Serum 25-Hydroxyvitamin D and Change in Estimated Glomerular Filtration Rate

Summary

Background and objectives

Mounting evidence suggests that 1,25-dihydroxyvitamin D prevents the progression of chronic kidney disease (CKD). It is not clear whether “nutritional” forms of vitamin D affect GFR.

Design, setting, participants, & measurements

We tested whether serum 25-hydroxyvitamin D concentration (25(OH)D), a measure of total vitamin D intake from cutaneous synthesis and dietary consumption, is associated with loss of estimated GFR among 1705 older adults with predominantly normal baseline kidney function participating in the Cardiovascular Health Study. Baseline 25(OH)D was measured by HPLC-tandem mass spectrometry. GFR was estimated at baseline and 4 years later using the CKD-EPI formula, with rapid GFR loss defined as 12 ml/min per 1.73 m² or more over 4 years.

Results

Rapid GFR loss was observed for 207 participants (12%). Each 10 ng/ml lower 25(OH)D was associated with a 25% greater risk of rapid GFR loss (95% confidence interval [CI] 5%, 49%, P = 0.01), adjusting for potential confounding characteristics. Compared with 25(OH)D ≥30 ng/ml, 25(OH)D concentrations 15 to 29 ng/ml and <15 ng/ml were associated with 29% (95% CI −13%, 91%) and 68% (95% CI 1%, 177%) greater adjusted risks of rapid GFR loss, respectively. Magnitudes of association were largest among participants with diabetes. Results were similar evaluating a composite outcome of rapid GFR loss, end stage renal disease, and death.

Conclusions

Insufficient 25(OH)D may be a modifiable risk factor for early GFR loss. We recommend clinical trials to determine whether vitamin D supplementation prevents the development and progression of CKD.     

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.     

Circulating Follistatin in Patients with Chronic Kidney Disease: Implications for Muscle Strength,Bone Mineral Density,Inflammation, and Survival

Summary

Background and objectives

Follistatin mediates muscle growth and bone mineralization. At present, it is unknown whether circulating follistatin levels are altered in chronic kidney disease (CKD) or links to CKD risk factors and outcomes.

Design, setting, participants, & measurements

Plasma follistatin levels were cross-sectionally analyzed in relation to protein-energy wasting (PEW), handgrip strength (HGS), bone mineral density (BMD), and inflammatory markers in 280 CKD stage 5 patients, 32 CKD stage 4 patients, 16 CKD stage 3 patients, and 32 control subjects. In CKD stage 5 patients survival was prospectively investigated during a follow-up period of up to 5 years.

Results

The plasma follistatin concentration was not higher in CKD stage 5 patients than in other CKD stages or controls. In CKD stage 5 patients, circulating follistatin positively correlated with age, high-sensitivity C-reactive protein (hsCRP), and IL-6; negatively correlated with HGS, serum creatinine, and BMD; and was increased in patients with PEW. In a multivariate logistic regression model, lower HGS, lower BMD, and higher hsCRP independently correlated with higher follistatin levels. In a Cox regression model, follistatin levels were not associated with all-cause mortality.

Conclusions

Circulating follistatin levels were neither elevated nor predicted outcome in patients with CKD. However, increased follistatin levels occurred together with increased inflammation, reduced muscle strength, and low BMD, suggesting an involvement of a mechanism including follistatin in the uremic wasting process.     

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.     

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.     

Predictors of Subclinical Atheromatosis Progression over 2 Years in Patients with Different Stages of CKD

Background and objectives

Ultrasonographic detection of subclinical atheromatosis is a noninvasive method predicting cardiovascular events. Risk factors predicting atheromatosis progression in CKD are unknown. Predictors of atheromatosis progression were evaluated in patients with CKD.

Design, setting, participants, & measurements

Our multicenter, prospective, observational study included 1553 patients with CKD (2009–2011). Carotid and femoral ultrasounds were performed at baseline and after 24 months. A subgroup of 476 patients with CKD was also randomized to undergo ultrasound examination at 12 months. Progression of atheromatosis was defined as an increase in the number of plaque territories analyzed by multivariate logistic regression.

Results

Prevalence of atheromatosis was 68.7% and progressed in 59.8% of patients after 24 months. CKD progression was associated with atheromatosis progression, suggesting a close association between pathologies. Variables significantly predicting atheromatosis progression, independent from CKD stages, were diabetes and two interactions of age with ferritin and plaque at baseline. Given that multiple interactions were found between CKD stage and age, phosphate, smoking, dyslipidemia, body mass index, systolic BP (SBP), carotid intima-media thickness, plaque at baseline, uric acid, cholesterol, 25-hydroxy vitamin D (25OH vitamin D), and antiplatelet and phosphate binders use, the analysis was stratified by CKD stages. In stage 3, two interactions (age with phosphate and plaque at baseline) were found, and smoking, diabetes, SBP, low levels of 25OH vitamin D, and no treatment with phosphate binders were positively associated with atheromatosis progression. In stages 4 and 5, three interactions (age with ferritin and plaque and plaque with smoking) were found, and SBP was positively associated with atheromatosis progression. In dialysis, an interaction between body mass index and 25OH vitamin D was found, and age, dyslipidemia, carotid intima-media thickness, low cholesterol, ferritin, and uric acid were positively associated with atheromatosis progression.

Conclusions

Atheromatosis progression affects more than one half of patients with CKD, and predictive factors differ depending on CKD stage.     

Chronic Kidney Disease Awareness Among Individuals with Clinical Markers of Kidney Dysfunction

Summary

Background and objectives

Awareness of chronic kidney disease (CKD) among providers and patients is low. Whether clinical cues prompt recognition of CKD is unknown. We examined whether markers of kidney disease that should trigger CKD recognition among providers are associated with higher individual CKD awareness.

Design, setting, participants, & measurements

CKD awareness was assessed in 1852 adults with an estimated GFR <60 ml/min per 1.73 m² using 1999 to 2008 National Health and Nutrition Examination Survey data. CKD awareness was a “yes” answer to “Have you ever been told you have weak or failing kidneys?” Participants were grouped by distribution of the following abnormal markers of CKD: hyperkalemia, acidosis, hyperphosphatemia, elevated blood urea nitrogen, anemia, albuminuria, and uncontrolled hypertension. Odds of CKD awareness associated with each abnormal marker and groupings of markers were estimated by multivariable logistic regression.

Results

Among individuals with kidney disease, only those with albuminuria had greater odds of CKD awareness (adjusted odds ratio, 4.0, P < 0.01) than those without. Odds of CKD awareness increased with each additional manifested clinical marker of CKD (adjusted odds ratio, 1.3, P = 0.05). Nonetheless, 90% of individuals with two to four markers of CKD and 84% of individuals with ≥5 markers of CKD were unaware of their disease.

Conclusions

Although individuals who manifest many markers of kidney dysfunction are more likely to be aware of their CKD, their CKD awareness remains low. A better understanding of mechanisms of awareness is required to facilitate earlier detection of CKD and implement therapy to minimize associated complications.     

Associations of Left Ventricular Hypertrophy and Geometry with Adverse Outcomes in Patients with CKD and Hypertension

Background and objectives

Left ventricular hypertrophy (LVH) and abnormal left ventricular (LV) geometry predict adverse outcomes in the general and hypertensive populations, but findings in CKD are still inconclusive.

Design, setting, participants, & measurements

We enrolled 445 patients with hypertension and CKD stages 2–5 in two academic nephrology clinics in 1999–2003 who underwent both echocardiography and ambulatory BP monitoring. LVH (LV mass >100 g/m² [women] and >131 g/m² [men]) and relative wall thickness (RWT) were used to define LV geometry: no LVH and RWT≤0.45 (normal), no LVH and RWT>0.45 (remodeling), LVH and RWT≤0.45 (eccentric), and LVH and RWT>0.45 (concentric). We evaluated the prognostic role of LVH and LV geometry on cardiovascular (CV; composite of fatal and nonfatal events) and renal outcomes (composite of ESRD and all-cause death).

Results

Age was 64.1±13.8 years old; 19% had diabetes, and 22% had CV disease. eGFR was 39.9±20.2 ml/min per 1.73 m². LVH was detected in 249 patients (56.0%); of these, 125 had concentric LVH, and 124 had eccentric pattern, whereas 71 patients had concentric remodeling. Age, women, anemia, and nocturnal hypertension were independently associated with both concentric and eccentric LVH, whereas diabetes and history of CV disease associated with eccentric LVH only, and CKD stages 4 and 5 associated with concentric LVH only. During follow-up (median, 5.9 years; range, 0.04–15.3), 188 renal deaths (112 ESRD) and 103 CV events (61 fatal) occurred. Using multivariable Cox analysis, concentric and eccentric LVH was associated with higher risk of CV outcomes (hazard ratio [HR], 2.59; 95% confidence interval [95% CI], 1.39 to 4.84 and HR, 2.79; 95% CI, 1.47 to 5.26, respectively). Similarly, greater risk of renal end point was detected in concentric (HR, 2.33; 95% CI, 1.44 to 3.80) and eccentric (HR, 2.30; 95% CI, 1.42 to 3.74) LVH. Sensitivity analysis using LVH and RWT separately showed that LVH but not RWT was associated with higher cardiorenal risk.

Conclusions

In patients with CKD, LVH is a strong predictor of the risk of poor CV and renal outcomes independent from LV geometry.     

Estimated Glomerular Filtration Rate Is a Poor Predictor of Concentration for a Broad Range of Uremic Toxins

Summary

Background and objectives

The degree of chronic kidney disease (CKD) is currently expressed in terms of GFR, which can be determined directly or estimated according to different formulas on the basis of serum creatinine and/or cystatin C measurements (estimated GFR [eGFR]). The purpose of this study was to investigate whether eGFR values are representative for uremic toxin concentrations in patients with different degrees of CKD.

Design, setting, participants, & measurements

Associations between eGFR based on serum cystatin C and different uremic solutes (mol wt range 113 to 240 D; determined by colorimetry, HPLC, or ELISA) were evaluated in 95 CKD patients not on dialysis (CKD stage 2 to 5). The same analysis was also applied for six other eGFR formulas.

Results

There was a substantial disparity in fits among solutes. In linear regression, explained variance of eGFR was extremely low for most solutes, with eGFR > 0.4 only for creatinine. The other eGFR formulations gave comparably disappointing results with regard to their association to uremic solutes. Relative similarity in R² values per solute for the different eGFR values and the strong disparity in values between solutes suggest that the differences in R² are mainly due to discrepancies in solute handling apart from GFR.

Conclusions

eGFR is poorly associated with concentrations of all studied uremic toxins in patients with different degrees of CKD, correlates differently with each individual solute, and can thus not be considered representative for evaluating the accumulation of solutes in the course of CKD.     

Implications of the CKD-EPI GFR Estimation Equation in Clinical Practice

Summary

Background and objectives

Chronic kidney disease (CKD) is a significant public health problem whose diagnosis and staging relies upon GFR-estimating equations, including the new CKD-EPI equation. CKD-EPI demonstrated superior performance compared with the existing MDRD equation but has not been applied to a healthcare system.

Design, setting, participants, & measurements

We identified 53,759 patients with stages 3 to 5 CKD on the basis of either MDRD or CKD-EPI equations using two eGFR values <60 ml/min per 1.73 m² >90 days apart from an outpatient setting. We compared patient characteristics, presence of related diagnosis codes, and time CKD classification between equations.

Results

The number of patients identified with CKD decreased 10% applying CKD-EPI versus MDRD. Changes varied substantially by patient characteristics including a 35% decrease among patients <60 years and a 10% increase among patients >90 years. Women, non-African Americans, nondiabetics, and obese patients were less likely to be classified on the basis of CKD-EPI. Time to CKD classification was significantly longer with CKD-EPI among younger patients. 14% of patients identified with CKD on the basis of either estimating equation also had a related ICD-9 diagnosis, ranging from 19% among patients <60 years to 7% among patients >90 years.

Conclusions

Consistent with findings in the general population, CKD-EPI resulted in substantial declines in equation-based CKD diagnoses in a large healthcare system. Further research is needed to determine whether widespread use of CKD-EPI with current guidelines could lead to delayed needed care among younger patients or excessive referrals among older patients.     

Prognosis of CKD Patients Receiving Outpatient Nephrology Care in Italy

Summary

Background and objectives

Prognosis in nondialysis chronic kidney disease (CKD) patients under regular nephrology care is rarely investigated.

Design, setting, participants, & measurements

We prospectively followed from 2003 to death or June 2010 a cohort of 1248 patients with CKD stages 3 to 5 and previous nephrology care ≥1 year in 25 Italian outpatient nephrology clinics. Cumulative incidence of ESRD or death before ESRD were estimated using the competing-risk approach.

Results

Estimated rates (per 100 patient-years) of ESRD and death 8.3 (95% confidence interval [CI], 7.4 to 9.2) and 5.9 (95% CI 5.2 to 6.6), respectively. Risk of ESRD and death increased progressively from stages 3 to 5. ESRD was more frequent than death in stage 4 and 5 CKD, whereas the opposite was true in stage 3 CKD. Younger age, lower body mass index, proteinuria, and high phosphate predicted ESRD, whereas older age, diabetes, previous cardiovascular disease, ESRD, proteinuria, high uric acid, and anemia predicted death (P < 0.05 for all). Among modifiable risk factors, proteinuria accounted for the greatest contribution to the model fit for either outcome.

Conclusions

In patients receiving continuity of care in Italian nephrology clinics, ESRD was a more frequent outcome than death in stage 4 and 5 CKD, but the opposite was true in stage 3. Outcomes were predicted by modifiable risk factors specific to CKD. Proteinuria used in conjunction with estimated GFR refined risk stratification. These findings provide information, specific to CKD patients under regular outpatient nephrology care, for risk stratification that complement recent observations in the general population.     

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.     

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Summary

Background & objectives

Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA).

Design, setting, participants, & measurements

In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-α was studied followed by an evaluation of nuclear factor (NF)–κB activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo.

Results

Monocytes incubated with SDMA showed increased IL-6 and TNF-α expression and a rise in active NF-κB. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 ± 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-α, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-α at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 ± 0.05) directly followed that of C-reactive protein (AUC: 0.82 ± 0.04) and albumin (AUC: 0.72 ± 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002).

Conclusions

The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-κB and resulting in enhanced expression of IL-6 and TNF-α, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.     

Effects of Antiproteinuric Intervention on Elevated Connective Tissue Growth Factor (CTGF/CCN-2) Plasma and Urine Levels in Nondiabetic Nephropathy

Summary

Background and objectives

Connective Tissue Growth Factor (CTGF/CCN-2) is a key player in fibrosis. Plasma CTGF levels predict end-stage renal disease and mortality in diabetic chronic kidney disease (CKD), supporting roles in intra- and extrarenal fibrosis. Few data are available on CTGF in nondiabetic CKD. We investigated CTGF levels and effects of antiproteinuric interventions in nondiabetic proteinuric CKD.

Design, setting, participants, & measurements

In a crossover randomized controlled trial, 33 nondiabetic CKD patients (3.2 [2.5 to 4.0] g/24 h proteinuria) were treated during 6-week periods with placebo, ARB (100 mg/d losartan), and ARB plus diuretics (100 mg/d losartan plus 25 mg/d hydrochlorothiazide) combined with consecutively regular and low sodium diets (193 ± 62 versus 93 ± 52 mmol Na⁺/d).

Results

CTGF was elevated in plasma (464 [387 to 556] pmol/L) and urine (205 [135 to 311] pmol/24 h) of patients compared with healthy controls (n = 21; 96 [86 to 108] pmol/L and 73 [55 to 98] pmol/24 h). Urinary CTGF was lowered by antiproteinuric intervention, in proportion to the reduction of proteinuria, with normalization during triple therapy (CTGF 99 [67 to 146] in CKD versus 73 [55 to 98] pmol/24 h in controls). In contrast, plasma CTGF was not affected.

Conclusions

Urinary and plasma CTGF are elevated in nondiabetic CKD. Only urinary CTGF is normalized by antiproteinuric intervention, consistent with amelioration of tubular dysfunction. The lack of effect on plasma CTGF suggests that its driving force might be independent of proteinuria and that short-term antiproteinuric interventions are not sufficient to correct the systemic profibrotic state in CKD.     

Associations among Estimated Glomerular Filtration Rate,Proteinuria, and Adverse Cardiovascular Outcomes

Summary

Background and objectives

Most studies of chronic kidney disease (CKD) and outcomes focus on mortality and ESRD, with limited data on other adverse outcomes. This study examined the associations among proteinuria, eGFR, and adverse cardiovascular (CV) events.

Design, setting, participants, & measurements

This was a population-based longitudinal study with patients identified from province-wide laboratory data from Alberta, Canada, between 2002 and 2007. Selected for this study from a total of 1,526,437 patients were 920,985 (60.3%) patients with at least one urine dipstick measurement and 102,701 patients (6.7%) with at least one albumin-creatinine ratio (ACR) measurement. Time to hospitalization was considered for one of four indications: congestive heart failure (CHF), coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), peripheral vascular disease (PVD), and stroke/transient ischemic attacks [TIAs] (cerebrovascular accident [CVA]/TIA).

Results

After a median follow-up of 35 months, in fully adjusted models and compared with patients with estimated GFR (eGFR) of 45 to 59 ml/min per 1.73 m² and no proteinuria, patients with heavy proteinuria by dipstick and eGFR ≥ 60 ml/min per 1.73 m² had higher rates of CABG/PCI and CVA/TIA. Similar results were obtained in patients with proteinuria measured by ACR.

Conclusions

Risks of major CV events at a given level of eGFR increased with higher levels of proteinuria. The findings extend current data on risk of mortality and ESRD. Measurement of proteinuria is of incremental prognostic benefit at every level of eGFR. The data support use of proteinuria measurement with eGFR for definition and risk stratification in 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.     

Patterns and Prognostic Value of Total and Differential Leukocyte Count in Chronic Kidney Disease

Summary

Background and objectives

The purpose of this study was to evaluate the levels and patterns of total and differential leukocyte counts and their prognostic importance in a cohort of people with and without chronic kidney disease (CKD).

Design, setting, participants, & measurements

Among 153 veterans without CKD and 267 with, blood leukocyte count was measured at baseline and then repeatedly over a decade. The patterns of change in leukocyte count between the two groups were compared. In the CKD cohort, the spikes in leukocyte counts were compared to the combined endpoint of ESRD and death.

Results

Patients with CKD had more granulocytes and eosinophils and fewer lymphocytes. Over time, granulocytes increased and lymphocytes decreased in those with and without CKD. In addition, in those with CKD, over time eosinophils fell and monocytes increased. Compared with their non-CKD counterparts, patients with CKD had between 1.5- and 3.0-fold more spikes in leukocyte counts. Independent risk factors for the combined endpoint were associated with spikes in the leukocyte counts of absolute and percent eosinophil count, percent granulocyte, and percent monocyte counts. In a multivariate adjusted joint model, both granulocyte and monocyte spikes were independently associated with ESRD and death (hazard ratio 1.67 and 1.52 respectively, P < 0.05).

Conclusions

Compared with those without CKD, patients with CKD have more eosinophils and granulocytes and fewer lymphocytes. Greater variation in leukocytes is seen. Spikes in granulocyte and monocyte percentages among patients with CKD are of independent prognostic importance.     

Chronic Kidney Disease as a Coronary Disease Equivalent—A Comparison with Diabetes over a Decade

Summary

Background and objectives

Whether chronic kidney disease (CKD) should also be considered a coronary disease equivalent like diabetes is not clear.

Design, setting, participants, & methods

Veterans with and without diabetes and with and without CKD were prospectively recruited. A competing Cox regression model was used to describe the risk of myocardial infarction (MI) in the two groups (CKD and diabetes) over a decade of follow-up.

Results

The incidence rate of MI in those without CKD was 0.047/yr and in those with CKD was 0.206/yr. Multivariate adjustment revealed the incident rate ratio for MI in CKD as 3.5 and for diabetes mellitus as 2.5. The cumulative incidence for MI was influenced by CKD and diabetes. CKD was associated with a subhazard ratio for MI of 3.74; in contrast, diabetes was associated with a subhazard ratio for MI of 2.6. For the outcome of all-cause mortality, after multivariate adjustment, CKD was associated with a hazard ratio (HR) of 1.86, which was similar to the HR of 2.27 for prevalent coronary artery disease. The HR for diabetes was NS at 1.35.

Conclusions

CKD is associated with a risk of death similar to that of established coronary artery disease and higher than that of diabetes mellitus. CKD is associated with a risk of MI that is at least as much as that from diabetes mellitus. Among veterans, CKD appears to be a coronary disease equivalent.     

Association of Serum Bicarbonate with Incident Functional Limitation in Older Adults

Background and objectives

Cross-sectional studies have found that low serum bicarbonate is associated with slower gait speed. Whether bicarbonate levels independently predict the development of functional limitation has not been previously studied. Whether bicarbonate was associated with incident persistent lower extremity functional limitation and whether the relationship differed in individuals with and without CKD were assessed in participants in the Health, Aging, and Body Composition study, a prospective study of well functioning older individuals

Design, setting, participants, & measurements

Functional limitation was defined as difficulty in walking 0.25 miles or up 10 stairs on two consecutive reports 6 months apart in the same activity (stairs or walking). Kidney function was measured using eGFR by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation, and CKD was defined as an eGFR<60 ml/min per 1.73 m². Serum bicarbonate was measured using arterialized venous blood gas. Cox proportional hazards analysis was used to assess the association of bicarbonate (<23, 23–25.9, and ≥26 mEq/L) with functional limitation. Mixed model linear regression was performed to assess the association of serum bicarbonate on change in gait speed over time.

Results

Of 1544 participants, 412 participants developed incident persistent functional limitation events over a median 4.4 years (interquartile range, 3.1 to 4.5). Compared with ≥26 mEq/L, lower serum bicarbonate was associated with functional limitation. After adjustment for demographics, CKD, diabetes, body mass index, smoking, diuretic use, and gait speed, lower serum bicarbonate was significantly associated with functional limitation (hazard ratio, 1.35; 95% confidence interval, 1.08 to 1.68 and hazard ratio, 1.58; 95% confidence interval, 1.12 to 2.22 for bicarbonate levels from 23 to 25.9 and <23, respectively). There was not a significant interaction of bicarbonate with CKD. In addition, bicarbonate was not significantly associated with change in gait speed.

Conclusions

Lower serum bicarbonate was associated with greater risk of incident, persistent functional limitation. This association was present in individuals with and without CKD.     

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

Background and objectives

Low circulating 25-hydroxyvitamin D [25(OH)D] and high sodium intake are both associated with progressive albuminuria and renal function loss in CKD. Both vitamin D and sodium intake interact with the renin-angiotensin-aldosterone system. We investigated whether plasma 25(OH)D or 1,25-dihydroxyvitamin D [1,25(OH)₂D] is associated with developing increased albuminuria or reduced renal function and whether these associations depend on sodium intake.

Design, setting, participants, & measurements

Baseline plasma 25(OH)D and 1,25(OH)₂D were measured by liquid chromatography tandem mass spectrometry, and sodium intake was assessed by 24-hour urine collections in the general population–based Prevention of Renal and Vascular End-Stage Disease cohort (n=5051). Two primary outcomes were development of urinary albumin excretion >30 mg/24 h and eGFR (creatinine/cystatin C–based CKD Epidemiology Collaboration) <60 ml/min per 1.73 m². Participants with CKD at baseline were excluded. In Cox regression analyses, we assessed associations of vitamin D with developing increased albuminuria or reduced eGFR and potential interaction with sodium intake.

Results

During a median follow-up of 10.4 (6.2–11.4) years, 641 (13%) participants developed increased albuminuria, and 268 (5%) participants developed reduced eGFR. Plasma 25(OH)D was inversely associated with increased albuminuria (fully adjusted hazard ratio [HR] per SD higher, 0.86; 95% confidence interval [95% CI], 0.78 to 0.95; P=0.003) but not reduced eGFR (HR, 0.99; 95% CI, 0.87 to 1.12; P=0.85). There was interaction between 25(OH)D and sodium intake for risk of developing increased albuminuria (P interaction =0.03). In participants with high sodium intake, risk of developing increased albuminuria was inversely associated with 25(OH)D (lowest versus highest quartile: adjusted HR, 1.81; 95% CI, 1.20 to 2.73, P<0.01), whereas this association was nonsignificant in participants with low sodium intake (HR, 1.29; 95% CI, 0.94 to 1.77; P=0.12). Plasma 1,25(OH)₂D was not significantly associated with increased albuminuria or reduced eGFR.

Conclusions

Low plasma 25(OH)D is associated with higher risk of developing increased albuminuria, particularly in individuals with high sodium intake, but not of developing reduced eGFR. Plasma 1,25(OH)2D is not associated with risk of developing increased albuminuria or reduced eGFR.