A Randomized Trial of Postoperative Handgrip Exercises for Fistula Maturation in Patients With Newly Created Wrist Radiocephalic Arteriovenous Fistulas.

Introduction: We aimed to substantiate the benefit of postoperative handgrip exercises (HGEs) in enhancing the maturation of an arteriovenous wrist fistula. Methods: We randomly assigned 119 patients aged 20 to 80 years who had wrist arteriovenous fistulas (AVFs) to undergo either a basic HGE program (group A), an advanced program (group B), or an advanced-plus upper arm banding program (group C). Outcomes were assessed by ultrasonographic evaluation of the diameter and flow at each follow-up. The attending nephrologist decided the clinical use of the fistula. Results: We identified no significant differences among the HGE groups in the mean diameter and blood flow 14, 30, 60, and 90 days after the creation of the wrist AVF (P = 0.55, 0.88, 0.21, and 0.19 for the diameter; 0.94, 0.81, 0.49, and 0.56 for the flow, respectively). The intent-to-treat analysis also found no difference in the clinical use of fistulas for hemodialysis (HD) (P = 0.997). Conclusion: In patients with a newly created wrist AVF, advancing frequency, with or without adding intensity using an upper arm tourniquet, of postoperative HGEs did not enhance the growth of the fistula or increase the rate of clinical use over 3 months. (ClinicalTrials.gov ID: NCT03077815).

Age-Dependent Effects of Acute Kidney Injury on End-Stage Kidney Disease and Mortality in Patients with Moderate to Severe Chronic Kidney Disease.

INTRODUCTION: Old age has been considered as a positive modifier of chronic kidney disease (CKD), but the progression of CKD is often accelerated by acute kidney injury (AKI) in older adults. This study aimed to investigate this paradoxical interplay and identify age-specific predictors of end-stage kidney disease (ESKD). METHODS: This retrospective cohort included 6,101 patients with CKD stage 3B-5 followed at a single center during 2005-2018. Participants were stratified into four age groups to explore age-dependent influences on the risk of ESKD and all-cause mortality. Multivariate Cox proportional hazard regression model with competing risk analysis was used to identify predictors of outcomes. RESULTS: During a median follow-up of 2.68 years, 1,650 (27.0%) patients developed ESKD and 541 (8.9%) patients died. The rate of ESKD decreased with advancing age, being lowest in the very old-aged (>75 years) group who displayed the slowest rate of estimated glomerular filtration rate (eGFR) decline. Multivariate Cox proportional hazard regression adjusted for competing death showed that younger ages, compared with patients aged >75 years, together with AKI episodes and several traditional risk factors were identified as predictors for ESKD. The impact of AKI episodes on ESKD development was most prominent in patients aged >75 years. These results were confirmed with subgroup analyses in patients with outcomes of different ages. CONCLUSION: Older adults with CKD exhibited a slower decline rate of eGFR, yet they were more likely to develop ESKD following AKI episodes. These results suggest tackling AKI is needed to prevent accelerated initiation of renal replacement therapy in elderly patients with pre-existing CKD.

Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells.

Plasma levels of angiopoietin-2 are increased in patients with chronic kidney disease (CKD). Moreover, mouse models of progressive kidney disease also demonstrate increased angiopoietin-2 in both plasmas and kidneys. The role of dysregulated angiopoietins in the progression of kidney disease has not been thoroughly investigated. Here, we found in a cohort of 319 patients with CKD that plasma angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratios were positively associated with the development of kidney failure. In mice with progressive kidney disease induced by either ureteral obstruction or ischemia-reperfusion injury, overexpression of human angiopoietin-1 in the kidney tubules not only reduced macrophage infiltration in the initial stage post-injury but also attenuated endothelial cell apoptosis, microvascular rarefaction, and fibrosis in the advanced disease stage. Notably, angiopoietin-1 attenuated chemokine C-C motif ligand 2 (CCL2) expression in the endothelial cells of the fibrosing kidneys, and these protective effects led to attenuation of functional impairment. Mechanistically, angiopoietin-1 reduced CCL2-activated macrophage migration and protected endothelial cells against cell apoptosis induced by angiopoietin-2 and Wnt ligands. Based on this, we applied L1-10, an angiopoietin-2 inhibitor, to the mouse models of progressive kidney disease and found inhibitory effects on macrophage infiltration, microvascular rarefaction, and fibrosis. Thus, we defined the detrimental impact of increased angiopoietin-2 on kidney survival of patients with CKD which appears highlighted by angiopoietin-2 induced endothelial CCL2-activated macrophage infiltration and endothelial cell apoptosis in their kidneys undergoing fibrosis.

Is the rating result reliable? A new approach to respond to a medical trainee's concerns about the reliability of Mini-CEX assessment.

PURPOSE: Whether the rating result of mini-clinical evaluation exercise (Mini-CEX) for rating clinical skills is reliable is of a medical trainee's great concerns. The objectives of this study were to analyze the test-retest reliability, interrater reliability and internal consistency reliability of Mini-CEX. METHODS: Three clinical scenarios, each played by a standardized patient and resident, were developed and videotaped. A group of assessors were recruited to rate the resident's clinical skills using Mini-CEX with a nine-point grading scale in each videotaped clinical scenario. Each assessor was required: (1) to watch the videotaped clinical scenarios a sequential order; (2) to rate each medical trainee's clinical skills in each clinical scenario for two rating sessions, and there must be a minimum three-week interval between the first and the second Mini-CEX rating session. RESULTS: A total of 38 assessors participated in this study. This study showed that: (1) an assessor carried out similar rating reuslts under the same clinical performance based on an acceptable test-retest reliability (Pearson's correlation coefficients = 0.24-0.76, P value=<0.01-0.14); (2) assessors gave similar rating results to a medical trainee's clinical performance based on a good interrater reliability (intra-class correlation coefficient = 0.57-0.83, P value=<0.01-0.03); and (3) the items reflected unidimensionally a construct-a medical trainee's clinical skills based on an excellent internal consistency reliability (Cronbach's alpha = 0.92-0.97). CONCLUSION: This study convincingly showed that Mini-CEX is a reliable assessment tool for rating clinical skills, and can be widely used to assess medical trainees' clinical skills.

Spectrum of cancer patients receiving renal biopsy.

BACKGROUND: The frontier of onco-nephrology, particularly renal complications of cancer and treatment, remains unexplored. We revisit the fundamental tool of diagnosing kidney disease, renal biopsy, in cancer patients with renal manifestation. METHODS: Patients who received renal biopsy from July 2015 to July 2019 were analyzed. Primary outcomes included end-stage renal disease (ESRD), mortality, and catastrophic outcome defined as either ESRD or mortality. A Cox proportional hazards model and Kaplan-Meier technique were used to assess the association with outcome measurements and survival analyses. Immunosuppression after renal biopsy and response to the treatment were evaluated. RESULTS: Among the 77 patients, the median age was 66 years (interquartile range [IQR] 59-73 years) and 46 (59.7%) were male. At the time of renal biopsy, 57 patients (74%) had various degrees of renal insufficiency. Tubulointerstitial damage score, quantified by renal pathology, were associated with higher hazards of ESRD (hazard ratio [HR], 1.77; 95% confidence interval [95% CI], 1.20 to 2.61; P = 0.004) and catastrophic outcome (HR, 1.30; 95% CI, 0.99 to 1.70; P = 0.058). The response rate to immunosuppression was lower in those diagnosed with tubulointerstitial nephritis (1 of 4 patients, 25%) than those with glomerulopathy (10 of 20 patients, 50%). CONCLUSION: Renal biopsy may improve diagnostic accuracy and assist in treatment guidance of cancer patients with renal manifestation. Renal biopsy should be encouraged with clinical indication. Collaboration between oncologists and nephrologists is of paramount importance to provide more comprehensive care for caner patients.

Angiopoietin-2 is associated with metabolic syndrome in chronic kidney disease.

BACKGROUNDS: Metabolic syndrome is a subclinical status in promoting atherosclerotic cardiovascular disease and type 2 diabetes mellitus. The significance of metabolic syndrome and pathophysiology in chronic kidney disease is not investigated. METHODS: We enrolled adult patients with CKD stages 3 to 5 from December 2006 to December 2007. Metabolic syndrome was defined by the US National Cholesterol Education Programme Adult Treatment Panel III guidelines. Plasma levels of angiogenic growth factors were measured. Univariate and multivariate logistic regression analyses were used. RESULTS: Total 451 patients were analyzed with median estimated glomerular filtration rate of 27.0 ml/min per 1.73m2 (interquartile range 14.3-41.3). Patients with metabolic syndrome were older (P = 0.002), had higher percentage using diuretics (P = 0.002) but lower percentage using pentoxifylline (P = 0.017). Patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein (P < 0.0001), uric acid (P = 0.009) and angiopoietin-2 (P = 0.001). Multivariate logistic regression analyses revealed significant association between plasma levels of angiopoietin-2 and metabolic syndrome (P = 0.042). CONCLUSION: The prevalence of metabolic syndrome in advanced CKD was higher than general population. CKD patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein, uric acid and angiopoietin-2. Plasma levels of angiopoietin-2 were significantly associated with metabolic syndrome in patients with CKD. Metabolic syndrome in CKD may be not only a prognostic factor but also an interventional target, possibly through ameliorating inflammation. Prospective and interventional studies are necessary to establish the pathophysiology.

Outcomes of coronavirus 2019 infection in patients with chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Information on coronavirus disease 2019 (COVID-19) infection in patients with chronic kidney disease (CKD) remains limited. To understand the influence of COVID-19 infection in patients with pre-existing CKD, we conducted a systematic review and meta-analysis to evaluate and compare the risks of all-cause mortality, hospitalization, and critical progression between patients with and without CKD. METHODS: We selected randomized controlled trials (RCTs), prospective or retrospective observational, case-control, cross-sectional, and case-series studies analyzing outcomes of COVID-19 infection in patients with pre-existing CKD from the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases published on the Internet before 16 July 2020. RESULTS: A total of 27 studies comprising 77,856 patients with COVID-19 infection was identified; 3922 patients with pre-existing CKD were assigned CKD group, and 73,934 patients were assigned to the non-CKD group. The pooled analysis showed that patients with CKD had a significantly higher risk of all-cause mortality and hospitalization than those without CKD [odds ratio (OR) 2.25, 95% confidence interval (CI) 1.91-2.66, p < 0.001; OR 4.29, 95% CI 2.93-6.28, p < 0.001; respectively]. Patients with CKD had a higher risk of critically ill conditions than those without CKD in the pooled analysis of studies with multivariable adjustment (adjusted OR 2.12, 95% CI 0.95-4.77, p = 0.07) and in the analysis of all included studies (OR 1.27, 95% CI 0.71-2.26, p = 0.41), but both analyses did not attain statistical significance. CONCLUSION: COVID-19 infected patients with CKD had significantly increased risks of all-cause mortality and hospitalization compared with those without CKD.

FGF23 ameliorates ischemia-reperfusion induced acute kidney injury via modulation of endothelial progenitor cells: targeting SDF-1/CXCR4 signaling.

The levels of fibroblast growth factor 23 (FGF23) rapidly increases after acute kidney injury (AKI). However, the role of FGF23 in AKI is still unclear. Here, we observe that pretreatment with FGF23 protein into ischemia-reperfusion induced AKI mice ameliorates kidney injury by promoting renal tubular regeneration, proliferation, vascular repair, and attenuating tubular damage. In vitro assays demonstrate that SDF-1 induces upregulation of its receptor CXCR4 in endothelial progenitor cells (EPCs) via a non-canonical NF-κB signaling pathway. FGF23 crosstalks with the SDF-1/CXCR4 signaling and abrogates SDF-1-induced EPC senescence and migration, but not angiogenesis, in a Klotho-independent manner. The downregulated pro-angiogenic IL-6, IL-8, and VEGF-A expressions after SDF-1 infusion are rescued after adding FGF23. Diminished therapeutic ability of SDF-1-treated EPCs is counteracted by FGF23 in a SCID mouse in vivo AKI model. Together, these data highlight a revolutionary and important role that FGF23 plays in the nephroprotection of IR-AKI.

The impact of baseline glomerular filtration rate on subsequent changes of glomerular filtration rate in patients with chronic kidney disease.

Higher baseline glomerular filtration rate (GFR) may yield subsequent steeper GFR decline, especially in patients with diabetes mellitus (DM). However, this correlation in patients with chronic kidney disease (CKD) and the presence or absence of DM remains controversial. We conducted a longitudinal cohort study in a single medical center between 2011 and 2018. Participants with CKD stage 1 to 3A were enrolled and divided into DM groups and non-DM groups, and then followed up at least every 6 months. We used a linear mixed regression model with centering time variable to overcome the problem of mathematical coupling in the analysis of the relation between baseline GFR and the changes, and compared the results from correct and incorrect specifications of the mixed models. A total number of 1002 patients with 285 diabetic and 717 non-diabetic persons was identified. The linear mixed regression model revealed a significantly negative correlation between baseline GFR and subsequent GFR change rate in both diabetic group and non-diabetic group (r = - 0.44 [95% confidence interval [CI], - 0.69 to - 0.09]), but no statistical significance in non-diabetic group after within-subject mean centering of time variable (r = - 0.09 [95% CI, - 0.41 to 0.25]). Our study showed that higher baseline GFR was associated with a subsequent steeper GFR decline in the DM group but not in the non-DM group among patients with early-stage CKD. Exact model specifications should be described in detail to prevent from a spurious conclusion.

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis.

Prolyl hydroxylase domain enzyme (PHD) inhibitors are effective in the treatment of chronic kidney disease (CKD)-associated anemia by stabilizing hypoxia inducible factor (HIF), thereby increasing erythropoietin and consequently erythropoiesis. However, concern for CKD progression needs to be addressed in clinical trials. Although pre-clinical studies showed an anti-inflammatory effect in kidney disease models, the effect of PHD inhibitors on kidney fibrosis was inconsistent probably because the effects of HIF are cell type and context dependent. The major kidney erythropoietin-producing cells are pericytes that produce erythropoietin through HIF-2α-dependent gene transcription. The concern for the impact of HIF in pericytes on kidney fibrosis arises from the fact that pericytes are the major precursor cells of myofibroblasts in CKD. Since cells expressing Gli1 fulfill the morphologic and anatomic criteria for pericytes, we induced Gli1+ cell-specific HIF stabilization or knockout to study the impact of HIF in pericytes on kidney pathology of mice with or without fibrotic injury induced by unilateral ureteral obstruction. Compared with the littermate controls, mice with pericyte-specific HIF stabilization due to von Hippel-Lindau protein or PHD2 knockout showed increased serum erythropoietin and polycythemia rather than a discernible difference in kidney fibrosis. Compared with Gli1+ pericytes sorted from littermate controls, Gli1+ pericytes sorted from PHD2 knockout mice showed increased erythropoietin gene expression rather than discernible changes in Col1a1 or Acta2 expression. Furthermore, pericyte-specific knockout of HIF-1α or HIF-2α did not affect kidney fibrosis. Thus, our study supports the absence of negative effects of PHD inhibitors on kidney fibrosis of mice despite HIF stabilization in pericytes.

Renin-angiotensin-aldosterone system inhibition decreased contrast-associated acute kidney injury in chronic kidney disease patients.

BACKGROUND/PURPOSE: Chronic kidney disease (CKD) is a risk factor for contrast associated acute kidney injury (CA-AKI). The risk of renin-angiotensin-aldosterone system inhibitor (RASi) use in patients with CKD before the administration of contrast is not clear. METHODS: In this nested case-control study, 8668 patients received contrast computed tomography (CT) from 2013 to 2018 during index administration in a multicenter hospital cohort. The identification of AKI is based on the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria within 48 h after contrast medium used. RESULTS: Finally, 986 patients (age, 63.36 ± 12.22; men, 72.92%) with CKD (estimated glomerular filtration rate (eGFR) = 35.0 ± 19.8 mL/min/1.73 m2) were eligible for analysis. After the index date, RASi users (n = 315) were less likely to develop CA-AKI (13.65% vs 30.4%, p < 0.001), and had a lower hospital mortality (8.25% vs 19.23%, p < 0.001) compared with non-users. The pre-contrast use of RASi decrease the risk of AKI (OR, 0.342, p < 0.001) and hospital mortality (OR, 0.602, p = 0.045). Even a few defined daily doses (DDDs) of RASi treatment, more than 0.02 prior to contrast CT could attenuate CA-AKI. The hospital mortality was higher in RASi non-users if their eGFR value was more than 17.9 mL/min/1.73 m2. CONCLUSION: RASi use in patients with CKD prior to contrast CT has the potential to mitigate the incidence of AKI and hospital mortality. Even a low dose of RASi will noticeably decrease the risk of AKI and will not increase the risk of hyperkalemia.

High plasma C-terminal FGF-23 levels predict poor outcomes in patients with chronic kidney disease superimposed with acute kidney injury.

BACKGROUND: Elevated plasma C-terminal fibroblast growth factor-23 (cFGF-23) levels are associated with higher mortality in patients with chronic kidney disease (CKD) and acute kidney injury (AKI). Our study explored the outcome forecasting accuracy of cFGF-23 in critically ill patients with CKD superimposed with AKI (ACKD). METHODS: Urine and plasma biomarkers from 149 CKD patients superimposed with AKI before dialysis were checked in this multicenter prospective observational cohort study. Endpoints were 90-day mortality and 90 days free from dialysis after hospital discharge. Associations with study endpoints were assessed using hierarchical clustering analysis, the generalized additive model, the Cox proportional hazard model, competing risk analysis, and discrimination evaluation. RESULTS: Over a median follow up of 40 days, 67 (45.0%) patients died before the 90th day after hospital discharge and 39 (26.2%) progressed to kidney failure with replacement therapy (KFRT). Hierarchical clustering analysis demonstrated that cFGF-23 levels had better predictive ability for 90-day mortality than did other biomarkers. Higher serum cFGF-23 levels were independently associated with greater risk for 90-day mortality [hazard ratio (HR): 2.5; 95% confidence interval (CI) 1.5-4.1; p < 0.001]. Moreover, adding plasma cFGF-23 to the Demirjian AKI risk score model substantially improved risk prediction for 90-day mortality than the Demirjian model alone (integrated discrimination improvement: 0.06; p < 0.05; 95% CI 0.02-0.10). The low plasma cFGF-23 group was predicted having more weaning from dialysis in surviving patients (HR = 0.53, 95% CI, 0.29-0.95, p = 0.05). CONCLUSIONS: In patients with ACKD, plasma cFGF-23 levels are an independent risk factor to forecast 90-day mortality and 90-day progression to KFRT. In combination with the clinical risk score, plasma cFGF-23 levels could substantially improve mortality risk prediction.

Renin-Angiotensin-Aldosterone System Inhibitors and Risks of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Systematic Review and Meta-Analysis.

The viral spike coat protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engages the human ACE (angiotensin-converting enzyme) 2 cell surface receptor to infect the host cells. Thus, concerns arose regarding theoretically higher risk for coronavirus disease-19 (COVID-19) in patients taking ACE inhibitors/angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). We systematically assessed case-population and cohort studies from MEDLINE (Ovid), Cochrane Database of Systematic Reviews PubMed, Embase, medRXIV, the World Health Organization database of COVID-19 publications, and ClinicalTrials.gov through June 1, 2020, with planned ongoing surveillance. We rated the certainty of evidence according to Cochrane methods and the Grading of Recommendations Assessment, Development and Evaluation approach. After pooling the adjusted odds ratios from the included studies, no significant increase was noted in the risk of SARS-CoV-2 infection by the use of ACE inhibitors (adjusted odds ratio, 0.95 [95% CI, 0.86-1.05]) or ARBs (adjusted odds ratio, 1.05 [95% CI, 0.97-1.14]). However, the random-effects meta-regression revealed that age may modify the SARS-CoV-2 infection risk in subjects with the use of ARBs (coefficient, -0.006 [95% CI, -0.016 to 0.004]), that is, the use of ARBs, as opposed to ACE inhibitors, specifically augmented the risk of SARS-CoV-2 infection in younger subjects (<60 years old). The use of ACE inhibitors might not increase the susceptibility of SARS-CoV-2 infection, severity of disease, and mortality in case-population and cohort studies. Additionally, we discovered for the first time that the use of ARBs, as opposed to ACE inhibitors, specifically augmented the risk of SARS-CoV-2 infection in younger subjects, without obvious effects on COVID-19 outcomes.

Association between regional economic status and renal recovery of dialysis-requiring acute kidney injury among critically ill patients.

The association between regional economic status and the probability of renal recovery among patients with dialysis-requiring AKI (AKI-D) is unknown. The nationwide prospective multicenter study enrolled critically ill adult patients with AKI-D in four sampled months (October 2014, along with January, April, and July 2015) in Taiwan. The regional economic status was defined by annual disposable income per capita (ADIPC) of the cities the hospitals located. Among the 1,322 enrolled patients (67.1 ± 15.5 years, 36.2% female), 833 patients (63.1%) died, and 306 (23.1%) experienced renal recovery within 90 days following discharge. We categorized all patients into high (n = 992) and low economic status groups (n = 330) by the best cut-point of ADIPC determined by the generalized additive model plot. By using the Fine and Gray competing risk regression model with mortality as a competing risk factor, we found that the independent association between regional economic status and renal recovery persisted from model 1 (no adjustment), model 2 (adjustment to basic variables), to model 3 (adjustment to basic and clinical variables; subdistribution hazard ratio, 1.422; 95% confidence interval, 1.022-1.977; p = 0.037). In conclusion, high regional economic status was an independent factor for renal recovery among critically ill patients with AKI-D.

Nephrologist Follow-Up Care of Patients With Acute Kidney Disease Improves Outcomes: Taiwan Experience.

OBJECTIVES: Acute kidney injury (AKI) and acute kidney disease (AKD) are a continuum on a disease spectrum and frequently progress to chronic kidney disease. Benefits of nephrologist subspecialty care during the AKD period after AKI are uncertain. METHODS: Patients with AKI requiring dialysis who subsequently became dialysis independent and survived for at least 90 days, defined as the AKD period, were identified from the Taiwanese population's health insurance database. Cox proportional hazard models using death as the competing risk before and after propensity-score matching were applied to evaluate various endpoints. RESULTS: Among a total of 20 260 patients with AKI requiring dialysis who became dialysis independent, only 7550 (37.3%) patients were followed up with by a nephrologist (F/Unephrol group) during the AKD period. During a mean 4.04 ± 3.56 years of follow-up, the patients in the F/Unephrol group were more often administered statin, antihypertensives, angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), diuretics, antiplatelet agents, and antidiabetic agents. The patients in the F/Unephrol group had a lower mortality rate (hazard ratio [HR] = 0.87, P < .001) and were less likely to have major adverse cardiovascular events (MACE) (subdistribution HR [sHR] = 0.85, P < .001), congestive heart failure (CHF) (sHR = 0.81, P < .001), and severe sepsis (sHR = 0.88, P = .008) according to the Cox proportional model after adjusting for mortality as a competing risk. During the AKD period, an increase in the frequency of nephrology visits was associated with improved outcomes. CONCLUSIONS: In this population-based cohort, even after weaning off acute dialysis, only a minority of patients visited a nephrologist during the AKD period. We showed that nephrology follow-up is associated with a decrease in MACE, CHF exacerbations, and sepsis, as well as lower mortality; thus it may improve outcomes in patients with AKD.

Arterial Stiffness Is Associated with Clinical Outcome and Cardiorenal Injury in Lateralized Primary Aldosteronism.

CONTEXT: The association between arterial stiffness and clinical outcome in lateralized primary aldosteronism (PA) patients after adrenalectomy has not been clearly identified. OBJECTIVE: We hypothesized that arterial stiffness estimated by brachial-ankle pulse wave velocity (baPWV) before adrenalectomy was associated with the clinical outcomes and cardiorenal injury in lateralized PA patients after adrenalectomy. DESIGN AND PATIENTS: We designed a retrospective observational cohort study. We collected lateralized PA patients who had undergone adrenalectomy between 2013 and 2016 from the Taiwan Primary Aldosteronism Investigation database. The primary outcome was achieving complete clinical success at 1 year after adrenalectomy. The secondary outcome was estimated glomerular filtration rate declining over 20% and improved left ventricular mass index. RESULTS: We enrolled 221 patients with lateralized PA (50.7% men; mean age, 51.9 years), of whom 101 patients (45.7%) achieved complete clinical success at the 1-year follow-up assessment after adrenalectomy. Lower baPWV before adrenalectomy (odds ratio = 0.998; 95% confidence interval, 0.996-0.999; P = 0.003) correlated with higher likelihood of complete clinical success by multivariate logistic regression analysis. Multifactorial adjusted generalized additive model demonstrated that preoperative baPWV<1600 cm/sec was significantly associated with complete cure of hypertension. In addition, higher preoperative baPWV was associated with renal function decline and less left ventricular mass regression after adrenalectomy in lateralized PA patients during the follow-up period. CONCLUSIONS: Our study demonstrated that the preoperative severe arterial stiffness was associated with absent complete clinical success in lateralized PA patients after adrenalectomy, and this effect may contribute to cardiorenal injury, which at least partially explains kidney function deterioration and lessened regression of heart mass.

Methylation in pericytes after acute injury promotes chronic kidney disease.

The origin and fate of renal myofibroblasts is not clear after acute kidney injury (AKI). Here, we demonstrate that myofibroblasts were activated from quiescent pericytes (qPericytes) and the cell numbers increased after ischemia/reperfusion injury-induced AKI (IRI-AKI). Myofibroblasts underwent apoptosis during renal recovery but one-fifth of them survived in the recovered kidneys on day 28 after IRI-AKI and their cell numbers increased again after day 56. Microarray data showed the distinctive gene expression patterns of qPericytes, activated pericytes (aPericytes, myofibroblasts), and inactivated pericytes (iPericytes) isolated from kidneys before, on day 7, and on day 28 after IRI-AKI. Hypermethylation of the Acta2 repressor Ybx2 during IRI-AKI resulted in epigenetic modification of iPericytes to promote the transition to chronic kidney disease (CKD) and aggravated fibrogenesis induced by a second AKI induced by adenine. Mechanistically, transforming growth factor-ß1 decreased the binding of YBX2 to the promoter of Acta2 and induced Ybx2 hypermethylation, thereby increasing α-smooth muscle actin expression in aPericytes. Demethylation by 5-azacytidine recovered the microvascular stabilizing function of aPericytes, reversed the profibrotic property of iPericytes, prevented AKI-CKD transition, and attenuated fibrogenesis induced by a second adenine-AKI. In conclusion, intervention to erase hypermethylation of pericytes after AKI provides a strategy to stop the transition to CKD.

Effects and Safety of Statin and Ezetimibe Combination Therapy in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

The efficacy and safety of statin and ezetimibe combination therapy in patients with chronic kidney disease (CKD) remains unclear. To assess the effect of statin and ezetimibe combination therapy on controlling lipid profiles and reducing cardiovascular events in patients with CKD, we conducted a systematic review and meta-analysis. We selected randomized controlled trials comparing this combination therapy with statin monotherapy or placebo in patients with CKD from the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases published before September 1, 2018 on the Internet. Eight articles on seven studies, with a total of 14,016 patients with CKD, were selected from 412 full-text articles. Statin and ezetimibe combination therapy had beneficial effects on serum total cholesterol (weighted mean difference (WMD) -20.31 mg/dL, 95% confidence interval (CI), -26.87 to -13.75 mg/dL, P < 0.001), low-density lipoprotein cholesterol (WMD -17.22 mg/dL, 95% CI, -18.93 to -15.51 mg/dL, P < 0.001), and triglycerides (WMD -15.08 mg/dL, 95% CI, -23.41 to -6.75 mg/dL, P < 0.001) compared with statin monotherapy. Statin and ezetimibe combination therapy significantly reduced all-cause mortality and major adverse cardiovascular events (risk ratio 0.86, 95% CI, 0.77 to 0.97, P = 0.01). The incidence of adverse events was low, with no significant difference between statin and ezetimibe combination therapy and statin monotherapy. In conclusion, the statin and ezetimibe combination therapy significantly improved serum lipid profiles and reduced risks of all-cause deaths and major adverse cardiovascular events compared with the control group in patients with CKD.

Familial Aggregation and Heritability of Aldosteronism with Cardiovascular Events.

CONTEXT: To date, the effect of positive family history as a risk factor of primary aldosteronism (PA) is largely unknown. Studies have failed to distinguish the heritability of PA as well as the associations between positive family history of PA and clinical outcomes. OBJECTIVES: We quantified the prevalence, the extent of familial aggregation, the heritability of PA among family members of patients with PA, and the association between positive PA family history and major cardiovascular events (MACE). DESIGN AND SETTINGS: Using the Taiwan National Health Insurance Database, 30 245 077 National Health Insurance beneficiaries (both alive and those deceased between January 1, 1999, and December 31, 2015) were identified. RESULTS: We identified 7902 PA patients. Forty-four had PA (0.3%) among 10 234 individuals with affected parents, 2298 with affected offspring, 1924 with affected siblings, and 22 with affected twins. A positive family history was associated with the adjusted relative risk (RR) (95% confidence interval [CI]) of 11.60 (7.63-17.63) for PA in people with an affected first-degree relative. In subgroup analysis, the risk for PA across all relationships (parent, siblings, offspring, and spouse) showed highly significant differences to PA without family history. The accountability for phenotypic variance of PA was 51.0% for genetic factors, 24.9% for shared environmental factors, and 24.1% for nonshared environmental factors. PA patients with an affected first-degree relative were associated with an increased risk for composite major cardiovascular events (RR 1.31; 95% CI 1.24-1.40, P < .001) compared with PA patients without family history. CONCLUSION: Familial clustering of PA exists among a population-based study, supporting a genetic susceptibility leading to PA. There is increased coaggregation of MACE in first-degree relatives of PA patients. Our findings suggest a strong genetic component in the susceptibility of PA, involving different kinships.