Association between Serum Inorganic Phosphorus Levels and Adverse Outcomes in Chronic Kidney Disease: The Fukushima CKD Cohort Study

Objective Although an association between serum inorganic phosphorus levels and a poor prognosis has been noted in dialysis patients, these associations have been insufficiently reported in non-dialysis-dependent chronic kidney disease (NDD-CKD) patients. This study attempted to determine the association between serum inorganic phosphorus levels and adverse outcomes in Japanese NDD-CKD patients. Methods We investigated the relationships between serum inorganic phosphorus levels and adverse outcomes, such as kidney events, cardiovascular events, and all-cause death, in Japanese NDD-CKD patients using longitudinal data from the Fukushima CKD Cohort Study with a median follow-up period of 2.8 years. The study evaluated 822 patients with NDD-CKD enrolled between June 2012 and July 2014. A kidney event was defined as a combination of doubling of the baseline serum creatinine or end-stage renal disease. Cox regression was performed to analyze the relationships of the quartile of the serum inorganic phosphorus with kidney events, cardiovascular events, and all-cause death. Results The frequency of kidney events per 1,000 person-years exhibited a U-shaped distribution based on serum inorganic phosphorus levels, with these levels not significantly associated with an increased risk of cardiovascular events and all-cause death. A multivariable Cox regression analysis showed an increased risk of kidney events for the highest quartile of the serum inorganic phosphorus levels (≥3.7 mg/dL) versus the second quartile (2.9-3.2 mg/dL, hazard ratio, 3.30; 95% confidence interval, 1.50-7.28; p=0.003). There were no significant associations between the serum calcium levels and adverse outcomes. Conclusion Serum inorganic phosphorus levels were associated with an increased risk of CKD progression in Japanese NDD-CKD patients.     

Relation of Serum Lipids and Lipoproteins with Progression of CKD: The CRIC Study

Background and objectives

Hyperlipidemia is common in patients with CKD. The objective of this study was to evaluate whether measures of plasma lipids and lipoproteins predict progression of kidney disease in patients with CKD.

Design, setting, participants, & measurements

Prospective cohort study in adults (n=3939) with CKD aged 21–74 years recruited between 2003 and 2008 and followed for a median of 4.1 years. At baseline, total cholesterol, triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), apoA-I , apoB, and lipoprotein(a) [Lp(a)] were measured. The outcomes were composite end point of ESRD or 50% decline in eGFR from baseline (rate of change of GFR).

Results

Mean age of the study population was 58.2 years, and the mean GFR was 44.9 ml/min per 1.73 m²; 48% of patients had diabetes. None of the lipid or lipoprotein measures was independently associated with risk of the composite end point or rate of change in GFR. However, there were significant (P=0.01) interactions by level of proteinuria. In participants with proteinuria<0.2 g/d, 1-SD higher LDL-C was associated with a 26% lower risk of the renal end point (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.59 to 0.92; P=0.01), and 1-SD higher total cholesterol was associated with a 23% lower risk of the renal end point (HR, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In participants with proteinuria>0.2 g/d, neither LDL-C (HR, 0.98; 95% CI, 0.98 to 1.05) nor total cholesterol levels were associated with renal outcomes. Treatment with statins was reported in 55% of patients and was differential across lipid categories.

Conclusions

In this large cohort of patients with CKD, total cholesterol, triglycerides, VLDL-C, LDL-C, HDL-C, apoA-I, apoB, and Lp(a) were not independently associated with progression of kidney disease. There was an inverse relationship between LDL-C and total cholesterol levels and kidney disease outcomes in patients with low levels of proteinuria.     

Retinopathy and Progression of CKD: The CRIC Study

Background and objectives

Retinal abnormalities may be associated with changes in the renal vasculature. This study assessed the association between retinopathy and progression of kidney disease in participants of the Chronic Renal Insufficiency Cohort (CRIC) study.

Design, setting, participants, & measurements

This was a prospective study in which patients with CKD enrolled in CRIC had nonmydriatic fundus photographs of both eyes. All CRIC participants in six clinical sites in which fundus cameras were deployed were offered participation. Photographs were reviewed at a reading center. The presence and severity of retinopathy and vessel calibers were assessed using standard protocols by graders masked to clinical information. The associations of retinal features with changes in eGFR and the need for RRT (ESRD) were assessed.

Results

Retinal images and renal progression outcomes were obtained from 1852 of the 2605 participants (71.1%) approached. During follow-up (median 2.3 years), 152 participants (8.2%) developed ESRD. Presence and severity of retinopathy at baseline were strongly associated with the risk of subsequent progression to ESRD and reductions in eGFR in unadjusted analyses. For example, participants with retinopathy were 4.4 times (95% confidence interval [95% CI], 3.12 to 6.31) more likely to develop ESRD than those without retinopathy (P<0.001). However, this association was not statistically significant after adjustment for initial eGFR and 24-hour proteinuria. Venular and arteriolar diameter calibers were not associated with ESRD or eGFR decline. The results showed a nonlinear relationship between mean ratio of arteriole/vein calibers and the risk of progression to ESRD; participants within the fourth arteriole/vein ratio quartile were 3.11 times (95% CI, 1.51 to 6.40) more likely to develop ESRD than those in the first quartile (P<0.001).

Conclusions

The presence and severity of retinopathy were not associated with ESRD and decline in eGFR after taking into account established risk factors.     

Risk Factors for CKD Progression: Overview of Findings from the CRIC Study

The Chronic Renal Insufficiency Cohort (CRIC) Study is an ongoing, multicenter, longitudinal study of nearly 5500 adults with CKD in the United States. Over the past 10 years, the CRIC Study has made significant contributions to the understanding of factors associated with CKD progression. This review summarizes findings from longitudinal studies evaluating risk factors associated with CKD progression in the CRIC Study, grouped into the following six thematic categories: (1) sociodemographic and economic (sex, race/ethnicity, and nephrology care); (2) behavioral (healthy lifestyle, diet, and sleep); (3) genetic (apoL1, genome-wide association study, and renin-angiotensin-aldosterone system pathway genes); (4) cardiovascular (atrial fibrillation, hypertension, and vascular stiffness); (5) metabolic (fibroblast growth factor 23 and urinary oxalate); and (6) novel factors (AKI and biomarkers of kidney injury). Additionally, we highlight areas where future research is needed, and opportunities for interdisciplinary collaboration.     

Clinical,Genetic, and Urinary Factors Associated with Uromodulin Excretion

Background and objectives

The urinary excretion of uromodulin is influenced by common variants in the UMOD gene, and it may be related to NaCl retention and hypertension. Levels of uromodulin are also dependent of the renal function, but other determinants remain unknown.

Design, setting, participants, & measurements

We tested associations between the urinary excretion of uromodulin; medical history and medication; serum and urinary levels of electrolytes, glucose, and uric acid; and the genotype at the UMOD/Protein Disulfide Isomerase–Like, Testis Expressed locus (rs4293393 and rs12446492); 943 participants from the CARTaGENE Cohort, a random sample from the Canadian population of 20,004 individuals, were analyzed. Participants with available genotyping were obtained from a substudy addressing associations between common variants and cardiovascular disease in paired participants with high and low Framingham risk scores and vascular rigidity indexes.

Results

The population studied was 54±9 years old, with 51% women and eGFR of 9±14 ml/min per 1.73 m². Uromodulin excretion was 25 (11–42) mg/g creatinine. Using linear regression, it was independently higher among patients with higher eGFR, the TT genotype of rs4293393, and the TT genotype of rs12446492. The fractional excretions of urate and sodium showed a strong positive correlation with uromodulin, likely linked to the extracellular volume status. The presence of glycosuria and the use of uricosuric drugs, which both increased the fraction excretion of urate, were independently associated with a lower uromodulin excretion, suggesting novel interactions between uric acid and uromodulin excretion.

Conclusions

In this large cohort, the excretion of uromodulin correlates with clinical, genetic, and urinary factors. The strongest associations were between uric acid, sodium, and uromodulin excretions and are likely linked to the extracellular volume status.     

Preoperative Hemoglobin and Outcomes in Patients with CKD Undergoing Cardiac Surgery

Background and objectives

Preoperative anemia adversely affects outcomes of cardiothoracic surgery. However, in patients with CKD, treating anemia to a target of normal hemoglobin has been associated with increased risk of adverse cardiac and cerebrovascular events. We investigated the association between preoperative hemoglobin and outcomes of cardiac surgery in patients with CKD and assessed whether there was a level of preoperative hemoglobin below which the incidence of adverse surgical outcomes increases.

Design, setting, participants, & measurements

This prospective observational study included adult patients with CKD stages 3–5 (eGFR<60 ml/min per 1.73 m²) undergoing cardiac surgery from February 2000 to January 2010. Patients were classified into four groups stratified by preoperative hemoglobin level: <10, 10–11.9, 12–13.9, and ≥14 g/dl. The outcomes were postoperative AKI requiring dialysis, sepsis, cerebrovascular accident, and mortality.

Results

In total, 788 patients with a mean eGFR of 43.5±13.7 ml/min per 1.73 m² were evaluated, of whom 22.5% had preoperative hemoglobin within the normal range (men: 14–18 g/dl; women: 12–16 g/dl). Univariate analysis revealed an inverse relationship between the incidence of all adverse postoperative outcomes and hemoglobin level. Using hemoglobin as a continuous variable, multivariate logistic regression analysis showed a proportionally greater frequency of all adverse postoperative outcomes per 1-g/dl decrement of preoperative hemoglobin (mortality: odds ratio, 1.38; 95% confidence interval, 1.23 to 1.57; P<0.001; sepsis: odds ratio, 1.31; 95% confidence interval, 1.14 to 1.49; P<0.001; cerebrovascular accident: odds ratio, 1.31; 95% confidence interval, 1.00 to 1.67; P=0.03; postoperative hemodialysis: odds ratio, 1.38; 95% confidence interval, 1.11 to 1.75; P<0.01). Moreover, preoperative hemoglobin<12 g/dl was an independent risk factor for postoperative mortality (odds ratio, 2.6; 95% confidence interval, 1.1 to 7.3; P=0.04).

Conclusions

Similar to the general population, preoperative anemia is associated with adverse postoperative outcomes in patients with CKD. Whether outcomes could be improved by therapeutically targeting higher preoperative hemoglobin levels before cardiac surgery in patients with underlying CKD remains to be determined.     

Nocturnal Systolic Hypertension and Adverse Prognosis in Patients with CKD

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中国终末期肾脏疾病的现状问题和对策

慢性肾脏病(CKD)和终末期肾脏疾病(ESRD)的防治已经成为中国重要的公共卫生问题。文章概括介绍中国CKD和ESRD的现状、危害以及防治中的问题,简述了中华医学会肾脏病学分会做出的工作,提出了今后防治ESRD的对策。目的在于提高社会、政府、公众以及医务人员对防治ESRD迫切性的认识,提高中国ESRD防治水平。     

Coronary Artery Disease in Patients with Chronic Kidney Disease: A Clinical Update

Chronic kidney disease (CKD) is an independent risk factor for coronary artery disease (CAD). Coronary artery disease is the leading cause of morbidity and mortality in patients with CKD. The outcomes of CAD are poorer in patients with CKD. In addition to traditional risk factors, several uremia-related risk factors such as inflammation, oxidative stress, endothelial dysfunction, coronary artery calcification, hyperhomocysteinemia, and immunosuppressants have been associated with accelerated atherosclerosis. A number of uremia-related biomarkers are identified as predictors of cardiac outcomes in CKD patients. The symptoms of CAD may not be typical in patients with CKD. Both dobutamine stress echocardiography and radionuclide myocardial perfusion imaging have moderate sensitivity and specificity in detecting obstructive CAD in CKD patients. Invasive coronary angiography carries a risk of contrast nephropathy in patients with advanced CKD. It should be reserved for those patients with a high risk for CAD and those who would benefit from revascularization. Guideline-recommended therapies are, in general, underutilized in renal patients. Medical therapy should be considered the initial strategy for clinically stable CAD. The effects of statins in patients with advanced CKD have been neutral despite a lipid-lowering effect. Compared to non-CKD population, percutaneous coronary intervention (PCI) is associated with higher procedure complications, restenosis, and future cardiac events even in the drug-eluting stent era in patients with CKD. Compared with PCI, coronary artery bypass grafting (CABG) reduces repeat revascularizations but is associated with significant perioperative morbidity and mortality. Screening for CAD is an important part of preoperative evaluation for kidney transplant candidates.     

Baseline Urinary Angiotensinogen Excretion Predicts Deterioration of the Kidney Function in Patients with Chronic Kidney Disease

Objective The intrarenal renin-angiotensin system (RAS) is activated in patients with chronic kidney disease (CKD), and urinary angiotensinogen (AGT) levels, a surrogate marker of the intrarenal RAS activation, are associated with blood pressure (BP) and urinary albumin excretion. In addition, it has been shown that changes in urinary AGT levels correlate with annual changes in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes and that elevated levels of urinary AGT in type 2 diabetic patients with albuminuria are a high-risk factor for worsening renal and cardiovascular complications. However, whether or not baseline urinary AGT levels predict deterioration of the kidney function in all patients with CKD is unclear. Methods We recruited 62 patients with CKD whose eGFR was ＞15 mL/min/1.73 m². We performed 24-hour ambulatory BP monitoring at 30-min intervals and daily urinary collection to examine the urinary AGT levels and albumin excretion and measured the levels of plasma angiotensin II (Ang II), a surrogate marker of circulating RAS. In addition, annual changes in the eGFR were followed up for 3.4±1.5 years. Results Annual changes in the eGFR were significantly and negatively associated with urinary AGT levels (r=-0.31, p=0.015) as well as the age, systolic BP, and urinary albumin levels. In contrast, annual changes in the eGFR were not correlated with plasma Ang II levels. Furthermore, when dividing patients into quartiles according to urinary AGT levels, patients with the highest urinary AGT levels showed a progressive decline in the eGFR. Conclusion These results suggest that elevated baseline urinary AGT levels can predict renal dysfunction in patients with CKD.     

Chronic Renal Insufficiency Cohort Study (CRIC): Overview and Summary of Selected Findings

The Chronic Renal Insufficiency Cohort (CRIC) Study is a United States multicenter, prospective study of racially and ethnically diverse patients with CKD. Although the original aims of the study were to identify novel predictors of CKD progression and to elucidate the risk and manifestations of cardiovascular disease among nearly 4000 individuals with CKD, the CRIC Study has evolved into a national resource for investigation of a broad spectrum of CKD-related topics. The study has produced >90 published scientific articles, promoted many young investigative careers in nephrology, and fostered international collaborations focused on understanding the global burden of CKD. The third phase of the CRIC Study will complete enrollment of 1500 additional study participants in 2015 and is designed to answer questions regarding morbidity and mortality in mild-to-moderate CKD and to assess the burden of CKD in older persons. This review highlights some of the salient findings of the CRIC Study in the areas of race and ethnicity, CKD progression, CKD and cognition, and cardiovascular disease outcomes; it also outlines the ongoing and forthcoming opportunities for the global nephrology community to enhance its understanding of CKD and related complications through the study.     

伴有血脂异常的老年慢性肾小球肾炎CKD1-2期患者临床及病理分析

目的探讨伴有血脂异常的老年慢性肾小球肾炎CKD1-2期患者临床及病理特点,以评估血脂异常对慢性肾脏病的影响。方法纳入2014年至2017年首次行肾活检诊断并符合CKD1-2期原发性慢性肾小球肾炎的老年患者111例,根据有无高脂血症分为高脂血症组(HL组,76例)和非高脂血症组(非HL组,35例),回顾分析两组患者的一般资料、临床及病理特点。结果(1)两组患者年龄、性别比、体质指数、高血压患病率、病理分布类型、血肌酐、高敏C反应蛋白等差异无统计学意义。HL组的血尿酸水平、24 h尿蛋白定量、尿转铁蛋白、尿白蛋白、尿α1微球蛋白、尿NAG酶均高于非HL组,血清白蛋白低于非HL组(P<0.05);(2)HL组血管损伤评分高于非HL组(P<0.05),而肾小球硬化比例、新月体比例、系膜增生、肾小管损伤等评分两组差异无统计学意义;(3)通过二元变量相关分析,24 h尿蛋白、尿转铁蛋白与血清胆固醇、甘油三酯、低密度脂蛋白、高密度脂蛋白相关,血尿酸、尿白蛋白与与血清胆固醇、甘油三酯、低密度脂蛋白相关,血清白蛋白、尿NAG酶与血清胆固醇、甘油三酯、低密度脂蛋白相关。结论伴血脂异常的老年慢性肾小球肾炎CKD1-2期患者尿蛋白、肾小管损伤更重,肾微血管病变程度更高。     

Urinary Biomarkers and Risk of ESRD in the Atherosclerosis Risk in Communities Study

Background and objectives

Liver fatty acid binding protein (L-FABP), kidney injury molecule 1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), and neutrophil gelatinase–associated lipocalin (NGAL) are urinary markers of tubular injury that may also be markers of chronic kidney damage. We evaluated the association of these markers with incident ESRD in a community-based sample from the Atherosclerosis Risk in Communities Study.

Design, setting, participants, & measurements

This was a matched case-control study of 135 patients with ESRD and 186 controls who were matched on sex, race, kidney function, and diabetes status at baseline (Atherosclerosis Risk in Communities Study visit 4, 1996–1998). Urinary KIM-1 indexed to creatinine (Cr), NAG/Cr, NGAL/Cr, and L-FABP/Cr were measured in stored spot urine samples from the baseline examination. Associations of KIM-1/Cr, NAG/Cr, and NGAL/Cr with patients with incident ESRD through 2008 were modeled continuously and categorically (quartiles) using conditional logistic regression. L-FABP/Cr was modeled only categorically because of a large number of measurements below the lower limit of detection for the assay (2.4 ng/ml).

Results

No significant associations were observed for NAG/Cr, NGAL/Cr, or L-FABP/Cr with ESRD. Those in the highest category for KIM-1/Cr had a higher risk of ESRD compared with those with undetectable biomarker levels (reference group) in unadjusted models (odds ratio, 2.24; 95% confidence interval, 1.97 to 4.69; P=0.03) or adjustment for age (odds ratio, 2.23; 95% confidence interval, 1.06 to 4.67; P=0.03). This association was attenuated with additional adjustment for baseline kidney function (odds ratio, 2.02; 95% confidence interval, 0.95 to 4.31; P=0.07 after additional adjustment for eGFR and natural log of the urinary albumin-to-creatinine ratio). No association between KIM-1/Cr and ESRD was found when KIM-1/Cr was analyzed as a continuous variable.

Conclusions

Elevated urinary KIM-1/Cr may be associated with a higher risk of incident ESRD, but it does not add to risk prediction after accounting for traditional markers of kidney function in this population.     

Glycated Hemoglobin Level and Mortality in a Nondiabetic Population with CKD

Background and objectives

Glycated hemoglobin (HbA_1c) is used to diagnose diabetes mellitus (DM) and guide its management. The association between higher HbA_1c and progression to ESRD and mortality has been demonstrated in populations with DM. This study examined the association between HbA_1c and these end points in a population with CKD and without DM.

Design, setting, participants, & measurements

In the hospital-based NephroTest cohort study, measured GFR (mGFR) was taken by ⁵¹Cr-EDTA renal clearance and HbA_1c in 1165 adults with nondialysis CKD stages 1–5 and without DM between January 2000 and December 2010. The median follow-up was 3.48 years (interquartile range, 1.94–5.82) for the competing events of ESRD and pre-ESRD mortality. Time-fixed and time-dependent Cox models were used to estimate hazard ratios (HRs) for ESRD and mortality according to HbA_1c, treated continuously or in tertiles.

Results

At inclusion, the mean mGFR was 42.2±19.9 ml/min per 1.73 m², and the mean HbA_1c value was 5.5%±0.5%. During follow-up, 109 patients died, and 162 patients reached ESRD. Pre-ESRD mortality was significantly associated with HbA_1c treated continuously: for every 1% higher HbA_1c, the crude HR was 2.16 (95% confidence interval [95% CI], 1.27 to 3.68), and it was 1.85 (95% CI, 1.05 to 3.24) after adjustment for mGFR and other risk factors of death. After excluding incident diabetes over time, the updated mean of HbA_1c remained significantly associated with higher mortality risk: adjusted HR for the highest (5.7%–6.4%) versus the lowest tertile (<5.3%) was 2.62 (95% CI, 1.16 to 5.91). There was no association with ESRD risk after adjustment for risk factors of CKD progression.

Conclusions

In a CKD cohort, HbA_1c values in the prediabetes range are associated with mortality. Such values should be therefore included among the risk factors for negative outcomes in CKD populations.     

Changes in hemostatic factors after kidney transplantation: A retrospective cohort study

Chronic kidney disease affects hemostasis in complex ways, producing both thrombotic and hemorrhagic diatheses. These changes may impact patient morbidity and mortality pre-transplantation, as well as allograft survival after kidney transplantation (KT). This study was conducted to analyze changes in hemostatic factors in the early post-KT period.We retrospectively analyzed 676 recipients of kidney allografts from December 2009 to December 2014. Patients receiving plasmapheresis pre- or post-KT, experiencing early allograft failure, or receiving anticoagulants or antiplatelet agents pre- or post-KT were excluded.Of the 367 included patients, acute (≤1 month) rejection occurred in 4.1% and delayed graft function occurred in 3.3%. Postoperative bleeding complications occurred in 7.9% of patients and thrombotic complications in 3.3%. Pre-transplantation, recipients had below normal hemoglobin, above normal d-dimer and homocysteine levels, and elevated rates of antiphospholipid antibodies. Hemoglobin increased to almost normal by postoperative day (POD) 28 (P < .001). d-dimer increased on POD7, 14, and 28, although the values were not significantly different from pre-KT. The pattern of d-dimer changes suggested that they were a nonspecific consequence of major surgery. Homocysteine decreased to normal by POD7 (P < .001). The percentage of patients with ≥1 prothrombotic factor was 82.0% pre-KT and only 14.2% on POD28 (P < .001).The most of patients exhibited prothrombotic tendencies, including increased d-dimer and homocysteine, and increased prevalence of antiphospholipid antibodies before transplantation. They also had pre-transplantation anemia, suggesting a concomitant bleeding diathesis. However, most of these abnormal hemostatic factors improved or resolved after KT.