Cystatin C, kidney function and cardiovascular disease

Cystatin C, an endogenous low-molecular-weight marker of glomerular filtration rate, has recently been shown to be associated with future cardiovascular disease in healthy elderly populations and patients with documented atherosclerosis in a dose-dependent manner that possibly reflects a very early stage of chronic renal dysfunction. At the same time, local cystatin C deficiency has been demonstrated in atherosclerotic and aneurismal lesions, suggesting a protective role of cystatin C in the vessel wall, possibly in concert with TGF-β1. Although cystatin C is not an acute phase reactant, large epidemiological studies have documented a highly significant association between serum cystatin C and mildly increased C-reactive protein (CRP) levels, the hallmark of the chronic inflammatory state associated with atherosclerosis and chronic renal failure. Since cystatin C is produced by all nucleated cells, it is unlikely that local variations in cystatin C synthesis in diseased arteries – rather than global cystatin C production and renal elimination – should determine its serum concentration. Consequently, the present review proposes microinflammation as the unifying concept for both lines of evidence.An erratum to this article can be found at     

Cystatin C/creatinine ratio in pediatric kidney disease

Clinical and Experimental Nephrology -     

Cystatin C as a marker of renal function in kidney transplant patients

INTRODUCTION: Serum creatinine (sCr) is the most commonly used biochemical parameter for gauging kidney function, but, due to its limitations, it is not the ideal marker for glomerular filtration rate (GFR). Cystatin C (sCyC) appears to be an endogenous marker of GFR. AIM: To assess the use of sCyC as a marker of renal function in kidney transplant patients, we compared it with sCr and with creatinine clearance either in a 24-hour urine or calculated using the Cockroft-Gault formula. METHODS: Among 78 patients (62.8% men, 37.2% women) undergoing kidney transplantation (average age 44.87 +/- 13.37 years) we determined at 2, 5, 7, 15, and 30 days, and 6, 12 and 18 months after kidney transplantation: sCr (using the Jaffé colorimetric method), sCyC (immunonephelometry), creatinine clearance with a 24-hour urine, creatinine clearance using the Cockroft-Gault formula. RESULTS: During the first 30 days following transplantation, there was a progressive decline in sCr levels. sCyC increased up to the fifth day, coinciding with the highest doses of steroids, and then decreased. At 6, 12, and 18 months, there was a correlation between sCyC and sCr, creatinine clearance in a 24-hour urine or calculated with the Cockroft-Gault formula (R = 0.859; R = -0.713, and R = -0.684, respectively, P < .001.) CONCLUSIONS: sCyC is an endogenous marker of GFR. Its limitations relate to its being affected by the high doses of steroids in the first days following transplantation. In the 18-month posttransplant period, it correlated with creatinine clearance in a 24-hour urine or calculated by the Cockroft-Gault formula.     

Cystatin C identifies chronic kidney disease patients at higher risk for complications

Although cystatin C is a stronger predictor of clinical outcomes associated with CKD than creatinine, the clinical role for cystatin C is unclear. We included 11,909 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) and assessed risks for death, cardiovascular events, heart failure, and ESRD among persons categorized into mutually exclusive groups on the basis of the biomarkers that supported a diagnosis of CKD (eGFR <60 ml/min per 1.73 m(2)): creatinine only, cystatin C only, both, or neither. We used CKD-EPI equations to estimate GFR from these biomarkers. In MESA, 9% had CKD by the creatinine-based equation only, 2% had CKD by the cystatin C-based equation only, and 4% had CKD by both equations; in CHS, these percentages were 12, 4, and 13%, respectively. Compared with those without CKD, the adjusted hazard ratios (HR) for mortality in MESA were: 0.80 (95% CI 0.50 to 1.26) for CKD by creatinine only; 3.23 (95% CI 1.84 to 5.67) for CKD by cystatin C only; and 1.93 (95% CI 1.27 to 2.92) for CKD by both; in CHS, the adjusted HR were 1.09 (95% CI 0.98 to 1.21), 1.78 (95% CI 1.53 to 2.08), and 1.74 (95% CI 1.58 to 1.93), respectively. The pattern was similar for cardiovascular disease (CVD), heart failure, and kidney failure outcomes. In conclusion, among adults diagnosed with CKD using the creatinine-based CKD-EPI equation, the adverse prognosis is limited to the subset who also have CKD according to the cystatin C-based equation. Cystatin C may have a role in identifying persons with CKD who have the highest risk for complications.     

Vascular calcification and cardiovascular function in chronic kidney disease.

BACKGROUND: Vascular calcification and arterial stiffening are independent predictors of all causes and cardiovascular mortality in chronic kidney disease (CKD). Few data are currently available comparing vascular calcification and its attendant functional cardiovascular consequences between CKD stage 4 patients and both peritoneal dialysis (PD) and haemodialysis (HD) (CKD stage 5) patients. METHOD: We studied 134 subjects (60 HD, 28 PD and 46 CKD 4). Vascular calcification was quantified using multi-slice spiral CT scanning of a 5 cm standardized segment of superficial femoral artery. Pulse wave analysis and pulse wave velocity were assessed using applanation tonometry, to determine arterial compliance. Further digital arterial pulse wave analysis was used to measure systemic haemodynamic variables. All medications were recorded and biochemical variables were time averaged for the 6 months prior to entering the study. RESULTS: Forty-seven percent of CKD 4 patients demonstrated vascular calcification as compared with CKD 5 (71% PD and 73% HD, P = 0.02). HD patients had higher calcification scores (median 121) than either PD (median 21) or CKD 4 (median 0) (P = 0.008). There were no significant differences in baseline characteristics between the groups. Comparing tertiles of patients (based on calcification score), increased calcification score was associated with a reduction in arterial compliance (mean PWV 8.9 +/- 1.1, 11 +/- 3.6, 11.3 +/- 3.7 m/s, P = 0.005). The degree of calcification did not influence systolic blood pressure (BP), diastolic BP or heart rate. However, more heavily calcified patients demonstrated significantly higher mean pulse pressures (58 +/- 19, 74 +/- 22 and 72 +/- 25 mmHg, P = 0.001), lower total peripheral resistance (1.5 +/- 1, 1.3 +/- 0.8, 0.9 +/- 0.4, P = 0.01) and higher stroke volume (84 +/- 25, 95 +/- 29, 106 +/- 39 ml, P = 0.01). More heavily calcified patients were significantly older and predominantly male. CONCLUSION: This study has successfully utilized a novel technique for the quantification of calcification. We have demonstrated vascular calcification and associated cardiovascular dysfunction in CKD 4, PD and HD with significant differences between the groups. Thirty percent of individuals show no calcification, even those established on renal replacement therapy for a prolonged period of time. Further work is required to identify factors which promote progression of arterial calcification in those who are susceptible.     

胱抑素C对评价慢性肾脏病患者代谢指标的应用价值

目的 研究胱抑素C对慢性肾脏病患者代谢指标及心脏疾病患病率的评价作用.方法 制作慢性肾脏病患者估算肾小球滤过率、血清肌酐、胱抑素C分别与血红蛋白、血钾、碳酸氢根、血磷散点图,并行直线回归相关分析.使用完全随机设计的单因素ANOVA分析胱抑素C与慢性肾脏病患者心脏疾病关系.结果 胱抑素C在评价慢性肾脏病患者贫血程度、高钾血症、高磷血症中的作用优于估算肾小球滤过率及血清肌酐.胱抑素C及血清肌酐在评价慢性肾脏病患者代谢性酸中毒的作用优于估算肾小球滤过率.胱抑素C水平高低与慢性肾脏病患者的心脏疾病的患病率成正相关(P＜0.05).结论 通过估算肾小球滤过率和血清肌酐,胱抑素C在评价慢性肾脏病患者代谢指标方面及评估患者心脏疾病患病率方面存在优势.     

Cystatin C and creatinine after successful kidney transplantation in children

BACKGROUND: Serum creatinine is commonly used for the monitoring of allograft function following renal transplantation (RTX). Due to lower muscle mass, creatinine production rate is reduced in children, thus decreasing its sensitivity for the detection of allograft dysfunction. In children, the serum concentration of cystatin C, a low molecular weight protein of 13.3 kDa, reflects glomerular filtration rate independent of age, height and body composition. We, therefore, sought to assess the potential of cystatin C as a marker of allograft function in children. METHODS: Cystatin C and creatinine were measured in parallel at least daily in 24 children (14 boys, 10 girls; mean age 10.5+/-5.1 years) during hospitalization after successful RTX. Cystatin was determined immunoturbidimetrically, creatinine enzymatically. RESULTS: Within one hour after RTX, cystatin C (mean+/-SE) almost halved from 6.69+/-0.45 mg/l to 3.69+/-0.38 mg/l while creatinine declined from 862 +/-65.4 to 633+/-62.9 micromol/l. Following a nadir of 1.82+/-0.18 mg/l on day 2, there was a secondary increase in cystatin C concentrations to 2.69+/-0.35 mg/l on day 10. Creatinine concentrations continued to decline until day 9 reaching 80.5+/-13.1 micromol/l. Day-to-day variation at steady-state was comparable. In the course of 9 acute rejection episodes, both parameters rose in parallel, the increase in creatinine concentration being much greater. CONCLUSION: Cystatin C was an early indicator of allograft function following successful RTX in children. It did not prove superior to creatinine for the recognition of acute allograft dysfunction, however.     

血清胱抑素C应用于急性肾损伤分级的研究

目的 探讨血清胱抑素C（Cystatin C,Cys C）应用于危重患者急性肾损伤（acute kidney injury,AKI）的分级,初步分析Cys C对患者短期病死率的预测作用.方法 筛查2009年8月至2010年4月四川大学华西医院重症监护病房（intense care unit,ICU）所有住院患者共4 642例,记录患者一般情况,建立数据库.参照AKI网络（acute kidney injury network,AKIN）分期标准,按照Cys C增加达到基线值的1.5倍,Cys C升高至2倍以上,Cys C升高至3倍以上.做成Cys C标准并分成三期,分别采用Cys C标准和AKIN标准对所有患者进行诊断和分期,比较2种标准的诊断敏感性及预测患者30 d死亡的精确性.结果 共有1 036例危重患者纳入研究.Cys C标准与AKIN标准诊断的危重患者AKI发病率比较,差异无统计学意义（34.2% 比 36.2%,P＞0.05）.Cys C标准与AKIN标准诊断的AKI患者的30 d病死率以及对应各期患者的30 d病死率比较,差异均无统计学意义（P＞0.05）.Logistic回归分析显示,根据Cys C标准和AKIN分期标准评估对应各期AKI患者发生院内死亡的相对危险度均较为接近.Cys C标准和AKIN的AKI分期标准预测患者30 d死亡的ROC曲线下面积分别为 0.680 和 0.722（P＜0.01）.一致性检验显示,AKIN标准中AKI 1期与AKI 2期区别无统计学意义（P＞0.05）,与AKI 3期区别有统计学意义（P＜0.05）;AKI 2期与AKI 3期区别无统计学意义（P＞0.05）;而Cys C标准仅AKI 2期与AKI 3期区别无统计学意义（P＞0.05）.结论 与AKIN标准比较,Cys C标准在对危重患者AKI诊断的敏感性及患者30 d死亡预测的精确性方面未显示出明显的优势,但是对于AKI各分级间的分辨率较AKIN标准好.     

Anemia and cardiovascular and kidney disease

PURPOSE OF REVIEW: The joint occurrence of cardiovascular disease, kidney disease and anemia has been termed the 'cardio-renal-anemia syndrome'. This review will examine each of these relationships as they pertain to coronary heart disease. RECENT FINDINGS: Important contributions from the recent literature included observations suggesting that African-Americans with chronic kidney disease and no previous history of cardiovascular disease were more likely than caucasians to have incident cardiovascular disease than caucasians with chronic kidney disease but that this difference did not apply to risk of recurrent cardiovascular disease. Recent reports have brought attention to a continued lack of clinical trials evidence to support anemia treatment for cardioprotection, further concern that higher hemoglobin levels may increase cardiovascular risk and evidence that anemia and kidney function interact to increase risk for coronary heart disease. Finally, additional observational studies and small clinical trials continue to support a role of anemia treatment in protection of residual kidney function, although a recent meta-analysis failed to demonstrate a conclusive benefit of erythropoietin treatment on progressive kidney disease. SUMMARY: The cardio-renal-anemia syndrome is a set of complex and interrelated phenomena that are poorly understood. Current evidence is insufficient to demonstrate a conclusive benefit of treatment with erythropoietin on risk of cardiovascular disease or progression of kidney disease. Future research is needed to further clarify these issues.     

Cystatin C and serum creatinine as predictors of kidney graft outcome

Purpose

Serum cystatin C (Cys C) was evaluated as a predictor of kidney graft failure progression, and its predictive ability was compared to other markers of graft function.

Methods

The following kidney graft markers were determined in 91 patients who came for regular checkups of kidney graft function to our outpatient service in February 2008: Cys C, serum creatinine (sCr), 24-h proteinuria and 24-h urinary creatinine clearance (CCr). Glomerular filtration rate (eGFR) was estimated using sCr-based and Cys C formula. Patients were regularly monitored until February 2013 or to graft failure.

Results

During follow-up, graft failure occurred in 21 recipients. The Cys C ≥2.65 mg/l discriminated patients with and without graft failure (sensitivity of 80.95 % and specificity of 92.86 %). According to c statistic, the highest performance was achieved for Cys C (0.874). In addition, Cys C area under the curve (AUC) was significantly better than CCr AUC (p = 0.007), 24-h proteinuria AUC (p = 0.03), eGFR estimated by the chronic kidney disease epidemiology collaboration (EPI) AUC (p = 0.05), but not better than sCr or eGFR AUCs calculated by other formulas. In the multivariable model, sCr, CCr, Cys C and eGFRs were predictors of graft failure. Combination of Cys C, sCr and logarithm of 24 h proteinuria (0.883) or Cys C, CCr and logarithm of 24-h proteinuria (0.884) had the highest AUC for predicting graft outcome that exceed insignificantly Cys C or sCr areas.

Conclusions

The most reliable predictors of graft outcome were Cys C, sCr and proteinuria. Because Cys C is unavailable in many transplant centers, from the practical point of view, sCr remains the most sensitive predictor of graft outcome.     

Epidemiology of non-dialysis-requiring chronic kidney disease and cardiovascular disease

PURPOSE OF REVIEW: To review recent literature about the relationship between non-dialysis-requiring chronic kidney disease and cardiovascular disease as well as possible explanatory factors. RECENT FINDINGS: Reduced estimated glomerular filtration rate below 60 ml/min/1.73 m independently predicts the risk of death and cardiovascular events in persons with or without known cardiovascular disease as well as those undergoing coronary or peripheral arterial revascularization. This risk is not linearly associated with level of kidney function. Chronic kidney disease is associated with a larger burden of traditional vascular risk factors but is also linked to abnormalities in a variety of nontraditional pathways such as dysregulation of mineral metabolism and arterial calcification, vessel stiffness and endothelial dysfunction, insulin resistance, inflammation, malnutrition, and anemia, among others. Other novel kidney-specific proteins (e.g. renalase) may play direct mediating roles. The relative contribution of these factors to excess cardiovascular disease in chronic kidney disease remains unclear. SUMMARY: Recent evidence demonstrates the importance of non-dialysis-requiring chronic kidney disease as a potent predictor of cardiovascular disease and its complications. Randomized trials should be performed to determine whether modification of traditional and nontraditional risk factors can reduce incident cardiovascular disease as well as which interventions can optimize treatment outcomes in persons with chronic kidney disease and cardiovascular disease.     

Homocysteine,renal function,and risk of cardiovascular disease

BACKGROUND: Patients with renal impairment have markedly elevated homocysteine levels and are at particularly high risk of ischemic heart disease (IHD) and stroke, but the relevance of elevated homocysteine levels in this population is uncertain. METHODS: We examined the association with IHD from a meta-analysis of 30 population studies of differences in homocysteine concentrations (involving 5000 IHD and 1100 stroke events in apparently healthy individuals), and from a meta-analysis of 40 studies (involving 11,000 IHD events) of the association of methylene-tetrahydrofolate reductase (MTHFR) and homocysteine with IHD. We explored the association of renal function with homocysteine levels in a cross-sectional study of 1200 healthy elderly individuals. RESULTS: Among prospective studies, a 25% lower blood homocysteine level was associated with an 11% lower risk of IHD and about a 20% lower risk of stroke, after adjustment for known cardiovascular risk factors. Individuals who had the TT genotype for MTHFR compared with those with CC had 25% higher homocysteine levels and a 16% higher risk of IHD. Among individuals aged over 65 years, a 1% higher serum creatinine level was associated with about a 1% higher homocysteine concentration. CONCLUSIONS: The concordance of the IHD risks obtained in the studies of genetically determined differences in homocysteine and the population-based studies of homocysteine suggest that these associations are likely to be causal. Renal function is an important determinant of circulating homocysteine concentrations. Results of ongoing randomized trials of folic acid-based vitamins in patients with renal disease are required to clarify the relevance of lowering homocysteine for vascular disease.     

Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease

Renal function impairment goes along with a disturbed calcium, phosphate, and vitamin D metabolism, resulting in secondary hyperparathyroidism (sHPT). These mineral metabolism disturbances are associated with soft tissue calcifications, particularly arteries, cardiac valves, and myocardium, ultimately associated with increased risk of mortality in patients with chronic kidney disease (CKD). sHPT may lead to cardiovascular calcifications by other mechanisms including an impaired effect of parathyroid hormone (PTH), and a decreased calcium-sensing receptor (CaR) expression on cardiovascular structures. PTH may play a direct role on vascular calcifications through activation of a receptor, the type-1 PTH/PTHrP receptor, normally attributed to PTH-related peptide (PTHrP). The CaR in vascular cells may also play a role on vascular mineralization as suggested by its extremely reduced expression in atherosclerotic calcified human arteries. Calcimimetic compounds increasing the CaR sensitivity to extracellular calcium efficiently reduce serum PTH, calcium, and phosphate in dialysis patients with sHPT. They upregulate the CaR in vascular cells and attenuate vascular mineralization in uremic states. In this article, the pathophysiological mechanisms associated with cardiovascular calcifications in case of sHPT, the impact of medical and surgical correction of sHPT, the biology of the CaR in vascular structures and its function in CKD state, and finally the role played by the CaR and its modulation by the calcimimetics on uremic-related cardiovascular calcifications are reviewed.     

Chronic kidney disease and cardiovascular disease in the Medicare population

BACKGROUND: The extent of diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD) in the Medicare population is relatively unknown. Also unknown is the effect of these diseases on patient survival before end-stage renal disease (ESRD). METHODS: Prevalent cohorts of Medicare enrollees from 1996 to 2000 were assessed for diabetes and CKD, presence of CVD, and probability of death versus ESRD in the follow-up period. Hospitalization rates and, in diabetics, lipid testing and glycemic control monitoring were also assessed. RESULTS: The prevalence of diabetes in the Medicare population increased at 4.4% per year, reaching 18.9% in the 1999-2000 cohort. Approximately 726,000 elderly Medicare enrollees carry a diagnosis code for CKD. Those with CKD are 5 to 10 times more likely to die before reaching ESRD than the non-CKD group. In CKD patients, CVD is twice as common and advances at twice the rate. Cardiovascular disease advances at a similarly higher rate in CKD patients who die and those who survive to ESRD. Heart failure hospitalizations are 5 times greater in CKD patients and only 30% less than those in dialysis patients. Only half of the CKD patients with diabetes who advance to ESRD had a lipid or glycosylated hemoglobin test done in the year before or after dialysis initiation. CONCLUSION: Diabetes, the leading cause of ESRD, is increasing in the general Medicare population at 4.4% per year. Cardiovascular disease is common, progresses at twice the rate, is associated with death before ESRD, and patients receive suboptimal risk factor monitoring. Active identification and treatment of CKD patients is needed.     

Mechanism of albuminuria associated with cardiovascular disease and kidney disease

The major underlying factors associated with tissue damage and fibrosis in cardiovascular and kidney disease are the up-regulation and action of growth factors such as transforming growth factor-beta (TGF-beta) and cytokines produced in response to changes in systemic factors, particularly blood pressure or hyperglycemia. This study identifies the relationship of elevated levels of TGF-beta to increased levels of intact albumin in the urine (micro- and macroalbuminuria). This mechanism may be directly linked to the effect of TGF-beta on albumin uptake and the lysosomal breakdown of filtered albumin by proximal tubular cells prior to excretion.     

Infections and cardiovascular disease in patients with chronic kidney disease

Although interest in the nexus of cardiovascular disease and chronic kidney disease (CKD) has mushroomed, especially in the in past 5 years, activity in the arena of CKD-related infection has been much more modest. This development is surprising when one considers the increasing evidence that links inflammation, kidney disease, and cardiovascular disease. Also, major infections, such as pneumonia and septicemia, are paradigmatic inflammatory states, and accumulating evidence indicates that they are a common antecedent of new cardiovascular events in dialysis patients. Major infections are associated with higher rates of cardiovascular events and death in dialysis patients, and similar associations have been observed in community settings. Although recent studies suggest that hospitalization for major infections is much more common in nondialysis CKD than in the general population, the prognostic implications remain unexplored.     

血浆维生素D与慢性肾脏病患者心血管疾病的相关性研究

目的了解慢性肾脏病(chronic kidney disease,CKD)患者维生素D状态及缺乏原因,并探讨血浆维生素D缺乏是否独立影响CKD患者心血管疾病(cardiovasculardisease,CVD)的发生。方法选取北京医院肾脏内科住院的CKD 1~5期非透析患者80例为研究对象,门诊健康查体人群10例为对照组,测定其血浆25-OH-D_3、1,25(OH)_2D_3水平并进行相关实验室检查。根据血浆25-OH-D_3水平将患者分为维生素D缺乏组和非维生素D缺乏组,比较组间临床和实验室检查资料以及心脏超声检查相关参数差异;根据超声心动图结果,将患者分为左室肥厚(1eft ventricular hypertrophy,LVH)组和非LVH组,比较组间患者相关临床资料差异,并采用多因素分析CKD患者LVH的独立危险因素。结果 CKD组及对照组25-OH-D3分别为(15.09±2.44)μg/L和(18.60±1.88)μg/L;2组维生素D水平均较低,但CKD组较对照组更低,组间有统计学差异(P0.05)。CKD患者维生素D水平普遍偏低,血浆25-OH-D_3波动于10.29~20.51μg/L,1,25(OH)2 D3波动于16.23~54.32 ng/L,两者之间存在线性相关,两者与CKD患者肾功能分期均无线性相关。CKD患者维生素D缺乏组(≤15μg/L)和非维生素D缺乏组(15μg/L)组间比较,发现2组血磷、左心室质量指数存在统计学差异(P0.05)。维生素D水平与左心室质量指数无线性相关;比较LVH组及非LVH组相关临床资料,单因素分析发现血肌酐、尿素氮、估算肾小球滤过率、脑钠肽、肌钙蛋白、血红蛋白、红细胞比容、24h尿蛋白定量、高密度脂蛋白均存在统计学差异(P0.05);多元逐步Logistic回归发现BNP升高(≥1 000 ng/L),24h尿蛋白定量(≥3.5 g),LDL升高(≥2.59 mmol/L)可进入方程(P0.05)。结论 CKD患者25-OH-D_3水平低于普通人群,但与CKD患者肾功能水平无线性相关;BNP升高、24h尿蛋白定量、高低密度脂蛋白血症是CKD患者左室肥厚的独立危险因素,目前尚不认为25-OH-D_3水平下降影响CKD患者左室肥厚的发生。