFO group (P < 0.001 for both) and remained so after propensity score-matching. Furthermore, patients in the FO group demonstrated a higher overall mortality risk after adjustment for age, sex, systolic blood pressure, Charlson comorbidity index, Acute Physiology and Chronic Health Evaluation II score, serum albumin, creatinine, diuretic use, and mechanical ventilation status (hazard ratio, 1.38; 95% confidence interval, 1.13 to 1.89; P < 0.001). Among survivors, both the duration of CRRT and the total duration of hospitalization from CRRT initiation showed no difference between the FO and NFO groups. Conclusion: A higher CFB value is associated with an increased risk of mortality in elderly patients with AKI requiring CRRT.ope