Leukocyte Proliferation and Immune Modulator Production in Patients with Chronic Kidney Disease

Introduction

In Chronic Kidney Disease (CKD), immune cells are affected by uremic retention toxins. Given this effect, we analyzed lymphocyte proliferative response and immune modulators production following in vitro stimulation.

Methods

Whole blood was drawn from healthy controls, patients with eGFR <20 ml/min/1.73 m² (Pre-dialysis, CKD stages 4 and 5) and hemodialysis patients (stage 5D). Peripheral cells were incubated for six days with pokeweed mitogen, concanavalin A, Staphylococcus enterotoxin A or influenza A vaccine. Peripheral lymphocyte proliferation was then analyzed by the “Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood” (FASCIA) method, and cytokine profile in the cell supernatants was analyzed by the Milliplex multi-array method.

Results

The absolute number of lymphoblasts in response to mitogenic stimulation and the number of cells in each CD4+ and CD8+ subpopulation were similar comparing the three groups, except for a single decline in number of lymphoblasts after stimulation with Staphylococcus enterotoxin A, comparing dialysis patients with healthy controls. Levels of interleukin (IL)-2 (p=0.026), -10 (p=0.019) and -15 (p=0.027) in the Staphylococcus enterotoxin A-stimulated supernatant were lower in hemodialysis patients compared to healthy controls. Levels of IL-15 (p=0.017) from pre-dialysis patients and levels of IL-5 (p=0.019) from hemodialysis patients in influenza A vaccine-stimulated supernatants were also lower compared to controls. In pokeweed mitogen–stimulated supernatant, IL-2 levels (p=0.013) were lower in hemodialysis patients compared to pre-dialysis patients. TNF-α, IL-10, IL-12, IL-15, IL-8, MCP-1, IP-10, IFN-α2, IL-1α and eotaxin levels were all significantly higher in plasma obtained from CKD patients.

Conclusion

Our results suggest that T-cells from CKD patients have similar proliferative response to stimulation compared with healthy individuals. Moreover, however the immune cells show inability to produce selected cytokines, most likely due to the uremic milieu or dialysis procedure.     

Assessment of Vascular Function in Patients With Chronic Kidney Disease

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this is only partially explained by traditional CVD risk factors. Vascular dysfunction is an important non-traditional risk factor, characterized by vascular endothelial dysfunction (most commonly assessed as impaired endothelium-dependent dilation [EDD]) and stiffening of the large elastic arteries. While various techniques exist to assess EDD and large elastic artery stiffness, the most commonly used are brachial artery flow-mediated dilation (FMD_BA) and aortic pulse-wave velocity (aPWV), respectively. Both of these noninvasive measures of vascular dysfunction are independent predictors of future cardiovascular events in patients with and without kidney disease. Patients with CKD demonstrate both impaired FMD_BA, and increased aPWV. While the exact mechanisms by which vascular dysfunction develops in CKD are incompletely understood, increased oxidative stress and a subsequent reduction in nitric oxide (NO) bioavailability are important contributors. Cellular changes in oxidative stress can be assessed by collecting vascular endothelial cells from the antecubital vein and measuring protein expression of markers of oxidative stress using immunofluorescence. We provide here a discussion of these methods to measure FMD_BA, aPWV, and vascular endothelial cell protein expression.     

Efficacy of Benzbromarone in Hyperuricemic Patients Associated with Chronic Kidney Disease

We have retrospectively evaluated the uric acid control status and renal function changes over a period of up to 7 years in 35 patients with renal impairment who had stage 3 or higher chronic kidney disease (CKD; stage 3 in 32 patients, stage 4 in 2 patients, and stage 5 in 1 patient) associated with hyperuricemia and were receiving monotherapy with benzbromarone as an antihyperuricemic drug. Serum uric acid levels significantly decreased from 8.5 ± 0.9 to 6.1 ± 0.8 mg/dL at 6 months and were subsequently controlled at less than 7.0 mg/dL in most patients. Most patients received benzbromarone at a dose of 25–50 mg/day, whereas 150–200 mg/day was used in some patients with stage 4 or 5 CKD. No significant changes in estimated glomerular filtration rate (eGFR) from the baseline value of 46.2 ± 11.5 mL/minute/1.73 m² were found after benzbromarone therapy. Although the renal function impairment did not improve by reducing the serum uric acid levels with benzbromarone, the renal function did not deteriorate further on the therapy. These results suggest that benzbromarone is applicable to the management of hyperuricemia associated with renal impairment.     

慢性肾脏病患者心脏结构与功能变化的超声心动图研究

目的:研究慢性肾脏病(CKD)患者心脏结构及功能的变化.方法:选择我院肾内科175例慢性肾脏病未透析患者,按照2003年美国国家肾脏基金会-肾脏病转归质量(NKF-K/DOQI)指南的标准进行分期,观察所有患者心脏结构及功能在超声中的变化.结果:慢性肾脏病患者随着肾功能的恶化,各组之间比较,室间隔厚度(IVST)、左心室后壁厚度(LVPW)、左心室心肌重量指数(LVMI)、左心室舒张末期内径(LVDd)、左心房内径(LAD)具有升高的趋势(P＜0.05,P＜0.01);但E/A比值未出现伴随着肾功能恶化而逐渐减低的趋势(P＞0.05);射血分数(EF)、短轴缩短卒(FS)在各期之间无明显变化(P＞0.05);而TVI技术测定的Em、Em/Am具有显著减低的趋势(P＜0.05,P＜0.01);瓣膜返流以二尖瓣返流为主.结论:慢性肾脏病患者心脏结构与功能随肾功能减退而加重,超声心动图检查结合组织速度显像(TVI)技术能更好地检测心脏结构和功能变化,尤其是检测左心室舒张功能障碍.     

Independent Role of Underlying Kidney Disease on Renal Prognosis of Patients with Chronic Kidney Disease under Nephrology Care

Primary kidney disease is suggested to affect renal prognosis of CKD patients; however, whether nephrology care modifies this association is unknown. We studied patients with CKD stage I-IV treated in a renal clinic and with established diagnosis of CKD cause to evaluate whether the risk of renal event (composite of end-stage renal disease and eGFR decline ≥40%) linked to the specific diagnosis is modified by the achievement or maintenance in the first year of nephrology care of therapeutic goals for hypertension (BP ≤130/80 mmHg in patients with proteinuria ≥150 mg/24h and/or diabetes and ≤140/90 in those with proteinuria <150 mg/24h and without diabetes) anemia (hemoglobin, Hb ≥11 g/dL), and proteinuria (≤0.5 g/24h). Survival analysis started after first year of nephrology care. We studied 729 patients (age 64±15 y; males 59.1%; diabetes 34.7%; cardiovascular disease (CVD) 44.9%; hypertensive nephropathy, HTN 53.8%; glomerulonephritis, GN 17.3%; diabetic nephropathy, DN 15.9%; tubule-interstitial nephropathy, TIN 9.5%; polycystic kidney disease, PKD 3.6%). During first year of Nephrology care, therapy was overall intensified in most patients and prevalence of main therapeutic goals generally improved. During subsequent follow up (median 3.3 years, IQR 1.9-5.1), 163 renal events occurred. Cox analysis disclosed a higher risk for PKD (Hazard Ratio 5.46, 95% Confidence Intervals 2.28–10.6) and DN (1.28,2.99–3.05), versus HTN (reference), independently of age, gender, CVD, BMI, eGFR or CKD stage, use of RAS inhibitors and achievement or maintenance in the first year of nephrology care of each of the three main therapeutic goals. No interaction was found on the risk of CKD progression between diagnostic categories and month-12 eGFR (P=0.737), as with control of BP (P=0.374), Hb (P=0.248) or proteinuria (P=0.590). Therefore, in CKD patients under nephrology care, diagnosis of kidney disease should be considered in conjunction with the main risk factors to refine renal risk stratification.     

Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphism and Left Ventricular Function in Early Chronic Kidney Disease

Background

Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated.

Methods

140 non-dialysis CKD patients, who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of two clinical trials, were genotyped for eNOS Glu298Asp SNP retrospectively.

Results

The median estimated glomerular filtration rate (eGFR) was 50mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction in this cohort. There were significant differences in LVEF across eNOS genotypes with GG genotype being associated with a worse LVEF compared to other genotypes (LVEF: GG 71%, TG 76%, TT 73%, p = 0.006). After multivariate analysis, (adjusting for age, eGFR, baseline mean arterial pressure, contemporary CMR heart rate, total cholesterol, high sensitive C-reactive protein, body mass index and gender) GG genotype was associated with a worse LVEF, and increased LV end-diastolic and systolic index (p = 0.004, 0.049 and 0.009 respectively).

Conclusions

eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses.     

Circulating Adipocytokines and Chronic Kidney Disease

Background

Adipokines have been associated with atherosclerotic heart disease, which shares many common risk factors with chronic kidney disease (CKD), but their relationship with CKD has not been well characterized.

Methods

We investigated the association of plasma leptin, resistin and adiponectin with CKD in 201 patients with CKD and 201 controls without. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² or presence of albuminuria. Quantile regression and logistic regression models were used to examine the association between adipokines and CKD adjusting for multiple confounding factors.

Results

Compared to controls, adjusted median leptin (38.2 vs. 17.2 ng/mL, p<0.0001) and adjusted mean resistin (16.2 vs 9.0 ng/mL, p<0.0001) were significantly higher in CKD cases. The multiple-adjusted odds ratio (95% confidence interval) of CKD comparing the highest tertile to the lower two tertiles was 2.3 (1.1, 4.9) for leptin and 12.7 (6.5, 24.6) for resistin. Median adiponectin was not significantly different in cases and controls, but the odds ratio comparing the highest tertile to the lower two tertiles was significant (1.9; 95% CI, 1.1, 3.6). In addition, higher leptin, resistin, and adiponectin were independently associated with lower eGFR and higher urinary albumin levels.

Conclusions

These findings suggest that adipocytokines are independently and significantly associated with the risk and severity of CKD. Longitudinal studies are warranted to evaluate the prospective relationship of adipocytokines to the development and progression of CKD.     

Prevalence of Ventricular Arrhythmia and Its Associated Factors in Nondialyzed Chronic Kidney Disease Patients

Background and Objectives

Sudden cardiac death is the most common cause of mortality in chronic kidney disease patients, and it occurs mostly due to ventricular arrhythmias. In this study, we aimed at investigating the prevalence of ventricular arrhythmia and the factors associated with its occurrence in nondialyzed chronic kidney disease patients.

Design, Setting, Participants and Measurements

This cross-sectional study evaluated 111 chronic kidney disease patients (estimated glomerular filtration rate 34.7±16.1 mL/min/1.73 m², 57±11.4 years, 60% male, 24% diabetics). Ventricular arrhythmia was assessed by 24-hour electrocardiogram. Left ventricular hypertrophy (echocardiogram), 24-hour ambulatory blood pressure monitoring, and coronary artery calcification (multi-slice computed tomography) and laboratory parameters were also evaluated.

Results

Ventricular arrhythmia was found in 35% of the patients. Non-controlled hypertension was observed in 21%, absence of systolic decency in 29%, left ventricular hypertrophy in 27%, systolic dysfunction in 10%, and coronary artery calcification in 49%. Patients with ventricular arrhythmia were older (p<0.001), predominantly men (p = 0.009), had higher estimated glomerular filtration rate (p = 0.03) and hemoglobin (p = 0.005), and lower intact parathyroid hormone (p = 0.024) and triglycerides (p = 0.011) when compared to patients without ventricular arrhythmia. In addition, a higher left ventricular mass index (p = 0.002) and coronary calcium score (p = 0.002), and a lower ejection fraction (p = 0.001) were observed among patients with ventricular arrhythmia. In the multiple logistic regression analysis, aging, increased hemoglobin levels and reduced ejection fraction were independently related to the presence of ventricular arrhythmia.

Conclusions

Ventricular arrhythmia is prevalent in nondialyzed chronic kidney disease patients. Age, hemoglobin levels and ejection fraction were the factors associated with ventricular arrhythmia in these patients.     

Hypokalemia,Its Contributing Factors and Renal Outcomes in Patients with Chronic Kidney Disease

Background

In the chronic kidney disease (CKD) population, the impact of serum potassium (sK) on renal outcomes has been controversial. Moreover, the reasons for the potential prognostic value of hypokalemia have not been elucidated.

Design, Participants & Measurements

2500 participants with CKD stage 1–4 in the Integrated CKD care program Kaohsiung for delaying Dialysis (ICKD) prospective observational study were analyzed and followed up for 2.7 years. Generalized additive model was fitted to determine the cutpoints and the U-shape association between sK and end-stage renal disease (ESRD). sK was classified into five groups with the cutpoints of 3.5, 4, 4.5 and 5 mEq/L. Cox proportional hazard regression models predicting the outcomes were used.

Results

The mean age was 62.4 years, mean sK level was 4.2±0.5 mEq/L and average eGFR was 40.6 ml/min per 1.73 m². Female vs male, diuretic use vs. non-use, hypertension, higher eGFR, bicarbonate, CRP and hemoglobin levels significantly correlated with hypokalemia. In patients with lower sK, nephrotic range proteinuria, and hypoalbuminemia were more prevalent but the use of RAS (renin-angiotensin system) inhibitors was less frequent. Hypokalemia was significantly associated with ESRD with hazard ratios (HRs) of 1.82 (95% CI, 1.03–3.22) in sK <3.5mEq/L and 1.67 (95% CI,1.19–2.35) in sK = 3.5–4 mEq/L, respectively, compared with sK = 4.5–5 mEq/L. Hyperkalemia defined as sK >5 mEq/L conferred 1.6-fold (95% CI,1.09–2.34) increased risk of ESRD compared with sK = 4.5–5 mEq/L. Hypokalemia was also associated with rapid decline of renal function defined as eGFR slope below 20% of the distribution range.

Conclusion

In conclusion, both hypokalemia and hyperkalemia are associated with increased risk of ESRD in CKD population. Hypokalemia is related to increased use of diuretics, decreased use of RAS blockade and malnutrition, all of which may impose additive deleterious effects on renal outcomes.     

Cardiac Troponin I in Non- Acute Coronary Syndrome Patients with Chronic Kidney Disease

Objective

The aim of this study was to assess the results of troponin I (cTnI) in non- acute Coronary Syndrome (ACS) patients with chronic kidney disease (CKD). We also examined the risk factors for elevated cTnI in non-ACS patients with CKD and whether stage 5 CKD modifies the associations of elevated cTnI and the risk factors in non-ACS patients with CKD.

Methods

A retrospective study was performed. Logistic regression models were used.

Results

293 non-ACS patients with CKD were included in the current study. 43.34% non-ACS patients with CKD have an elevated cTnI level and 5.12% have an elevated cTnT level in MI range. In CKD patients without ACS and heart failure, only 26.03% (38/146) patients have an elevated cTnT level. In adjusted analyses, age, diastolic blood pressure and congestive heart failure is associated with an elevated cTnI level in non-ACS patients with CKD. Congestive heart failure is associated with an elevated cTnI level in non-ACS patients with CKD (OR 2.30, 95% CI 1.08,4.88, P=0.03). Stage 5 CKD does not modify the association of congestive heart failure and an elevated cTnI level.

Conclusion

43.34% non-ACS patients with CKD and 26.03% CKD patients without ACS and congestive heart failure have an elevated cTnI level. Congestive heart failure is associated with an elevated cTnI level in non-ACS patients with CKD. Stage 5 CKD does not modify the association of congestive heart failure and an elevated cTnI level.     

Relationship Between Hyperuricemia and Chronic Kidney Disease

Because approximately 70% of uric acid is excreted from the kidney, hyperuricemia occurs when renal function deteriorates. Until now, it has not been clear if the hyperuricemia seen in such renal diseases plays a role in the progression of renal disease. However, recent clinical studies show that the serum uric acid value is closely associated with hypertension in hyperuricemic patients (cross-sectional study), and also with the onset of hypertension (longitudinal study). Furthermore, one interesting report shows that treatment of hyperuricemia with allopurinol lowers blood pressure in juvenile essential hypertension patients with hyperuricemia. In addition, it is well known that hyperuricemia is closely associated with chronic kidney disease (CKD), is a risk factor for renal insufficiency in general populations, and is a poor prognostic factor of renal function in patients who also have IgA nephropathy. On the other hand, in intervention studies on hyperuricemia, the treatment of hyperuricemia with allopurinol in CKD has resulted in a fall in blood pressure and inhibition of the progression of renal damage. Conversely, the cessation of allopurinol treatment in CKD was followed by a rise in blood pressure and the development of renal damage. Furthermore, the rise of blood pressure and development of renal damage following cessation of allopurinol treatment are only seen in patients not receiving angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). This suggests that the renin angiotensin (RA) system plays an important role in the development of hypertension and renal damage from hyperuricemia.     

Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease

In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The results indicated that hepatitis A virus cellular receptor 1 (also known as Kidney Injury Molecule-1, KIM-1), lipocalin 2 (also known as neutrophil gelatinase-associated lipocalin, NGAL), SRY-box 9, WAP four-disulfide core domain 2, and NK6 homeobox 2 were differentially expressed in CKD. Their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury, determined by histopathological examination. The expression of these 5 genes was also increased as kidney damage progressed in a rodent unilateral ureteral obstruction model of CKD. We calculated a molecular score using the microarray gene expression profiles of the biopsy specimens. The composite area under the receiver operating characteristics curve plotted using this molecular score showed a high accuracy for diagnosing tubulointerstitial fibrosis and tubular cell damage. The robust sensitivity of this score was confirmed in a validation set of 5 individuals with CKD. These findings identified novel molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney.     

Cytomegalovirus Seropositivity Is Associated with Increased Arterial Stiffness in Patients with Chronic Kidney Disease

Background

Patients with chronic kidney disease have an increased cardiovascular risk that is not fully explained by traditional risk factors but appears to be related to increased arterial stiffness. Cytomegalovirus (CMV) infection is associated with increased cardiovascular risk although the mechanisms for this are unknown. We examined whether CMV seropositivity was associated with increased arterial stiffness in patients with chronic kidney disease.

Methodology and Principal Findings

In 215 non-diabetic patients with chronic kidney disease, CMV seropositivity was determined using an anti-CMV IgG ELISA. Pulse wave velocity was measured and aortic distensibility assessed in the ascending, proximal descending and distal descending thoracic aorta. Patients seropositive for CMV had a higher pulse wave velocity and lower aortic distensibility at all 3 levels. These differences (except for ascending aortic distensibility) persisted in a subcohort matched for age, gender and renal function, and when the whole cohort was divided into quartiles of age. In multivariable analyses, CMV seropositivity was an independent determinant of pulse wave velocity and proximal and distal descending aortic distensibility.

Conclusions

In patients with chronic kidney disease, CMV seropositivity is associated with increased arterial stiffness and decreased distensibility of the proximal descending and distal aorta. These findings suggest that further research is required to examine CMV as a possible cause of arterial disease and increased cardiovascular risk in patients with CKD and may be relevant more widely for CMV seropositive patients with normal renal function.     

The Renal Arterial Resistive Index and Stage of Chronic Kidney Disease in Patients with Renal Allograft

Objective

The study investigated the optimal threshold value of renal arterial resistive index as assessed by Doppler ultrasonography determining chronic kidney disease stage 4 or higher in patients with renal allograft.

Methods

In a cross-sectional study the renal arterial resistive index were obtained in interlobar arteries by Doppler ultrasonography in 78 patients with renal allograft. The stage of chronic kidney disease was determined by the estimated glomerular filtration rate equation.

Results

The median renal arterial resistive index was 0.61 (interquartile range, 0.56 to 0.66). We observed a significant association between renal arterial resistive index above the upper quartile and chronic kidney disease stage 4 or higher (relative risk, 4.64; 95% confidence interval, 1.71 to 12.55; p = 0.003 by Fisher’s exact test). Multivariate logistic regression analysis showed that renal arterial resistive indices (p = 0.02) and time since transplantation (p = 0.04), but not age, gender, or blood pressure were significantly associated with chronic kidney disease stage 4 or higher.

Conclusion

A renal arterial resistive index higher than 0.66 may determine the threshold value of chronic kidney disease stage 4 or higher in patients with renal allograft.     

A Population Pharmacokinetic and Pharmacodynamic Analysis of Peginesatide in Patients with Chronic Kidney Disease on Dialysis

Peginesatide (OMONTYS®) is an erythropoiesis-stimulating agent that was indicated in the United States for the treatment of anemia due to chronic kidney disease in adult patients on dialysis prior to its recent marketing withdrawal by the manufacturer. The objective of this analysis was to develop a population pharmacokinetic and pharmacodynamic model to characterize the time-course of peginesatide plasma and hemoglobin concentrations following intravenous and subcutaneous administration. Plasma samples (n = 2,665) from 672 patients with chronic kidney disease (on or not on dialysis) and hemoglobin samples (n = 18,857) from 517 hemodialysis patients (subset of the 672 patients), were used for pharmacokinetic-pharmacodynamic model development in NONMEM VI. The pharmacokinetic profile of peginesatide was best described by a two-compartment model with first-order absorption and saturable elimination. The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model. The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54. The estimate of peginesatide drug concentration required for 50% of maximal response (EC50) estimates was 0.4 µg/mL. Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%. Based upon ≤0.2 g/dL effects on simulated hemoglobin levels, none were considered clinically relevant.     

Comparison of Ambulatory Blood Pressure Parameters of Hypertensive Patients With and Without Chronic Kidney Disease

There is strong association between chronic kidney disease (CKD) and increased prevalence of hypertension, risk of end-organ damage, and cardiovascular disease (CVD). Non-dipping, as determined by ambulatory blood pressure (BP) monitoring (ABPM), is frequent in CKD and has also been consistently associated with increased CVD risk. The reported prevalence of non-dipping in CKD is highly variable, probably due to relatively small sample sizes, reliance only on a single, low-reproducibility, 24-h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary fixed clock-hour spans. Accordingly, we assessed the circadian BP pattern of patients with and without CKD by 48-h ABPM to increase reproducibility of the results. This cross-sectional study involved 10 271 hypertensive patients (5506 men/4765 women), 58.0?±?14.2 (mean?±?SD) yrs of age, enrolled in the Hygia Project. Among the participants, 3227 (1925 men/1302 women) had CKD. At the time of recruitment, 568/2234 patients with/without CKD were untreated for hypertension. Patients with than without CKD were more likely to be men and of older age, have diagnoses of obstructive sleep apnea, metabolic syndrome, diabetes, and/or obesity, plus have higher glucose, creatinine, uric acid, and triglyceride, but lower cholesterol, concentrations. In patients with CKD, ambulatory systolic BP (SBP) was significantly elevated (p?<?.001), mainly during the hours of nighttime sleep, independent of presence/absence of BP-lowering treatment. In patients without CKD, ambulatory diastolic BP (DBP), however, was significantly higher (p?<?.001), mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p?<?.001) for the entire 24?h in patients with CKD. Prevalence of non-dipping was significantly higher in patients with than without CKD (60.6% vs. 43.2%; p?<?.001). The largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean?>?awake SBP mean (17.6% vs. 7.1% in patients with and without CKD, respectively; p?<?.001). The riser BP pattern significantly and progressively increased from 8.1% among those with stage 1 CKD to a very high 34.9% of those with stage 5 CKD. Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with CKD; thus, among the uncontrolled hypertensive patients with CKD, 90.7% had nocturnal hypertension. Our findings document significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with CKD. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was 2.5-fold more prevalent in CKD, and up to 5-fold more prevalent in end-stage renal disease. Patients with CKD also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. Collectively, these findings indicate that CKD should be included among the clinical conditions for which ABPM is mandatory for proper diagnosis and CVD risk assessment, as well as a means to establish the best therapeutic scheme to increase CVD event-free survival. (Author correspondence: rhermida@uvigo.es)     

Cinacalcet in Patients with Chronic Kidney Disease: A Cumulative Meta-Analysis of Randomized Controlled Trials

Background

Calcimimetic agents lower serum parathyroid hormone levels in people with chronic kidney disease (CKD), but treatment effects on patient-relevant outcomes are uncertain. We conducted a systematic review and meta-analysis to summarize the benefits and harms of calcimimetic therapy in adults with CKD and used cumulative meta-analysis to identify how evidence for calcimimetic treatment has developed in this clinical setting.

Methods and Findings

Cochrane and Embase databases (through February 7, 2013) were electronically searched to identify randomized trials evaluating effects of calcimimetic therapy on mortality and adverse events in adults with CKD. Two independent reviewers identified trials, extracted data, and assessed risk of bias.Eighteen trials comprising 7,446 participants compared cinacalcet plus conventional therapy with placebo or no treatment plus conventional therapy in adults with CKD. In moderate- to high-quality evidence (based on Grading of Recommendations Assessment, Development, and Evaluation criteria) in adults with CKD stage 5D (dialysis), cinacalcet had little or no effect on all-cause mortality (relative risk, 0.97 [95% confidence interval, 0.89–1.05]), had imprecise effect on cardiovascular mortality (0.67 [0.16–2.87]), and prevented parathyroidectomy (0.49 [0.40–0.59]) and hypercalcemia (0.23 [0.05–0.97]), but increased hypocalcemia (6.98 [5.10–9.53]), nausea (2.02 [1.45–2.81]), and vomiting (1.97 [1.73–2.24]). Data for clinical outcomes were sparse in adults with CKD stages 3–5. On average, treating 1,000 people with CKD stage 5D for 1 y had no effect on survival and prevented about three patients from experiencing parathyroidectomy, whilst 60 experienced hypocalcemia and 150 experienced nausea. Analyses were limited by insufficient data in CKD stages 3–5 and kidney transplant recipients.

Conclusions

Cinacalcet reduces the need for parathyroidectomy in patients with CKD stage 5D, but does not appear to improve all-cause or cardiovascular mortality. Additional trials in CKD stage 5D are unlikely to change our confidence in the treatment effects of cinacalcet in this population. Please see later in the article for the Editors'' Summary     

Heart Failure in a Cohort of Patients with Chronic Kidney Disease: The GCKD Study

ConclusionsThe burden of self-reported and Gothenburg HF among patients with CKD is high. The proportion of patients who meet the criteria for Gothenburg HF in a European cohort of patients with moderate CKD is more than twice as high as the prevalence of self-reported HF. However, because of the shared signs, symptoms and medications of HF and CKD, the Gothenburg score cannot be used to reliably define HF in CKD patients. Our results emphasize the need for early screening for HF in patients with CKD.