Advanced Parameters of Cardiac Mechanics in Children with CKD: The 4C Study

Background and objectives

Newer parameters of cardiac mechanics provide additional insights on cardiac dysfunction in adult patients with CKD. The aim of this study was to identify prevalence of subclinical abnormalities in cardiac function through the analysis of novel indices of cardiac mechanics in a large population of children with CKD.

Design, setting, participants, & measurements

Between 2009 and 2011, the prospective observational Cardiovascular Comorbidity in Children with CKD Study enrolled patients with CKD ages 6–17 years old with eGFR=10–45 ml/min per 1.73 m² in 14 European countries. Cardiac morphology and function were assessed through echocardiography. The analysis presented encompasses global radial, longitudinal, and circumferential strains as well as time to peak analysis. Data were compared with 61 healthy children with comparable age and sex.

Results

Data on 272 patients with CKD with complete echocardiographic assessment are reported (age =12.8±3.5 years old; 65% boys). Patients with CKD showed mildly higher office BP values and higher prevalence of left ventricular hypertrophy, but no differences were observed among groups in left ventricular ejection fraction. Strain analysis showed significantly lower global radial strain (29.6%±13.3% versus 35.5%±8.9%) and circumferential strain components (−21.8%±4.8% versus −28.2%±5.0%; both P<0.05) in patients with CKD without significant differences observed in longitudinal strain (−15.9%±3.4% versus −16.2%±3.7%). Lower values of global radial strain were associated with lower circumferential endocardial-to-epicardial gradient (r=0.51; P<0.01). This association remained significant after adjusting for BP, eGFR, and presence of left ventricular hypertrophy. Eventually, patients with CKD also showed higher delay in time to peak cardiac contraction (58±28 versus 37±18 milliseconds; P<0.05).

Conclusions

A significant proportion of children with CKD show impaired systolic mechanics. Impaired systolic function is characterized by lower radial strain, transmural circumferential gradient, and mild cardiac dyssynchrony. This study suggests that analysis of cardiac strain is feasible in a large multicenter study in children with CKD and provides additional information on cardiac pathophysiology of this high-risk population.     

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial

Background and objectives

The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome–generated uremic toxins, IS and PCS, in patients with CKD.

Design, setting, participants, & measurements

Predialysis adult participants with CKD (eGFR=10–30 ml/min per 1.73 m²) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double–blind, placebo–controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1β, IL-6, IL-10, and TNF-α), serum oxidative stress biomarkers (F₂-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect.

Results

Of 37 individuals randomized (age =69±10 years old; 57% men; eGFR=24±8 ml/min per 1.73 m²), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (−2 μmol/L; 95% confidence interval [95% CI], −5 to 1 μmol/L) but did significantly reduce serum PCS (−14 μmol/L; 95% CI, −27 to −2 μmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, −25 μmol/L; 95% CI, −38 to −12 μmol/L; serum IS, −5 μmol/L; 95% CI, −8 to −1 μmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes.

Conclusion

In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large–scale clinical trials are justified.     

Serum 25-Hydroxyvitamin D Level and Kidney Function Decline in a Swiss General Adult Population

Background and objectives

Molecular evidence suggests that levels of vitamin D are associated with kidney function loss. Still, population-based studies are limited and few have considered the potential confounding effect of baseline kidney function. This study evaluated the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline, and incidence of CKD and albuminuria.

Design, setting, participants, & measurements

Baseline (2003–2006) and 5.5-year follow-up data from a Swiss adult general population were used to evaluate the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline (annual loss >3 ml/min per 1.73 m²), and incidence of CKD and albuminuria. Serum 25-hydroxyvitamin D was measured at baseline using liquid chromatography–tandem mass spectrometry. eGFR and albuminuria were collected at baseline and follow-up. Multivariate linear and logistic regression models were used considering potential confounding factors.

Results

Among the 4280 people included in the analysis, the mean±SD annual eGFR change was −0.57±1.78 ml/min per 1.73 m², and 287 (6.7%) participants presented rapid eGFR decline. Before adjustment for baseline eGFR, baseline 25-hydroxyvitamin D level was associated with both mean annual eGFR change and risk of rapid eGFR decline, independently of baseline albuminuria. Once adjusted for baseline eGFR, associations were no longer significant. For every 10 ng/ml higher baseline 25-hydroxyvitamin D, the adjusted mean annual eGFR change was −0.005 ml/min per 1.73 m² (95% confidence interval, −0.063 to 0.053; P=0.87) and the risk of rapid eGFR decline was null (odds ratio, 0.93; 95% confidence interval, 0.79 to 1.08; P=0.33). Baseline 25-hydroxyvitamin D level was not associated with incidence of CKD or albuminuria.

Conclusions

The association of 25-hydroxyvitamin D with eGFR decline is confounded by baseline eGFR. Sufficient 25-hydroxyvitamin D levels do not seem to protect from eGFR decline independently from baseline eGFR.     

Rate of Kidney Function Decline and Risk of Hospitalizations in Stage 3A CKD

Background and objectives

Risk of hospitalizations is increased in patients with CKD. We sought to examine the association between rate of kidney function decline and risk of hospitalization in a cohort of patients with early CKD.

Design, settings, participants, & measurements

We built a cohort of 247,888 United States veterans who had at least one eGFR measurement between October 1999 and September 2003 and an additional eGFR between October 2003 and September 2004. We selected patients whose initial eGFR was between 45 and 59 ml/min per 1.73 m². Rate of eGFR change (in milliliters per minute per 1.73 m² per year) was categorized as no decline (>0), mild (0 to −1, and served as the referent group), moderate (−1 to −5), or severe (>−5) eGFR decline. We built survival models to examine the association between the rate of kidney function decline and the risk of hospitalization and readmission and linear regression to estimate length of hospital stay.

Results

Over a median observation of 9 years (interquartile range, 5.28–9.00), patients with moderate and severe eGFR decline exhibited a higher risk of hospitalizations (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.19 to 1.26; and HR, 1.33; 95% CI, 1.28 to 1.39, respectively). Among patients with moderate and severe eGFR decline, the association between the rate of decline and the risk of hospitalizations was more pronounced with an increased number of hospitalizations (P<0.01). Patients with moderate and severe eGFR decline had a higher risk of readmission (HR, 1.19; 95% CI, 1.13 to 1.26; and HR, 1.53; 95% CI, 1.43 to 1.63, respectively). Among patients with severe eGFR decline, the association between the rate of kidney function decline and the risk of readmission was stronger with an increased number of readmissions (P<0.01). Patients with moderate and severe eGFR decline experienced an additional length of stay of 1.40 (95% CI, 0.88 to 1.92) and 5.00 days per year (95% CI, 4.34 to 5.66), respectively.

Conclusions

The rate of kidney function decline is associated with a higher risk of hospitalizations, readmissions, and prolonged length of hospital stay.     

The Microvasculature in Chronic Kidney Disease

Summary

Background and objectives

Individuals with chronic kidney disease (CKD) stages 3 to 5 have an increased risk of cardiac and other vascular disease. Here we examined the association of CKD 3 to 5 with small vessel caliber.

Design, setting, participants, & measurements

This was a cross-sectional observational study of 126 patients with CKD stages 3 to 5 (estimated GFR [eGFR] <60 ml/min per 1.73 m²) and 126 age- and gender-matched hospital patients with CKD 1 or 2. Retinal vessel diameters were measured from digital fundus images by a trained grader using a computer-assisted method and summarized as the central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE).

Results

Patients with CKD 3 to 5 had a smaller mean CRAE and CRVE than hospital controls (139.4 ± 17.8 μm versus 148.5 ± 16.0 μm, P < 0.001; and 205.0 ± 30.7 μm versus 217.4 ± 25.8 μm, respectively; P = 0.001). CRAE and CRVE decreased progressively with each stage of renal failure CKD1–2 to 5 (P for trend = 0.08 and 0.04, respectively). CKD and hypertension were independent determinants of arteriolar narrowing after adjusting for age, gender, diabetes, dyslipidemia, and smoking history. Patients with CKD 5 and diabetes had a larger mean CRAE and CRVE than nondiabetics (141.4 ± 14.9 μm versus 132.9 ± 14.2 μm; 211.1 ± 34.4 μm versus 194.8 ± 23.8 μm).

Conclusions

The microvasculature is narrowed in patients with reduced eGFR.     

Casual Blood Pressure and Neurocognitive Function in Children with Chronic Kidney Disease: A Report of the Children with Chronic Kidney Disease Cohort Study

Summary

Background and objectives

Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction, and over half have hypertension. Data on the potential contribution of hypertension to CKD-associated neurocognitive deficits in children are limited. Our objective was to determine whether children with CKD and elevated BP (EBP) had decreased performance on neurocognitive testing compared with children with CKD and normal BP.

Design, setting, participants, & measurements

This was a cross-sectional analysis of the relation between auscultatory BP and neurocognitive test performance in children 6 to 17 years enrolled in the Chronic Kidney Disease in Children (CKiD) project.

Results

Of 383 subjects, 132 (34%) had EBP (systolic BP and/or diastolic BP ≥90^th percentile). Subjects with EBP had lower mean (SD) scores on Wechsler Abbreviated Scales of Intelligence (WASI) Performance IQ than those with normal BP (normal BP versus EBP, 96.1 (16.7) versus 92.4 (14.9), P = 0.03) and WASI Full Scale IQ (97.0 (16.2) versus 93.4 (16.5), P = 0.04). BP index (subject''s BP/95^th percentile BP) correlated inversely with Performance IQ score (systolic, r = −0.13, P = 0.01; diastolic, r = −0.19, P < 0.001). On multivariate analysis, the association between lower Performance IQ score and increased BP remained significant after controlling for demographic and disease-related variables (EBP, β = −3.7, 95% confidence interval [CI]: −7.3 to −0.06; systolic BP index, β = −1.16 to 95% CI: −2.1, −0.21; diastolic BP index, β = −1.17, 95% CI: −1.8 to −0.55).

Conclusions

Higher BP was independently associated with decreased WASI Performance IQ scores in children with mild-to-moderate CKD.     

The Impact of Antihypertensive Drug Therapy on Endotoxemia in Elderly Patients with Chronic Kidney Disease

Summary

Background and objectives

Endotoxin (ET) is recognized to cause adverse effects on cardiovascular (CV) structure. Circulatory translocation of gut bacterial ET is described in heart failure. Chronic kidney disease (CKD) is common in older people and aggressive BP control is the cornerstone of management. We therefore studied ET after improvement of the overall CV milieu with introduction of optimized antihypertensive therapy (AHT).

Design, setting, participants, & measurements

We recruited 40 hypertensive nondiabetic patients (≥70 years) with CKD stages 3 and 4 and hypertensive non-CKD matched controls. Assessment was performed after complete AHT washout and repeated after AHT reintroduction to target BP 130/80 mmHg. Pulse wave velocity (PWV) and analysis were assessed by applanation tonometry, central hemodynamics by continuous digital pulse wave analysis, vascular calcification (VC) by superficial femoral artery CT, and serum ET by Limulus Amebocyte assay.

Results

Mean age was 76 ± 5 years, estimated GFR (eGFR) (CKD group) was 40 ± 14 ml/min per 1.73 m², and achieved BP was 128/69 mmHg. Washout ET was 0.042 ± 0.011 EU/ml and was independent of renal function, gender, age, BP, VC, arterial stiffness, and high-sensitivity C-reactive protein. ET significantly decreased with AHT (to 0.020 ± 0.028 EU/ml; P < 0.001) and was associated with eGFR (R = −0.38; P = 0.02), arterial wave reflection (Augmentation Index R = −0.42; P = 0.01), and degree of tonic vasodilatation (total peripheral resistance R = −0.37; P = 0.03), but not VC, PWV, gender, age, BP, or high-sensitivity C-reactive protein.

Conclusions

Elderly patients with hypertension have elevated serum ET. Improvement of their CV status with optimized AHT is associated with a significant reduction in endotoxemia. Further investigation of the potential pathophysiological mechanisms linking CV disease and CKD with this previously unappreciated effect of AHT appears warranted.     

Clinical Correlates of Insulin Sensitivity and Its Association with Mortality among Men with CKD Stages 3 and 4

Background and objectives

Insulin resistance participates in the pathogenesis of multiple metabolic and cardiovascular diseases. CKD patients have impaired insulin sensitivity, but the clinical correlates and outcome associations of impaired insulin sensitivity in this vulnerable population are not well defined.

Design, setting, participants, & measurements

The prospective cohort study was from the third examination cycle of the Uppsala Longitudinal Study of Adult Men, a population-based survey of elderly men ages 70–71 years; insulin sensitivity was assessed by glucose disposal rate as measured with euglycemic clamps. Inclusion criterion was eGFR<60 ml/min per 1.73 m² (n=543). Exclusion criteria were incomplete data on euglycemic clamp and diabetes (n=97), leaving 446 men with CKD stages 3 and 4 (eGFR median=51.9 ml/min per 1.73 m²; range=20.2–59.5 ml/min per 1.73 m²).

Results

The mean of glucose disposal rate was 5.4±1.9 mg/kg per minute. In multivariable analysis, the independent clinical correlates of glucose disposal rate were eGFR (slope, 0.02; 95% confidence interval, 0.01 to 0.04), hypertension (−0.48; 95% confidence interval, −0.86 to −0.11), hyperlipidemia (−0.51; 95% confidence interval, −0.84 to −0.18), and body mass index (−0.32; 95% confidence interval, −0.37 to −0.27). During follow-up (median=10.0 years; interquartile range=8.7–11.0 years), 149 participants died. In Cox regression models, glucose disposal rate was not associated with all-cause or cardiovascular mortality. Multiplicative interactions (P<0.05) were observed between glucose disposal rate and physical activity or smoking in total mortality association. After subsequent stratification, glucose disposal rate was an independent correlate of all-cause mortality in smokers (adjusted hazard ratio, 0.72; 95% confidence interval, 0.54 to 0.96 per 1 mg/kg per minute glucose disposal rate increase) and physically inactive individuals (hazard ratio, 0.77; 95% confidence interval, 0.61 to 0.97) but not their counterparts.

Conclusion

eGFR, together with various components of the metabolic syndrome, contributed to explain the variance of insulin sensitivity in men with CKD stages 3 and 4. Insulin sensitivity was associated with a lower mortality risk in individuals who smoked and individuals who were physically inactive.     

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

Background and objectives

High serum IL-6 is a major risk factor for cardiovascular disease (CVD) in the general population. This cytokine is substantially increased in patients with CKD, but it is still unknown whether the link between IL-6 and CVD in CKD is causal in nature.

Design, setting, participants, & measurements

In a cohort of 755 patients with stages 2–5 CKD, consecutively recruited from 22 nephrology units in southern Italy, this study assessed the relationship of serum IL-6 with history of CVD, as well as with incident cardiovascular (CV) events (mean follow up±SD, 31±10 months) and used the functional polymorphism (−174 G/C) in the promoter of the IL-6 gene to investigate whether the link between IL-6 and CV events is causal.

Results

In adjusted analyses, serum IL-6 above the median value was associated with history of CVD (P<0.001) and predicted the incidence rate of CV events (hazard ratio, 1.66; 95% confidence interval [95% CI], 1.11 to 2.49; P=0.01). Patients homozygous for the risk allele (C) of the −174 G/C polymorphism had higher levels of IL-6 than did those with other genotypes (P=0.04). Homozygous CC patients more frequently had a history of CVD (odds ratio, 2.15; 95% CI, 1.15 to 4.00; P=0.02) as well as a 87% higher rate of incident CV events (hazard ratio, 1.87; 95% CI, 1.02 to 3.44; P=0.04) compared with other genotypes.

Conclusions

In patients with stages 2–5 CKD, high serum IL-6 is associated with history of CVD and predicts incident CV events. The parallel relationship with history of CVD and incident CV events of the −174 G/C polymorphism in the IL-6 gene suggests that IL-6 may be causally involved in the high CV risk in this population.     

Outcomes After Post-Traumatic AKI Requiring RRT in United States Military Service Members

Background and objectives

Mortality and CKD risk have not been described in military casualties with post-traumatic AKI requiring RRT suffered in the Iraq and Afghanistan wars.

Design, setting, participants, & measurements

This is a retrospective case series of post-traumatic AKI requiring RRT in 51 military health care beneficiaries (October 7, 2001–December 1, 2013), evacuated to the National Capital Region, documenting in-hospital mortality and subsequent CKD. Participants were identified using electronic medical and procedure records.

Results

Age at injury was 26±6 years; of the participants, 50 were men, 16% were black, 67% were white, and 88% of injuries were caused by blast or projectiles. Presumed AKI cause was acute tubular necrosis in 98%, with rhabdomyolysis in 72%. Sixty-day all-cause mortality was 22% (95% confidence interval [95% CI], 12% to 35%), significantly less than the 50% predicted historical mortality (P<0.001). The VA/NIH Acute Renal Failure Trial Network AKI integer score predicted 60-day mortality risk was 33% (range, 6%–96%) (n=49). Of these, nine died (mortality, 18%; 95% CI, 10% to 32%), with predicted risks significantly miscalibrated (P<0.001). The area under the receiver operator characteristic curve for the AKI integer score was 0.72 (95% CI, 0.56 to 0.88), not significantly different than the AKI integer score model cohort (P=0.27). Of the 40 survivors, one had ESRD caused by cortical necrosis. Of the remaining 39, median time to last follow-up serum creatinine was 1158 days (range, 99–3316 days), serum creatinine was 0.85±0.24 mg/dl, and eGFR was 118±23 ml/min per 1.73 m². No eGFR was <60 ml/min per 1.73 m², but it may be overestimated because of large/medium amputations in 54%. Twenty-five percent (n=36) had proteinuria; one was diagnosed with CKD stage 2.

Conclusions

Despite severe injuries, participants had better in-hospital survival than predicted historically and by AKI integer score. No patient who recovered renal function had an eGFR<60 ml/min per 1.73 m² at last follow-up, but 23% had proteinuria, suggesting CKD burden.     

Added Value of Screening for CKD among the Elderly or Persons with Low Socioeconomic Status

Background and objective

Three screening approaches were compared for their ability to detect CKD cases, and identify patients with CKD who have a higher rate of incident cardiovascular disease (CVD) events and renal function decline. Approach 1 was the traditional CKD screening approach, targeting only individuals with known diabetes, hypertension, or CVD history. Approach 2 was defined as Approach 1+elderly, and Approach 3 as Approach 1+low–socioeconomic status (SES) individuals.

Design, setting, participants, & measurements

Data on 3411 individuals from the general population in The Netherlands were examined. Individuals aged >60 years were classified as elderly. Persons with low SES was defined as those with primary school or below primary school education. CKD was diagnosed during outpatient clinic visits. Individuals were followed for 9.4±2.6 years during four screening rounds.

Results

At baseline, 16%, 29%, and 25% of the general population was to be screened and 36%, 59%, and 51% of the CKD (n=263) cases were detected in Approaches 1, 2, and 3, respectively. The numbers of individuals needed to screen to detect one CKD case were 5.6 in Approach 1 and 6.5 each in Approach 2 and 3. In Approach 2 the hazard ratio for incident CVD events was 1.87 (95% confidence interval [95% CI], 1.35 to 2.61) in detected and 1.92 (95% CI, 1.01 to 3.64) in undetected CKD cases compared with persons without CKD, whereas in Approach 3 these values were 2.31 (95% CI, 1.64 to 3.25) and 1.28 (95% CI, 0.77 to 2.13), respectively. In Approach 2, the rate of renal function decline was −1.37 ml/min per 1.73 m² per year in detected and −1.13 ml/min per 1.73 m² per year in undetected CKD cases. In Approach 3, these figures were −1.41 and −1.14 ml/min per 1.73 m² per year, respectively.

Conclusions

Adding persons with low SES, rather than adding elderly persons, to the traditional high-risk groups may help detect more persons with CKD who have a higher rate of future CVD events and renal function decline.     

Association of Cognitive Function with Albuminuria and eGFR in the General Population

Summary

Background and objectives

Recent studies found different associations of cognitive function with albuminuria or estimated GFR (eGFR). Most studies were limited to the elderly or did not take both renal variables into account. Therefore, this study analyzed the association of cognitive function with albuminuria and eGFR in community-dwelling persons aged 35 to 82 years.

Design, setting, participants, & measurements

This was a cross-sectional study comprising 4095 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Cognitive function, measured with the Ruff Figural Fluency Test (RFFT), was treated as the dependent variable, and albuminuria and eGFR were treated as independent variables.

Results

The prevalence of albuminuria <10, 10 to 29, and ≥30 mg/24 h was 54%, 31%, and 15%, respectively. Mean eGFR (± SD) was 79 ± 15 ml/min per 1.73 m². Because of interaction between albuminuria and age, analyses were performed per age tertile. After multivariate adjustment, albuminuria ≥ 30 mg/24 h, but not eGFR, was associated with lower RFFT score in the youngest tertile (B −5.3; 95% CI, −0.6 to −9.2; P = 0.05), but not in older tertiles. Moreover, subjects in the youngest tertile with increasing albuminuria (5–15 and >15 mg/24 h) before RFFT measurement had lower mean RFFT scores than subjects with stable albuminuria: mean difference −4.9 (P = 0.3) and −6.7 (P = 0.03), respectively.

Conclusions

In this community-based cohort, elevated albuminuria was associated with worse cognitive function in young but not in old persons. There was no association of eGFR with cognitive function.     

Cardiac Resynchronization Therapy in CKD Stage 4 Patients

Background and objectives

Cardiac resynchronization therapy (CRT) is a well established heart failure treatment that has shown to improve renal function. However, landmark CRT trials excluded patients with severe renal dysfunction. Therefore, this study evaluated the effect of CRT on renal function and long-term prognosis in patients with stage 4 CKD.

Design, setting, participants, & measurements

This study evaluated 73 consecutive CRT patients (71±10 years) with stage 4 CKD who underwent echocardiographic and renal function evaluation at baseline and 6-month follow-up between 2000 and 2012. As a control group, 18 patients with stage 4 CKD who received an implantable cardioverter defibrillator (ICD) were selected. CRT recipients with ≥15% reduction in left ventricular end-systolic volume at 6-month follow-up were classified as CRT responders. During long-term follow-up (median, 33 months), appropriate defibrillator therapy, heart failure hospitalizations, and all-cause mortality (combined end point) were recorded.

Results

At 6-month follow-up, a significant reduction in left ventricular end-systolic volume was observed in CRT patients compared with patients with ICD (from 159±78 to 145±78 ml in CRT patients and from 126±54 to 119±49 ml in ICD patients; P=0.05), and CRT response was observed in 22 patients (30%). Compared with ICD patients, eGFR improved among CRT patients (from 25±4 to 30±9 ml/min per 1.73 m²; interaction time and group, P=0.04) and was more pronounced among CRT responders (25±3 to 34±9 ml/min per 1.73 m²; P<0.001). The combined end point was observed in 17 ICD and 62 CRT patients. CRT patients showed superior survival compared with ICD patients (log-rank P=0.03). More importantly, CRT response was independently associated with improved survival free from the combined end point (hazard ratio, 0.51; 95% confidence interval, 0.27 to 0.98; P=0.04) after adjustment for clinical and echocardiographic parameters.

Conclusions

Response to CRT occurs in approximately 30% of patients with stage 4 CKD, which is less than in the average CRT population. CRT was associated with better clinical outcome, and particularly, CRT response was associated with improvement in eGFR and better long-term prognosis.     

Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-Analysis of Randomized Controlled Trials

Background and objectives

People with CKD stages 3–5 and on dialysis (5D) have dramatically increased mortality, which has been associated with hyperphosphatemia in many studies. Oral phosphate binders are commonly prescribed to lower serum phosphate. We conducted an updated meta-analysis of the noncalcium–based binder (non-CBB) sevelamer versus CBBs in CKD stages 3–5D.

Design, setting, participants, & measurements

Randomized, controlled trials comparing sevelamer with CBBs were identified through MEDLINE and the Cochrane Central Register of Controlled Trials. Patient-level outcomes included all-cause mortality, cardiovascular events and mortality, hospitalization, and adverse effects. Intermediate outcomes included vascular calcification and bone changes. Biochemical outcomes included serum phosphate, calcium, parathyroid hormone, lipids, and hypercalcemia. We conducted and reported this review according to Cochrane guidelines.

Results

We included 25 studies to March 31, 2015 with 4770 participants (88% on hemodialysis). Patients receiving sevelamer had lower all–cause mortality (risk ratio [RR], 0.54; 95% confidence interval [95% CI], 0.32 to 0.93), no statistically significant difference in cardiovascular mortality (n=2712; RR, 0.33; 95% CI, 0.07 to 1.64), and an increase in combined gastrointestinal events of borderline statistical significance (n=384; RR, 1.42; 95% CI, 0.97 to 2.08). For biochemical outcomes, patients receiving sevelamer had lower total serum cholesterol (mean difference [MD], −20.2 mg/dl; 95% CI, −25.9 to −14.5 mg/dl), LDL-cholesterol (MD, −21.6 mg/dl; 95% CI, −27.9 to −15.4 mg/dl), and calcium (MD, −0.4 mg/dl; 95% CI, −0.6 to −0.2 mg/dl) and a reduced risk of hypercalcemia (RR, 0.30; 95% CI, 0.19 to 0.48). End of treatment intact parathyroid hormone was significantly higher for sevelamer (MD, 32.9 pg/ml; 95% CI, 0.1 to 65.7 pg/ml). Serum phosphate values showed no significant differences.

Conclusions

Patients with CKD stages 3–5D using sevelamer have lower all–cause mortality compared with those using CBBs. Because of a lack of placebo-controlled studies, questions remain regarding phosphate binder benefits for patients with CKD stages 3–5 and not on dialysis.     

Association of Urine α1-Microglobulin with Kidney Function Decline and Mortality in HIV-Infected Women

Background and objectives

Despite advances in therapy, HIV-infected individuals remain at higher risk for kidney dysfunction than uninfected individuals. It was hypothesized that urine levels of α1-microglobulin, a biomarker of proximal tubular dysfunction, would predict kidney function decline and mortality risk in HIV-infected and uninfected women.

Design, setting, participants, & measurements

In the Women’s Interagency HIV Study, urine α1-microglobulin and creatinine concentrations were measured in 903 HIV-infected and 287 uninfected women using stored urine from 1999 to 2000, when prevalence of tenofovir use was <1%. Participants were categorized into three categories by level of α1-microglobulin–to-creatinine ratio, and associations with kidney decline and all-cause mortality over 8 years were evaluated.

Results

Urine α1-microglobulin was detectable in 60% of HIV-infected and 40% of uninfected women (P<0.001). Among HIV-infected women, there were 177 (22%), 61 (7%), and 128 (14%) patients with incident CKD, with 10% annual eGFR decline, and who died, respectively. Compared with HIV-infected women in the lowest α1-microglobulin category, HIV-infected women in the highest α1-microglobulin category had a 2.1-fold risk of incident CKD (95% confidence interval, 1.3 to 3.4), 2.7-fold risk of 10% annual eGFR decline (95% confidence interval, 1.2 to 5.9), and 1.6-fold mortality risk (95% confidence interval, 1.0 to 2.6) in models adjusting for kidney risk factors, baseline eGFR, and albuminuria. Among uninfected women, the highest α1-microglobulin category was associated with 3% (relative risk, 2.2; 95% confidence interval, 1.4 to 3.5) and 5% (relative risk, 2.2; 95% confidence interval, 1.1 to 4.3) annual eGFR decline relative to the lowest α1-microglobulin category.

Conclusions

Proximal tubular dysfunction, indicated by urine α1-microglobulin, was independently associated with kidney function decline in HIV-infected and uninfected women and mortality risk among HIV-infected women.     

Ferric Citrate Hydrate for the Treatment of Hyperphosphatemia in Nondialysis-Dependent CKD

Background and objectives

Ferric citrate hydrate is a novel iron-based phosphate binder being developed for hyperphosphatemia in patients with CKD.

Design, setting, participants, & measurements

A phase 3, multicenter, randomized, double blind, placebo-controlled study investigated the efficacy and safety of ferric citrate hydrate in nondialysis-dependent patients with CKD. Starting in April of 2011, 90 CKD patients (eGFR=9.21±5.72 ml/min per 1.73 m²) with a serum phosphate≥5.0 mg/dl were randomized 2:1 to ferric citrate hydrate or placebo for 12 weeks. The primary end point was change in serum phosphate from baseline to the end of treatment. Secondary end points included the percentage of patients achieving target serum phosphate levels (2.5–4.5 mg/dl) and change in fibroblast growth factor-23 at the end of treatment.

Results

The mean change in serum phosphate was −1.29 mg/dl (95% confidence interval, −1.63 to −0.96 mg/dl) in the ferric citrate hydrate group and 0.06 mg/dl (95% confidence interval, −0.20 to 0.31 mg/dl) in the placebo group (P<0.001 for difference between groups). The percentage of patients achieving target serum phosphate levels was 64.9% in the ferric citrate hydrate group and 6.9% in the placebo group (P<0.001). Fibroblast growth factor-23 concentrations were significantly lower in patients treated with ferric citrate hydrate versus placebo (change from baseline [median], −142.0 versus 67.0 pg/ml; P<0.001). Ferric citrate hydrate significantly increased serum iron, ferritin, and transferrin saturation compared with placebo (P=0.001 or P<0.001). Five patients discontinued active treatment because of treatment-emergent adverse events with ferric citrate hydrate treatment versus one patient with placebo. Overall, adverse drug reactions were similar in patients receiving ferric citrate hydrate or placebo, with gastrointestinal disorders occurring in 30.0% of ferric citrate hydrate patients and 26.7% of patients receiving placebo.

Conclusion

In patients with nondialysis-dependent CKD, 12-week treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and fibroblast growth factor-23 while simultaneously increasing serum iron parameters.     

Racial and Ethnic Differences in Mortality among Individuals with Chronic Kidney Disease: Results from the Kidney Early Evaluation Program (KEEP)

Summary

Background and objectives

Chronic kidney disease (CKD) is prevalent in minority populations and racial/ethnic differences in survival are incompletely understood.

Design, setting, participants, & measurements

Secondary analysis of Kidney Early Evaluation Program participants from 2000 through 2008 with CKD, not on dialysis, and without previous kidney transplant was performed. Self-reported race/ethnicity was categorized into five groups: non-Hispanic white, African American, Asian, American Indian/Alaska Native, and Hispanic. CKD was defined as a urinary albumin to creatinine ratio of ≥30 mg/g among participants with an estimated GFR (eGFR) ≥60 ml/min per 1.73 m² or an eGFR of <60 ml/min per 1.73 m². The outcome was all-cause mortality. Covariates used were age, sex, obesity, diabetes, hypertension, albuminuria, baseline eGFR, heart attack, stroke, smoking, family history, education, health insurance, geographic region, and year screened.

Results

19,205 participants had prevalent CKD; 55% (n = 10,560) were White, 27% (n = 5237) were African American, 9% (n = 1638) were Hispanic, 5% (n = 951) were Asian, and 4% (n = 813) were American Indian/Alaska Native. There were 1043 deaths (5.4%). African Americans had a similar risk of death compared with Whites (adjusted Hazard Ratio (AHR) 1.07, 95% CI 0.90 to 1.27). Hispanics (AHR 0.66, 95% CI 0.50 to 0.94) and Asians (AHR 0.63, 95% CI 0.41 to 0.97) had a lower mortality risk compared with Whites. In contrast, American Indians/Alaska Natives had a higher risk of death compared with Whites (AHR 1.41, 95% CI 1.08 to 1.84).

Conclusions

Significant differences in mortality among some minority groups were found among persons with CKD detected by community-based screening.     

Masked Hypertension and Elevated Nighttime Blood Pressure in CKD: Prevalence and Association with Target Organ Damage

Background and objectives

Masked hypertension and elevated nighttime BP are associated with increased risk of hypertensive target organ damage and adverse cardiovascular and renal outcomes in patients with normal kidney function. The significance of masked hypertension for these risks in patients with CKD is less well defined. The objective of this study was to evaluate the association between masked hypertension and kidney function and markers of cardiovascular target organ damage, and to determine whether this relationship was consistent among those with and without elevated nighttime BP.

Design, setting, participants, & measurements

This was a cross-sectional study. We performed 24-hour ambulatory BP in 1492 men and women with CKD enrolled in the Chronic Renal Insufficiency Cohort Study. We categorized participants into controlled BP, white-coat, masked, and sustained hypertension on the basis of clinic and 24-hour ambulatory BP. We obtained echocardiograms and measured pulse wave velocity in 1278 and 1394 participants, respectively.

Results

The percentages of participants with controlled BP, white-coat, masked, and sustained hypertension were 49.3%, 4.1%, 27.8%, and 18.8%, respectively. Compared with controlled BP, masked hypertension independently associated with low eGFR (−3.2 ml/min per 1.73 m²; 95% confidence interval, −5.5 to −0.9), higher proteinuria (+0.9 unit higher in log₂ urine protein; 95% confidence interval, 0.7 to 1.1), and higher left ventricular mass index (+2.52 g/m^2.7; 95% confidence interval, 0.9 to 4.1), and pulse wave velocity (+0.92 m/s; 95% confidence interval, 0.5 to 1.3). Participants with masked hypertension had lower eGFR only in the presence of elevated nighttime BP (−3.6 ml/min per 1.73 m²; 95% confidence interval, −6.1 to −1.1; versus −1.4 ml/min per 1.73 m²; 95% confidence interval, −6.9 to 4.0, among those with nighttime BP <120/70 mmHg; P value for interaction with nighttime systolic BP 0.002).

Conclusions

Masked hypertension is common in patients with CKD and associated with lower eGFR, proteinuria, and cardiovascular target organ damage. In patients with CKD, ambulatory BP characterizes the relationship between BP and target organ damage better than BP measured in the clinic alone.     

Lifetime Risk of Stage 3–5 CKD in a Community-Based Sample in Iceland

Background and objectives

Lifetime risk estimates of CKD can be used effectively in public education campaigns. This study sought to estimate lifetime risk of incident CKD stage 3 and higher in Iceland for people without CKD by the age of 45 years.

Design, setting, participants, & measurements

This was a prospective cohort study with longitudinal creatinine measurements of residents in Reykjavik, Iceland, from 1967 to 2005. CKD was ascertained by two consecutive eGFR measurements <60 ml/min per 1.73 m², development of treated kidney failure, one eGFR<60 ml/min per 1.73 m² if the participant died before the next evaluation, or one eGFR<45 ml/min per 1.73 m² if it was the last eGFR.

Results

Mean follow-up was 25 (SD 10) years. Of the study participants, 727 (19%) developed the outcome and 942 (24%) died first. By age 85 years, the lifetime risks for 45-year-old women and men without prevalent CKD were 35.8% (95% confidence interval [95% CI], 32.7 to 38.9) and 21.3% (95% CI, 18.7 to 23.8), respectively. Risk was higher in individuals with a lower eGFR, hypertension, and a higher body mass index. Lifetime risk for higher stages of CKD 3b and 4 were less common than stage 3a; by age 85 years, the lifetime risks for CKD stages 3a, 3b, and 4 in women were 38.5% (95% CI, 25.8 to 51.1), 19.4% (95% CI, 8.9 to 29.9), and 3.6% (95% CI, 2.2 to 5.0), respectively.

Conclusions

The lifetime risk of developing CKD stage 3 or higher is substantial, emphasizing the importance of strategies to prevent development of CKD throughout the course of life. Estimates are lower than reported using single estimates of GFR, emphasizing the importance of confirming estimates of reduced GFR in studies of CKD.     

Is Coronary Artery Calcification Associated with Vertebral Bone Density in Nondialyzed Chronic Kidney Disease Patients?

Summary

Background and objectives

Low bone mineral density and coronary artery calcification (CAC) are highly prevalent among chronic kidney disease (CKD) patients, and both conditions are strongly associated with higher mortality. The study presented here aimed to investigate whether reduced vertebral bone density (VBD) was associated with the presence of CAC in the earlier stages of CKD.

Design, setting, participants, & measurements

Seventy-two nondialyzed CKD patients (age 52 ± 11.7 years, 70% male, 42% diabetics, creatinine clearance 40.4 ± 18.2 ml/min per 1.73 m²) were studied. VBD and CAC were quantified by computed tomography.

Results

CAC > 10 Agatston units (AU) was observed in 50% of the patients (median 120 AU [interquartile range 32 to 584 AU]), and a calcification score ≥ 400 AU was found in 19% (736 [527 to 1012] AU). VBD (190 ± 52 Hounsfield units) correlated inversely with age (r = −0.41, P < 0.001) and calcium score (r = −0.31, P = 0.01), and no correlation was found with gender, creatinine clearance, proteinuria, lipid profile, mineral parameters, body mass index, and diabetes. Patients in the lowest tertile of VBD had expressively increased calcium score in comparison to the middle and highest tertile groups. In the multiple logistic regression analysis adjusting for confounding variables, low VBD was independently associated with the presence of CAC.

Conclusions

Low VBD was associated with CAC in nondialyzed CKD patients. The authors suggest that low VBD might constitute another nontraditional risk factor for cardiovascular disease in CKD.