Kidney Failure Prediction Models: A Comprehensive External Validation Study in Patients with Advanced CKD

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Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

Both fibroblast growth factor 23 (FGF-23) and asymmetric dimethylarginine (ADMA) are associated with progression of CKD. We tested the hypothesis that ADMA and FGF23 are interactive factors for CKD progression in a cohort of 758 patients with CKD in Southern Europe (mean eGFR±SD, 36±13 ml/min per 1.73 m²) and in a central European cohort of 173 patients with CKD (MMKD study, mean eGFR, 64±39 ml/min per 1.73 m²). In the first cohort, 214 patients had renal events (decrease in eGFR of >30%, dialysis, or kidney transplantation) during a 3-year follow-up. Both intact FGF-23 and ADMA predicted the incidence rate of renal events in unadjusted and adjusted analyses (P<0.001). There was a strong competitive interaction between FGF-23 and ADMA in the risk of renal events (P<0.01 in adjusted analyses); the risk associated with raised ADMA levels was highest in patients with low FGF-23 levels. These results were confirmed in the MMKD cohort, in which FGF-23 level was again an effect modifier of the relationship between plasma ADMA level and renal events (doubling of baseline serum creatinine, dialysis, or kidney transplantation) in the adjusted analyses (P<0.01). Furthermore, in the MMKD cohort there was a parallel, independent competitive interaction between symmetric dimethylarginine level and c-terminal FGF-23 level for the risk for renal events (P=0.001). These findings indicate that the association of ADMA level with the risk of CKD progression is modified by FGF-23 level and provide further evidence that dysregulation of the nitric oxide system is involved in CKD progression.     

Fracture Burden and Risk Factors in Childhood CKD: Results from the CKiD Cohort Study

Childhood chronic kidney disease (CHD) poses multiple threats to bone accrual; however, the associated fracture risk is not well characterized. This prospective cohort study included 537 CKD in Children (CKiD) participants. Fracture histories were obtained at baseline, at years 1, 3, and 5 through November 1, 2009, and annually thereafter. We used Cox regression analysis of first incident fracture to evaluate potential correlates of fracture risk. At enrollment, median age was 11 years, and 16% of patients reported a prior fracture. Over a median of 3.9 years, 43 males and 24 females sustained incident fractures, corresponding to 395 (95% confidence interval [95% CI], 293–533) and 323 (95% CI, 216–481) fractures per 10,000 person-years, respectively. These rates were 2- to 3-fold higher than published general population rates. The only gender difference in fracture risk was a 2.6-fold higher risk in males aged ≥15 years (570/10,000 person-years, adjusted P=0.04). In multivariable analysis, advanced pubertal stage, greater height Z-score, difficulty walking, and higher average log-transformed parathyroid hormone level were independently associated with greater fracture risk (all P≤0.04). Phosphate binder treatment (predominantly calcium-based) was associated with lower fracture risk (hazard ratio, 0.37; 95% CI, 0.15–0.91; P=0.03). Participation in more than one team sport was associated with higher risk (hazard ratio, 4.87; 95% CI, 2.21–10.75; P<0.001). In conclusion, children with CKD have a high burden of fracture. Regarding modifiable factors, higher average parathyroid hormone level was associated with greater risk of fracture, whereas phosphate binder use was protective in this cohort.     

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study

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Metabolic Factors and Microinflammatory State Promote Kidney Injury in Type 2 Diabetes Mellitus Patients

Objective. This study examined the associations among the factors of metabolic syndrome, microinflammatory state, and kidney injury in type 2 diabetes mellitus patients. Methods. A retrospective study was conducted on 914 type 2 diabetes mellitus patients from January 2007 to May 2008. We observed the prevalence of chronic kidney disease in different groups of type 2 diabetes mellitus patients, and analyzed the association between metabolic syndrome and chronic kidney disease. We chose 84 cases randomly from this cohort to test their inflammatory biomarkers including tumor necrosis factor α, interleukin-6, and C‐reactive protein to study the relationship to chronic kidney disease. Results. The prevalence of chronic kidney disease was 39.17% (358 patients), and patients with metabolic factors had a significantly higher prevalence of chronic kidney disease than without metabolic factors (40.90% vs. 17.65%, p < 0.01). The metabolic factors and microinflammatory biomarkers were significantly higher in patients with chronic kidney disease. Patients who had more abnormal metabolic factors also had higher levels of microinflammatory biomarkers, as well as higher risk of chronic kidney disease. Multiple logistic regression analyses revealed that systolic blood pressure, serum triglyceride, low density lipoprotein, age, and duration of diabetes were independent risk factors of chronic kidney disease in type 2 diabetes mellitus patients. Conclusions. The abnormality of metabolic factors in type 2 diabetes mellitus had a close relationship to the microinflammatory state and chronic kidney disease. Hypertension and hyperlipidemia were independent factors of chronic kidney disease in type 2 diabetes mellitus.     

Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis

The effectiveness of cisplatin, a mainstay in the treatment of many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes AKI in 30% of patients. Patients who do not develop AKI by clinical standards during treatment are still at risk for long-term decline in kidney function and the development of CKD. The connection between AKI and CKD has become increasingly studied, with renal fibrosis a hallmark of CKD development. To prevent both the short- and long-term effects of cisplatin, researchers must use models that reflect both types of pathology. Although a lot is known about cisplatin-induced AKI, very little is known about the mechanisms by which repeated low levels of cisplatin lead to fibrosis development. In this review, strategies used in various rodent models to prevent kidney injury, its progression to fibrosis, or both, are examined to gain mechanistic insights and identify potential therapeutic targets for cisplatin-induced kidney pathologies. Reviewing the results from these models highlights the diverse and highly complex role of cell death, cell senescence, endoplasmic reticulum stress, autophagy, and immune cell activation in acute and chronic kidney injuries. The use of several models of kidney injury is needed for development of agents that will prevent all aspects of cisplatin-induced kidney injury.     

Conventional and Genetic Evidence on the Association between Adiposity and CKD

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Electrocardiographic Measures and Prediction of Cardiovascular and Noncardiovascular Death in CKD

Limited studies have assessed the resting 12-lead electrocardiogram (ECG) as a screening test in intermediate risk populations. We evaluated whether a panel of common ECG parameters are independent predictors of mortality risk in a prospective cohort of participants with CKD. The Chronic Renal Insufficiency Cohort (CRIC) study enrolled 3939 participants with eGFR<70 ml/min per 1.73 m² from June 2003 to September 2008. Over a median follow-up of 7.5 years, 750 participants died. After adjudicating the initial 497 deaths, we identified 256 cardiovascular and 241 noncardiovascular deaths. ECG metrics were independent risk markers for cardiovascular death (hazard ratio, 95% confidence interval): PR interval ≥200 ms (1.62, 1.19–2.19); QRS interval 100–119 ms (1.64, 1.20–2.25) and ≥120 ms (1.75, 1.17–2.62); corrected QT (QTc) interval ≥450 ms in men or ≥460 ms in women (1.72, 1.19–2.49); and heart rate 60–90 beats per minute (1.21, 0.89–1.63) and ≥90 beats per minute (2.35, 1.03–5.33). Most ECG measures were stronger markers of risk for cardiovascular death than for all-cause mortality or noncardiovascular death. Adding these intervals to a comprehensive model of cardiorenal risk factors increased the C-statistic for cardiovascular death from 0.77 to 0.81 (P<0.001). Furthermore, adding ECG metrics to the model adjusted for standard risk factors resulted in a net reclassification of 12.1% (95% confidence interval 8.1%–16.0%). These data suggest common ECG metrics are independent risk factors for cardiovascular death and enhance the ability to predict death events in a population with CKD.     

Prevalence of CKD and Its Relationship to eGFR-Related Genetic Loci and Clinical Risk Factors in the SardiNIA Study Cohort

The prevalence of CKD and of renal failure vary worldwide, yet parallel increases in leading risk factors explain only part of the differential prevalence. We measured CKD prevalence and eGFR, and their relationship with traditional and additional risk factors, in a Sardinian founder population cohort. The eGFR was calculated using equations from the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease studies. With use of the Kidney Disease Improving Global Outcomes guidelines, a cross-sectional analysis of 4842 individuals showed that CKD prevalence was 15.1%, including 3.6% of patients in the high-risk and 0.46% in the very-high-risk categories. Longitudinal analyses performed on 4074 of these individuals who completed three visits with an average follow-up of 7 years revealed that, consistent with other populations, average eGFR slope was −0.79 ml/min per 1.73 m² per year, but 11.4% of the participants had an eGFR decline >2.3 ml/min per 1.73 m² per year (fast decline). A genetic score was generated from 13 reported eGFR- and CKD-related loci, and univariable and multivariable analyses were applied to assess the relationship between clinical, ultrasonographic, and genetic variables with three outcomes: CKD, change in eGFR, and fast eGFR decline. Genetic risk score, older age, and female sex independently correlated with each outcome. Diabetes was associated with CKD prevalence, whereas hypertension and hyperuricemia correlated more strongly with fast eGFR decline. Diabetes, hypertension, hyperuricemia, and high baseline eGFR were associated with a decline of eGFR. Along with differential health practices, population variations in this spectrum of risk factors probably contributes to the variable CKD prevalence worldwide.     

老年2型糖尿病脉压和早期肾损害的相关性

目的：探讨老年2型糖尿病脉压水平与早期肾损害的关系。方法：将216例糖尿病患者根据有无合并高血压分成正常血压组（D组）和合并高血压组（DH组）。每组根据脉压水平不同分为3个亚组,进行血清尿素氮（BUN）、肌酐（Scr）、尿微量白蛋白（MAU）、尿β2微球蛋白（β2-MG）、尿N-乙酰-B-D-氨基葡萄糖苷酶（NAG）测定,分析脉压与肾功能指标的关系。结果：随着脉压差的增大,两组3个亚组间尿MAU、β2-MG、NAG的比较差异均有统计学意义,早期肾功能损害指标与脉压正相关。结论：脉压是2型糖尿病早期肾脏损害的预测因素。     

Two-Week Burden of Arrhythmias across CKD Severity in a Large Community-Based Cohort: The ARIC Study

BackgroundCKD is associated with sudden cardiac death and atrial fibrillation (AF). However, other types of arrhythmia and different measures of the burden of arrhythmias, such as presence and frequency, have not been well characterized in CKD.MethodsTo quantify the burden of arrhythmias across CKD severity in 2257 community-dwelling adults aged 71–94 years, we examined associations of major arrhythmias with CKD measures (eGFR and albuminuria) among individuals in the Atherosclerosis Risk in Communities study. Participants underwent 2 weeks of noninvasive, single-lead electrocardiogram monitoring. We examined types of arrhythmia burden: presence and frequency of arrhythmias and percent time in arrhythmias.ResultsOf major arrhythmias, there was a higher prevalence of AF and nonsustained ventricular tachycardia among those with more severe CKD, followed by long pause (>30 seconds) and atrioventricular block. Nonsustained ventricular tachycardia was the most frequent major arrhythmia (with 4.2 episodes per person-month). Most participants had ventricular ectopy, supraventricular tachycardia, and supraventricular ectopy. Albuminuria consistently associated with higher AF prevalence and percent time in AF, and higher prevalence of nonsustained ventricular tachycardia. When other types of arrhythmic burden were examined, lower eGFR was associated with a lower frequency of atrioventricular block. Although CKD measures were not strongly associated with minor arrhythmias, higher albuminuria was associated with a higher frequency of ventricular ectopy.ConclusionsCKD, especially as measured by albuminuria, is associated with a higher burden of AF and nonsustained ventricular tachycardia. Additionally, eGFR is associated with less frequent atrioventricular block, whereas albuminuria is associated with more frequent ventricular ectopy. Use of a novel, 2-week monitoring approach demonstrated a broader range of arrhythmias associated with CKD than previously reported.