Ae Jin Kim

The Effect of Renin-Angiotensin-Aldosterone System Blockade on Contrast-Induced Acute Kidney Injury: A Propensity-Matched Study

BACKGROUND The role of the angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) in the pathophysiology of contrast-induced acute kidney injury (AKI) is controversial, and the available literature is contradictory. STUDY DESIGN A retrospective propensity score-matched study to analyze the effect of ACE-inhibitor/ARB therapy on the development of contrast-induced AKI. SETTING & PARTICIPANTS Using propensity score matching, 1,322 ACE-inhibitor/ARB recipients and nonrecipients were paired for analysis from 5,299 patients and fulfilled the inclusion criteria among 11,447 patients receiving coronary angiography (CAG) or percutaneous coronary intervention. PREDICTORS ACE-inhibitor/ARB use based on prescription and risk factors for contrast-induced AKI. OUTCOMES The incidence of contrast-induced AKI defined by AKI Network (AKIN) criteria: an absolute increase in serum creatinine levels ≥0.3 mg/dL or a relative increase ≥50% from baseline values within 48 hours after exposure to the contrast medium. MEASUREMENTS Baseline serum creatinine, hemoglobin, and albumin levels; volume of contrast agents; preprocedural medication; and post-CAG serum creatinine levels. RESULTS An ACE inhibitor/ARB was prescribed for 64.0% of patients receiving CAG. ACE-inhibitor/ARB users showed an increased incidence of contrast-induced AKI after propensity score matching (11.4% vs 6.3%; P < 0.001). In multivariable analysis, use of ACE inhibitors/ARBs remained an independent and significant predictor of contrast-induced AKI in an unmatched cohort (OR, 1.39; 95% CI, 1.10-1.76; P = 0.06). In the matched cohort, use of ACE inhibitors/ARBs also was associated with a higher adjusted OR of contrast-induced AKI (OR, 1.43; 95% CI, 1.06-1.94; P = 0.02). LIMITATIONS A retrospective study at a single center. CONCLUSIONS Use of ACE inhibitors/ARBs during CAG has a possible influence to increase the incidence of contrast-induced AKI. Further randomized clinical trials are warranted to confirm the effect of ACE-inhibitor/ARB therapy on the development of contrast-induced AKI.

Low-Dose Aspirin for Prevention of Cardiovascular Disease in Patients with Chronic Kidney Disease

Background Chronic kidney disease (CKD) is a major risk factor for the development of cardiovascular disease (CVD). Previous trials have investigated the effects of low-dose aspirin on CVD prevention in patients with diabetes; however, patients with CKD were not examined. The role of aspirin in diabetics is controversial, and the available literature is contradictory. Therefore, we studied whether low-dose aspirin would be beneficial for patients with CKD, a group that is at high risk for CVD. Method From a total of 25340 patients with CKD, 1884 recipients of low-dose aspirin (100 mg/day) were paired 1∶1 with non-recipients for analysis using propensity score matching. The primary endpoint was the development of atherosclerotic CVD, including coronary arterial disease, stroke, and peripheral arterial disease. Secondary endpoints included death from any cause, bleeding events, doubling of serum creatinine, and renal death. Results The incidence of a primary endpoint of any atherosclerotic CVD was significantly higher in the aspirin users than in the non-users (P<0.001). Secondary endpoints, including all-cause mortality and composite bleeding events, were not significantly different between the aspirin users and the non-users. However, the doubling of serum creatinine levels (P = 0.001) and renal death (P = 0.042) were significantly associated with the use of aspirin. Conclusion These results suggest that the use of low-dose aspirin in patients with CKD may have harmful consequences related to the development of CVD and renal progression.

Circulating levels of soluble receptor for advanced glycation end product are inversely associated with vascular calcification in patients on haemodialysis independent of S100A12 (EN-RAGE) levels.

The receptor for advanced glycation end products (RAGE) has emerged as a central regulator of vascular inflammation and atherosclerosis. Soluble RAGE (sRAGE) has an anti‐inflammatory effect by quenching ligands for RAGE. On the other hand, extracellular RAGE‐binding protein S100A12 (EN‐RAGE) shows a pro‐inflammatory effect in a way, but may play pleiotropic roles related to inflammatory process. Therefore, we determined the levels of sRAGE and S100A12 in haemodialysis (HD) patients and evaluated their relationship with vascular calcification.

Hyperuricemia Is an Independent Risk Factor for Mortality Only if Chronic Kidney Disease Is Present

Background/Aims: Hyperuricemia has been considered a risk factor for renal disease and cardiovascular disease. However, the potential contribution of hyperuricemia to mortality remains uncertain, and the results in the available literature vary according to kidney function. The aim of this study was to determine the association between hyperuricemia and mortality in patients undergoing percutaneous coronary intervention (PCI) across the interaction of kidney function. Method: We retrospectively reviewed patients who underwent PCI from 2003 to 2009. Propensity scores for hyperuricemia (>7 mg/dl for males and >6 mg/dl for females) were used to assemble a matched cohort of 693 pairs of patients with and without hyperuricemia for analysis from the 3,201 patients who fulfilled the inclusion criteria among the 4,842 patients who underwent PCI. Results: Of the 3,201 patients who underwent PCI and for whom data were available regarding their baseline serum uric acid level, 763 (23.8%) had hyperuricemia. The hyperuricemia-associated hazard ratios (HRs) [95% confidence intervals (CIs)] for all-cause mortality were 1.780 (1.270-2.495) in the unmatched cohort and 1.655 (1.109-2.468) in the matched cohort. The HRs (95% CI) for all-cause mortality among those with and without chronic kidney disease (CKD) were 2.080 (1.318-3.283) and 1.592 (0.778-3.256), respectively (p for interaction, 0.001). Conclusions: Hyperuricemia is an independent risk factor for all-cause mortality in those patients with CKD but not in those without CKD.

Klotho and S100A8/A9 as Discriminative Markers between Pre-Renal and Intrinsic Acute Kidney Injury.

Early detection and accurate differentiation of the cause of AKI may improve the prognosis of the patient. However, to date, there are few reliable biomarkers that can discriminate between pre-renal and intrinsic AKI. In this study, we determined whether AKI is associated with altered serum and urinary levels of Klotho, S100A8/A9 (an endogenous ligand of toll-like receptor 4), and neutrophil gelatinase-associated lipocalin (NGAL), which may allow differentiation between pre-renal and intrinsic AKI. A volume-depleted pre-renal AKI model was induced in male Sprague Dawley rats fed a low-salt diet (0.03%) without water 96 h before two intraperitoneal (IP) injections of furosemide (20 mg/kg) at a 24 h interval. In contrast, in the cisplatin-induced intrinsic AKI model, animals were given a single IP injection of cisplatin (5 mg/kg). All of the animals were euthanized 72 h after the first IP injection. Serum and urinary levels of Klotho, S100A8/A9, and NGAL were measured using an enzyme-linked immunosorbent assay. We also performed a proof-of-concept cross-sectional study to measure serum and urinary biomarkers in 61 hospitalized patients with established AKI. Compared to the intrinsic AKI group, the pre-renal AKI group showed a marked depression in urinary Klotho levels (13.21±17.32 vs. 72.97±17.96 pg/mL; P = 0.002). In addition, the intrinsic AKI group showed marked elevation of S100A8/A9 levels compared to the pre-renal AKI group (2629.97±598.05 ng/mL vs. 685.09±111.65 ng/mL; P = 0.002 in serum; 3361.11±250.86 ng/mL vs. 741.72±101.96 ng/mL; P = 0.003 in urine). There was no difference in serum and urinary NGAL levels between the pre-renal and intrinsic AKI groups. The proof-of-concept study with the hospitalized AKI patients also demonstrated decreased urinary Klotho in pre-renal AKI patients and increased urinary S100A8/A9 concentrations in intrinsic AKI patients. The attenuation of urinary Klotho and increase in urinary S100A8/A9 may allow differentiation between pre-renal and intrinsic AKI.

Associations between Soluble Receptor for Advanced Glycation End Products (sRAGE) and S100A12 (EN-RAGE) with Mortality in Long-term Hemodialysis Patients

Hemodialysis (HD) patients experience vascular calcification, ultimately leading to high mortality rates. Previously, we reported associations between soluble receptor for advanced glycation end products (sRAGEs) and extracellular newly identified RAGE-binding protein S100A12 (EN-RAGE) and vascular calcification. Here, we extended our observations, investigating whether these biomarkers may be useful for predicting cardiovascular morbidity and mortality in these subjects. Thus, we evaluated the relationship between sRAGE and S100A12 and mortality in long-term HD patients. This was a prospective observational cohort study in 199 HD patients from an extended analysis of our previous study. Plasma sRAGE, S100A12, comorbidities, and other traditional risk factors were investigated. The cumulative incidences for death using Cox proportional hazards regression were evaluated in multivariable analyses. The observation period was 44 months. During the observation period, 27 (13.6%) patients died. Univariate analysis demonstrated that S100A12 was correlated with diabetes (P = 0.040) and high-sensitivity C-reactive protein (hsCRP) (P = 0.006). In multivariable analyses, plasma sRAGE (hazard ratio [HR] = 1.155; 95% confidence interval [CI] = 0.612–2.183; P = 0.656) and S100A12 (HR = 0.960; 95% CI = 0.566–1.630; P = 0.881) were not associated with mortality in HD patients, although traditional predictors of mortality, including age, history of cardiovascular diseases (CVDs), and serum levels of albumin and hsCRP were related to mortality. Powerful predictors of mortality were age, CVD, and albumin levels. Plasma sRAGE and S100A12 may be weak surrogate markers for predicting all-cause mortality in patients undergoing HD, although S100A12 was partly related to diabetes and inflammation.

Renin-Angiotensin-Aldosterone System Blockade in Critically Ill Patients Is Associated with Increased Risk for Acute Kidney Injury.

Acute kidney injury (AKI) is a major clinical problem and a predictor of outcomes in critically ill patients who frequently required treatments in the intensive care unit (ICU). Renin-angiotensin-aldosterone system (RAAS) blockers are commonly used for treating hypertension but demands caution because of accompanying illnesses including AKI. The aim of this study was to evaluate whether the use of RAAS blockers affected the incidence of AKI in ICU patients. From a total of 26,287 patients who were admitted to the ICU from January 2003 to December 2013 were included in the final analyses. The primary outcome was the incidence of AKI based on the prescription of RAAS blockers. The secondary outcomes were all-cause mortality. RAAS blocker users were more likely to develop AKI (P < 0.001) and remained an independent risk factor for AKI (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.37-1.79; P < 0.001) after adjusting confounding factors. There was no significant difference in the cumulative 90-day survival rate between the RAAS blocker users and non-users (P = 0.381). However, the adjusted mortality risk associated with AKI was 1.38 (95% CI, 1.22 to 1.56; P < 0.001) and increased as the severity of AKI stage increased from 1 to 3: 1.17 (1.02 to 1.36), 1.77 (1.45 to 2.16), and 1.93 (1.55 to 2.41; P < 0.01 for the trend). RAAS blockers may have a harmful influence to increase the incidence of AKI and temporary withholding of these medications may deserve careful consideration in ICU patients.

The Impact of Renin-Angiotensin System Blockade on Renal Outcomes and Mortality in Pre-Dialysis Patients with Advanced Chronic Kidney Disease.

Renin-angiotensin-system (RAS) blockade is thought to slow renal progression in patients with chronic kidney disease (CKD). However, it remains uncertain if the habitual use of RAS inhibitors affects renal progression and outcomes in pre-dialysis patients with advanced CKD. In this multicenter retrospective cohort study, we identified 2,076 pre-dialysis patients with advanced CKD (stage 4 or 5) from a total of 33,722 CKD patients. RAS blockade users were paired with non-users for analyses using inverse probability of treatment-weighted (IPTW) and propensity score (PS) matching. The outcomes were renal death, all-cause mortality, hospitalization for hyperkalemia, and interactive factors as composite outcomes. RAS blockade users showed an increased risk of renal death in PS-matched analysis (hazard ratio [HR], 1.381; 95% CI, 1.071–1.781; P = 0.013), which was in agreement with the results of IPTW analysis (HR, 1.298; 95% CI, 1.123–1.500; P < 0.001). The risk of composite outcomes was higher in RAS blockade users in IPTW (HR, 1.154; 95% CI, 1.016–1.310; P = 0.027), but was marginal significance in PS matched analysis (HR, 1.243; 95% CI, 0.996–1.550; P = 0.054). The habitual use of RAS blockades in pre-dialysis patients with advanced CKD may have a detrimental effect on renal outcome without improving all-cause mortality. Further studies are warranted to determine whether withholding RAS blockade may lead to better outcomes in these patients.

Efficacy of Statin Treatment in Early-Stage Chronic Kidney Disease

Chronic kidney disease (CKD) represents a major medical challenge and frequently coexists with cardiovascular disease (CVD), which can be treated by statin trerapy. However, whether statin treatment affects renal progression and outcomes in CKD patients remains unclear. We retrospectively reviewed CKD patients at Gachon University Gil Medical Center from 2003–2013. From a total of 14,497 CKD patients, 858 statin users were paired with non-users and analyze with propensity score matching was performed. The outcomes of this study were creatinine doubling, renal death, all-cause mortality, and interactive factors for composite outcomes. Statins were prescribed to 13.5% of the study subjects. Hazard ratios (HRs) [95% confidence intervals (CIs)] for statin treatment for the doubling of serum creatinine levels were significant only in CKD patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, and were 0.744 (0.635–0.873) in the unmatched cohort and 0.767 (0.596–0.986) in the matched cohort. In analyses of secondary outcomes, the HRs (95% CIs) for all-cause mortality were 0.655 (0.502–0.855) in the unmatched cohort and 0.537 (0.297–0.973) in the matched cohort. The HRs (95% CIs) for statin therapy for composite outcomes among patients with and without an eGFR ≥30 mL/min/1.73 m2 were 0.764 (0.613–0.952) and 1.232 (0.894–1.697), respectively (P for interaction, 0.017). Thus, statin treatment may have beneficial effects on renal progression and all-cause mortality only for the patients with early- stage CKD.

Outcomes of hepatitis B surface antigenaemia in patients with incident end‐stage renal disease

Hepatitis B virus (HBV) infection is an important risk factor for morbidity and mortality in the general population. However, limited data are available on the progression of HBV infection in patients with end‐stage renal disease (ESRD), and available data are controversial. Therefore, we investigated the association between hepatitis B surface antigen (HBsAg) seropositivity and mortality in patients with incident ESRD.