Chan Ho Kim

Circulating α-klotho levels in CKD and relationship to progression.

BACKGROUND α-Klotho is reported to have protective effects against kidney injury, and its renal expression is decreased in many experimental models of kidney disease. However, circulating α-klotho levels in human chronic kidney disease (CKD) and the relationship to progression are unknown. STUDY DESIGN Post hoc analysis of a prospective cohort study. SETTING & PARTICIPANTS 243 of 301 participants from a CKD cohort at our institution between January 2006 and December 2011 were eligible for the study. PREDICTOR Baseline α-klotho levels. OUTCOMES Primary outcome was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease, or death. End-stage renal disease was defined as onset of treatment by renal replacement therapy. MEASUREMENTS Serum α-klotho and fibroblast growth factor 23 (FGF-23) were measured using enzyme-linked immunosorbent assay. RESULTS Lower serum α-klotho levels were associated with more severe CKD stage in the cross-sectional analysis of the baseline data (P for trend < 0.001). In the adjusted multivariable linear regression model, log(α-klotho) was associated independently with estimated glomerular filtration rate (β = 0.154; P = 0.001). Cox regression analysis showed that baseline α-klotho level independently predicted the composite outcome after adjustment for age, diabetes, blood pressure, estimated glomerular filtration rate, proteinuria, parathyroid hormone level, and FGF-23 level (HR per 10-pg/mL increase, 0.96; 95% CI, 0.94-0.98; P < 0.001). When patients were categorized into 2 groups according to baseline median α-klotho value, 43 (35.2%) patients with α-klotho levels ≤396.3 pg/mL reached the primary composite outcome compared with 19 (15.7%) with α-klotho levels >396.3 pg/mL (HR, 2.03; 95% CI, 1.07-3.85; P = 0.03). LIMITATIONS Uncontrolled dietary phosphorus intake and use of frozen samples. CONCLUSIONS This observational study showed that low circulating α-klotho levels were associated with adverse kidney disease outcome, suggesting that α-klotho is a novel biomarker for CKD progression. More data from larger prospective longitudinal studies are required to validate our findings.

An increase in red blood cell distribution width from baseline predicts mortality in patients with severe sepsis or septic shock.

IntroductionA potential independent association was recently demonstrated between high red blood cell distribution width (RDW) and the risk of all-cause mortality in critically ill patients, although the mechanism underlying this relationship remains unclear. Little is known about the impact changes in RDW may have on survival in critically ill patients. Therefore, we investigated the prognostic significance of changes in RDW during hospital stay in patients with severe sepsis or septic shock.MethodsWe prospectively enrolled 329 patients who were admitted to the emergency department (ED) and received a standardized resuscitation algorithm (early-goal directed therapy) for severe sepsis or septic shock. The relationship between the changes in RDW during the first 72 hours after ED admission and all-cause mortality (28-day and 90-day) were analyzed by categorizing the patients into four groups according to baseline RDW value and ΔRDW72hr-adm (RDW at 72 hours – RDW at baseline).ResultsThe 28-day and 90-day mortality rates were 10% and 14.6%, respectively. Patients with increased RDW at baseline and ΔRDW72hr-adm >0.2% exhibited the highest risks of 28-day and 90-day mortality, whereas the patients with normal RDW level at baseline and ΔRDW72hr-adm ≤0.2% (the reference group) had the lowest mortality risks. For 90-day mortality, a significantly higher mortality risk was observed in the patients whose RDW increased within 72 hours of ED admission (normal RDW at baseline and ΔRDW72hr-adm >0.2%), compared to the reference group. These associations remained unaltered even after adjusting for age, sex, Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index, renal replacement therapy, albumin, hemoglobin, lactate, C-reactive protein and infection sites in multivariable models.ConclusionsWe found that an increase in RDW from baseline during the first 72 hours after hospitalization is significantly associated with adverse clinical outcomes. Therefore, a combination of baseline RDW value and an increase in RDW can be a promising independent prognostic marker in patients with severe sepsis or septic shock.

An increase in mean platelet volume from baseline is associated with mortality in patients with severe sepsis or septic shock.

Introduction Mean platelet volume (MPV) is suggested as an index of inflammation, disease activity, and anti-inflammatory treatment efficacy in chronic inflammatory disorders; however, the effect of MPV on sepsis mortality remains unclear. Therefore, we investigated whether the change in MPV between hospital admission and 72 hours (ΔMPV72h-adm) predicts 28-day mortality in severe sepsis and/or septic shock. Methods We prospectively enrolled 345 patients admitted to the emergency department (ED) who received standardized resuscitation (early goal-directed therapy) for severe sepsis and/or septic shock between November 2007 and December 2011. Changes in platelet indices, including ΔMPV72h-adm, were compared between survivors and non-survivors by linear mixed model analysis. The prognostic value of ΔMPV72h-adm for 28-day mortality was ascertained by Cox proportional hazards model analysis. Results Thirty-five (10.1%) patients died within 28 days after ED admission. MPV increased significantly during the first 72 hours in non-survivors (P = 0.001) and survivors (P < 0.001); however, the rate of MPV increase was significantly higher in non-survivors (P = 0.003). Nonetheless, the difference in the platelet decline rate over the first 72 hours did not differ significantly between groups (P = 0.360). In multivariate analysis, ΔMPV72h-adm was an independent predictor of 28-day mortality, after adjusting for plausible confounders (hazard ratio, 1.44; 95% confidence interval, 1.01–2.06; P = 0.044). Conclusions An increase in MPV during the first 72 hours of hospitalization is an independent risk factor for adverse clinical outcomes. Therefore, continuous monitoring of MPV may be useful to stratify mortality risk in patients with severe sepsis and/or septic shock.

DECREASED CIRCULATING KLOTHO LEVELS IN PATIENTS UNDERGOING DIALYSIS AND RELATIONSHIP TO OXIDATIVE STRESS AND INFLAMMATION

♦ Introduction: It has been reported that klotho deficiency is associated with oxidative stress and inflammation in experimental kidney disease models. Patients with endstage renal disease (ESRD) are particularly characterized by increased oxidative stress and inflammation. However, little is known about the relationship between these features and klotho in patients with ESRD. ♦ Methods: We conducted a single-center, cross-sectional study of 78 patients receiving peritoneal dialysis (PD). Serum concentrations of klotho, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and 8-isoprostane were measured by enzyme-linked immunosorbent assay. To define factors independently associated with klotho, we determined Spearman’s correlation coefficients for between co-variates and conducted multiple linear regression analyses. ♦ Results: Patients were classified by median concentration of klotho. In patients with klotho levels > 329.6 pg/mL, serum 8-isoprostane and IL-6 levels were significantly higher than in those with klotho levels < 329.6 pg/mL. In correlation analyses, log 8-isoprostane (γ = –0.310, p = 0.006) and log IL-6 (γ = –0.343, p = 0.002) were inversely correlated with log klotho. After adjustment for age, gender, mean arterial pressure, log intact parathyroid hormone, and log IL-6, log 8-isoprostane was independently associated with log klotho (β = –0.158, p = 0.040). However, the significant relationship between klotho and IL-6 was not seen in an adjusted model. ♦ Conclusions: This study showed that circulating klotho levels were significantly associated with 8-isoprostane levels in patients undergoing PD, suggesting a potential link between klotho deficiency and enhanced oxidative stress in ESRD patients.

Interdialytic Weight Gain and Cardiovascular Outcome in Incident Hemodialysis Patients

Background: Interdialytic weight gain (IDWG) has been regarded as a surrogate of volume overload, but also as a marker of a better nutritional status in end-stage renal disease (ESRD) patients on hemodialysis (HD). This paradoxical meaning of IDWG requires further investigation, particularly in adverse cardiovascular outcomes. Methods: A prospective cohort of 1,013 incident HD patients from 36 HD centers of the Clinical Research Center for ESRD in Korea was included. Patients were categorized into five groups according to the IDWG%, a ratio of absolute IDWG to dry weight: <1.0, ≥4.0, and every 1.0 increment in between. Primary outcome was major adverse cardiac and cerebrovascular events (MACCE). Results: During a mean follow-up of 18.7 months, primary outcome was observed in 104 patients (10.3%). In multivariate analysis, compared to patients with IDWG% of 1.0-1.9 (reference group), the hazard ratios (HRs) for primary outcome in the IDWG% <1.0, 2.0-2.9, 3.0-3.9, and ≥4.0 groups were 1.10 [95% confidence interval (CI) 0.55-2.20, p = 0.80], 1.15 (95% CI 0.59-2.27, p = 0.68), 1.80 (95% CI 0.95-3.41, p = 0.07), and 1.93 (95% CI 1.02-3.64, p = 0.04), respectively. Furthermore, even when residual renal function and 24-hour urine volume were adjusted, IDWG% ≥4.0 remained as a significant predictor of primary outcome (HR 2.03, 95% CI 1.02-4.02, p = 0.04). Conclusion: Increased IDWG% is a significant independent predictor of MACCE in incident HD patients. It could be helpful to prevent excessive IDWG for improving clinical outcomes in incident HD patients.

Progression of Aortic Arch Calcification Over 1 Year Is an Independent Predictor of Mortality in Incident Peritoneal Dialysis Patients

Backgrounds and Aims The presence and progression of vascular calcification have been demonstrated as important risk factors for mortality in dialysis patients. However, since the majority of subjects included in most previous studies were hemodialysis patients, limited information was available in peritoneal dialysis (PD) patients. Therefore, the aim of this study was to investigate the prevalence of aortic arch calcification (AoAC) and prognostic value of AoAC progression in PD patients. Methods We prospectively determined AoAC by chest X-ray at PD start and after 12 months, and evaluated the impact of AoAC progression on mortality in 415 incident PD patients. Results Of 415 patients, 169 patients (40.7%) had AoAC at baseline with a mean of 18.1±11.2%. The presence of baseline AoAC was an independent predictor of all-cause [Hazard ratio (HR): 2.181, 95% confidence interval (CI): 1.336–3.561, P = 0.002] and cardiovascular mortality (HR: 3.582, 95% CI: 1.577–8.132, P = 0.002). Among 363 patients with follow-up chest X-rays at 12 months after PD start, the proportion of patients with AoAC progression was significantly higher in patients with baseline AoAC (64.2 vs. 5.3%, P<0.001). Moreover, all-cause and cardiovascular death rates were significantly higher in the progression groups than in the non-progression group (P<0.001). Multivariate Cox analysis revealed that AoAC progression was an independent predictor for all-cause (HR: 2.625, 95% CI: 1.150–5.991, P = 0.022) and cardiovascular mortality (HR: 4.008, 95% CI: 1.079–14.890, P = 0.038) in patients with AoAC at baseline. Conclusions The presence and progression of AoAC assessed by chest X-ray were independently associated with unfavorable outcomes in incident PD patients. Regular follow-up by chest X-ray could be a simple and useful method to stratify mortality risk in these patients.

Urine output is associated with prognosis in patients with acute kidney injury requiring continuous renal replacement therapy.

PURPOSE Although some studies have found that early initiation of continuous renal replacement therapy (CRRT) is associated with better prognosis, no consensus exists on the best timing to start CRRT. We investigated whether the timing of CRRT initiation was relevant to overall mortality and explored which factors at the time of CRRT initiation were associated with better outcomes in critically ill patients with acute kidney injury (AKI). MATERIALS AND METHODS A total of 361 patients who received CRRT for AKI between 2009 and 2011 were collected and divided into 2 groups based on the median blood urea nitrogen (BUN) levels or 6-hour urine output immediately before CRRT was started. The impact of the timing of CRRT initiation stratified by BUN concentration or urine output on 28-day all-cause mortality was compared between groups. RESULTS When the timing of CRRT initiation was stratified by 6-hour urine output, 28-day all-cause mortality rates were significantly lower in the nonoliguric group compared with the oliguric group (P = .02). In contrast, clinical outcomes were not different between the low-BUN and the high-BUN groups (P = .30). Cox regression analysis revealed that 28-day all-cause mortality risk was significantly lower in the nonoliguric group stratified by 6-hour urine output, even after adjusting for age, sex, mean arterial pressure, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores, and serum biomarkers (hazard ratio, 0.85; 95% confidence interval, 0.65-0.99; P = .04). CONCLUSIONS Urine output but not BUN concentration was significantly associated with a better prognosis in critically ill patients with AKI requiring CRRT.

Clinical implication of crescentic lesions in immunoglobulin A nephropathy

BACKGROUND To date, there has been much controversy about the role of crescentic lesion as a significant prognostic factor in immunoglobulin A nephropathy (IgAN). This study evaluated whether crescentic lesions predict adverse renal outcomes in IgAN patients. METHODS A total of 430 patients with biopsy-proven IgAN between January 2000 and December 2009 were included. Histological variables of the Oxford classification (Oxford-MEST) and the presence of crescents were assessed. The primary endpoint was a 50% decline in estimated glomerular filtration rate. RESULTS Of the 430 patients, 81 (18.8%) had a crescentic lesion. During a mean follow-up of 61 months, the primary outcome occurred in 19 (23.5%) patients with crescents compared with 40 (11.5%) patients without crescents (P=0.01). A Kaplan-Meier plot showed that the 10-year renal survival rate was significantly lower in patients with crescents than patients without crescents (P=0.01). However, in a multivariable Cox analysis which included clinical factors and the Oxford-MEST, crescents were not significantly associated with an increased risk of developing the primary outcome [hazard ratio: 0.71, 95% confidence interval (CI) 0.36-1.41, P=0.33]. Furthermore, adding crescents to the Oxford-MEST did not improve the discriminative ability for the prediction of renal outcomes [c-statistic: 0.86 (0.81-0.91) vs. 0.86 (0.80-0.91), P=0.21]. CONCLUSION Crescentic lesion was not an independent prognostic factor, suggesting that crescents have limited value in predicting renal outcomes of IgAN.

Using the Oxford classification of IgA nephropathy to predict long-term outcomes of Henoch-Schönlein purpura nephritis in adults.

Recently, there has been emerging concern that crescents, the main histologic feature of Henoch–Schönlein purpura nephritis, merely reflect active inflammation, and may not be useful in predicting long-term outcomes. We therefore conducted a single-center retrospective study to evaluate whether the new Oxford classification of immunoglobulin A nephropathy can be used to predict long-term outcome in patients with Henoch–Schönlein purpura nephritis. We included 61 biopsy-proven patients with Henoch–Schönlein purpura nephritis between January 1991 and August 2010. In addition to the International Study of Kidney Disease in Children classification, pathologic findings were also evaluated by the Oxford classification. Primary outcomes were defined as either the onset of estimated glomerular filtration rate <60 ml/min per 1.73 m2 with ≥30% decrease in estimated glomerular filtration rate from baseline or end-stage renal disease. During a median follow-up of 49.3 months, 13 (21%) patients reached the primary end point. A Kaplan–Meier plot showed that renal event-free survival was significantly longer in patients with <50% crescents than in those with crescents in ≥50% of glomeruli (P=0.003). Among the components of the Oxford classification, patients with endocapillary hypercellularity (E1; P=0.016) and tubular atrophy/interstitial fibrosis (T1/T2; P=0.018) had lower renal survival rates than those with E0 and T0. In a multivariate Cox model adjusted for clinical and pathologic factors, E1 (hazard ratio=8.91; 95% confidence interval=1.47–53.88; P=0.017) and T1/T2 (hazard ratio=8.74; 95% confidence interval=1.40–54.38; P=0.020) were independently associated with reaching a primary outcome, whereas the extent of crescentic lesions was not. Our findings suggest that the Oxford classification can be used in predicting long-term outcomes of Henoch–Schönlein purpura nephritis.

The impact of dialysis modality on skin hyperpigmentation in haemodialysis patients

BACKGROUND Skin hyperpigmentation in end-stage renal disease (ESRD) patients has been attributed to the accumulation of middle-molecular-weight (MMW) substances. Although an MMW mechanism suggests that hyperpigmentation may be improved by high-flux haemodialysis (HF-HD) and haemodiafiltration (HDF), this possibility has not been explored. In the present study, we investigated the impact of different dialysis modalities on skin colour in HD patients. METHODS Eighty-two ESRD patients on HD were divided into low-flux HD (LF-HD), HF-HD and HDF groups. The melanin index (MI) and erythema index (EI) of the abdomen and the flexor side of the forearm (non-sun-exposed areas) and the forehead (sun-exposed area) were determined by using a narrow-band reflectance spectrophotometer at baseline and after 12 months. RESULTS Even though absolute values of baseline and follow-up MI and EI of the three sites were comparable among the three groups, forehead MI and EI were significantly decreased after 12 months in the HDF group (P < 0.05). In addition, the change in forehead MI was significantly greater in the HDF than in the LF-HD group (-1.0 +/- 2.4% versus 0.3 +/- 1.6%, P < 0.05). Moreover, beta(2)-microglobulin reduction rates were negatively correlated with both changes in forehead MI (P < 0.01) and EI (P < 0.05). CONCLUSIONS Skin colour of sun-exposed areas was signi- ficantly decreased in ESRD patients receiving HDF therapy, suggesting that enhanced removal of MMW substances by convection may prevent or reduce hyperpigmentation in HD patients.