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1.  Evaluation of hypophosphatemia: lessons from patients with genetic disorders 
Phosphate is a key element for several physiological pathways, such as skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys have a key role in phosphate homeostasis with three hormones playing important roles in renal phosphate handling (i.e., parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1-25 dihydroxy-vitamin D).
Independently of the genetic diseases affecting the FGF23 pathway (such as hypophosphatemic rickets), hypophosphatemia is a frequent condition in daily practice, and untreated severe hypophosphatemia can induce hemolysis, rhabdomyolysis, respiratory failure, cardiac dysfunction and neurological impairment, thus requiring a rapid correction to avoid severe complications.
The aims of this case report are to summarize the etiologies and the biological evaluation of hypophosphatemia in adults, and to provide an overview of our current understanding of phosphate metabolism.
doi:10.1053/j.ajkd.2011.08.035
PMCID: PMC4324571  PMID: 22075221
FGF23; hypophosphatemia; hypophosphatemic rickets; tumor-induced osteomalacia
2.  [No title available] 
PMCID: PMC3932114  PMID: 24461730
3.  [No title available] 
PMCID: PMC3944015  PMID: 24100126
4.  [No title available] 
PMCID: PMC3946885  PMID: 24182662
5.  [No title available] 
PMCID: PMC3946919  PMID: 23932089
6.  [No title available] 
PMCID: PMC4075014  PMID: 24183837
8.  Comparative Outcomes Between Continuous Ambulatory and Automated Peritoneal Dialysis: A Narrative Review 
Automated methods for delivering peritoneal dialysis (PD) to persons with end-stage renal disease continue to gain popularity worldwide, particularly in developed countries. However, the endeavor to automate the PD process has not been advanced on the strength of high-level evidence for superiority of automated over manual methods. This article summarizes available studies that have shed light on the evidence that compares the association of treatment with continuous ambulatory PD or automated PD (APD) with clinically meaningful outcomes. Published evidence, primarily from observational studies, has been unable to demonstrate a consistent difference in residual kidney function loss rate, peritonitis rate, maintenance of euvolemia, technique survival, mortality, or health-related quality of life in individuals undergoing continuous ambulatory PD versus APD. At the same time, the future of APD technology appears ripe for further improvement, such as the incorporation of voice commands and expanded use of telemedicine. Given these considerations, it appears that patient choice should drive the decision about PD modality.
doi:10.1053/j.ajkd.2013.11.025
PMCID: PMC4300314  PMID: 24423779
End-stage renal disease (ESRD); peritoneal dialysis (PD); continuous ambulatory peritoneal dialysis (CAPD); automated peritoneal dialysis (APD); residual kidney function; peritonitis; mortality; health-related quality of life
9.  Estimated GFR and Risk of Hip Fracture in Older Men: Comparison of Associations Using Cystatin C and Creatinine 
Background
Higher serum cystatin C is associated with an increased risk of hip fracture in postmenopausal white women, but there is a paucity of data in men. Whether an estimated GFR (eGFR) based on cystatin C (eGFRcys) is superior in predicting hip fracture risk to an eGFR based on creatinine (eGFRcr) or the combination (eGFRcr-cys) is also uncertain.
Study Design
Nested case-cohort.
Setting & Participants
Participants enrolled in the Osteoporotic Fractures in Men (MrOS) Study (5,994 men aged ≥65 years from six U.S. centers) including a random subcohort of 1602 men and 168 men with incident hip fractures (51 of whom were in the subcohort).
Predictor
eGFRcys, eGFRcr and eGFRcr-cys computed using the CKD-EPI equations and expressed in categories of <60, 60–74, and ≥75 mL/min/l.73 m2 (referent group).
Outcome
Incident hip fracture ascertained by participant contacts every 4 months and confirmed with radiographic reports.
Results
Median eGFRcys was 72.9 (IQR, 60.5–85.7) mL/min/1.73 m2. In unadjusted models, all measures of eGFR were associated with increased hip fracture risk. However, after adjustment for age, race, site and BMI, the association of lower eGFRcys (but not lower eGFRcr or lower eGFRcr-cys) with higher hip fracture risk remained: for <60 vs. ≥75 mL/min/l.73 m2, HRs were 1.96 [95% CI, 1.25–3.09], 0.84 [95% CI, 0.52–1.37], and 1.08 [95% CI, 0.66–1.77] for eGFRcys, eGFRcr, and eGFRcr-cys, respectively. Similarly, after adjustment for age, race, site and BMI, eGFR of <60 ml/min/1.73 m2 defined by eGFRcys but not eGFRcr or eGFRcr-cys, was associated with higher hip fracture risk. The association between eGFRcys and hip fracture was not explained by levels of calcitropic hormones or inflammatory markers, but the relationship was attenuated and no longer reached significance (for <60 vs. ≥75 mL/min/l.73 m2: HR, 1.43; 95% CI, 0.88–2.34) after consideration of additional clinical risk factors and bone mineral density.
Limitations
Findings not generalizable other populations; residual confounding may exist.
Conclusions
Older community-dwelling men with lower eGFRcys have an increased risk of hip fracture that is explained in large part by greater burden of risk factors among men with lower eGFRcys. In contrast, lower eGFRcr or lower eGFRcr-cys were not associated with a higher age-adjusted hip fracture risk.
doi:10.1053/j.ajkd.2013.05.022
PMCID: PMC3833961  PMID: 23890927
kidney function; cystatin C; creatinine; hip fracture; elderly; men
10.  Association of a Cystatin C Gene Variant With Cystatin C Levels, CKD, and Risk of Incident Cardiovascular Disease and Mortality 
Background
Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of CKD, and strengthen risk estimates for cardiovascular disease (CVD) and mortality.
Study Design
Observational.
Setting & Population
Four population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Compostion (Health ABC) studies.
Predictors
We estimated the association of rs13038305 with eGFRcys and eGFRcr, and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.
Outcomes
We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45–59, 60–89, and ≥90 mL/min/1.73 m2. We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.
Results
In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%), was associated with 6.4% lower cystatin C concentration, 5.5 mL/min/1.73 m2 higher eGFRcys, and 36% [95% CI, 29%–41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14–1.20) and mortality (HR, 1.22; 95% CI, 1.19–1.24) per 10- ml/min/1.73 m2 lower eGFRcys were similar with or without rs13038305 adjustment. In total, 1134 participants (7.7%) were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, −0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.
Limitations
rs13038305 only explains a small proportion of cystatin C variation.
Conclusions
Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.
doi:10.1053/j.ajkd.2013.06.015
PMCID: PMC3872167  PMID: 23932088
Cystatin C; chronic kidney disease; genetics; single nucleotide polymorphism; net reclassification improvement
11.  Objectives and Design of the Hemodialysis Fistula Maturation Study 
Background
A large proportion of newly created arteriovenous fistulas cannot be used for dialysis because they fail to mature adequately to support the hemodialysis blood circuit. The Hemodialysis Fistula Maturation (HFM) Study was designed to elucidate clinical and biological factors associated with fistula maturation outcomes.
Study Design
Multicenter prospective cohort study.
Setting & Participants
Approximately 600 patients undergoing creation of a new hemodialysis fistula will be enrolled at 7 centers in the United States and followed up for as long as 4 years.
Predictors
Clinical, anatomical, biological, and process-of-care attributes identified pre-operatively, intra-operatively, or post-operatively.
Outcomes
The primary outcome is unassisted clinical maturation defined as successful use of the fistula for dialysis for four weeks without any maturation-enhancing procedures. Secondary outcomes include assisted clinical maturation, ultrasound-based anatomical maturation, fistula procedures, fistula abandonment, and central venous catheter use.
Measurements
Pre-operative ultrasound arterial and venous mapping, flow-mediated and nitroglycerin-mediated brachial artery dilation, arterial pulse wave velocity, and venous distensibility; intra-operative vein tissue collection for histopathological and molecular analyses; post-operative ultrasounds at 1 day, 2 weeks, 6 weeks, and prior to fistula intervention and initial cannulation.
Results
Assuming complete data, no covariate adjustment, and unassisted clinical maturation of 50%, there will be 80% power to detect ORs of 1.83 and 1.61 for dichotomous predictor variables with exposure prevalences of 20% and 50%, respectively.
Limitations
Exclusion of two-stage transposition fistulas limits generalizability. The requirement for study visits may result in a cohort that is healthier than the overall population of patients undergoing fistula creation.
Conclusions
The HFM Study will be of sufficient size and scope to 1) evaluate a broad range of mechanistic hypotheses, 2) identify clinical practices associated with maturation outcomes, 3) assess the predictive utility of early indicators of fistula outcome, and 4) establish targets for novel therapeutic interventions to improve fistula maturation.
doi:10.1053/j.ajkd.2013.06.024
PMCID: PMC4134933  PMID: 23992885
13.  Correlation of Pre-existing Vascular Pathology With Arteriovenous Graft Outcomes in Hemodialysis Patients 
Background
Arteriovenous grafts (AVGs) are prone to neointimal hyperplasia leading to AVG failure. We hypothesized that pre-existing pathologic abnormalities of the vessels used to create AVG (including venous intimal hyperplasia, arterial intimal hyperplasia, arterial medial fibrosis, and arterial calcification) are associated with inferior AVG survival.
Study Design
Prospective observational study.
Setting & Participants
Patients with chronic kidney disease undergoing placement of a new AVG at a large medical center who had vascular specimens obtained at the time of surgery (n=76)
Predictor
Maximal intimal thickness of the arterial and venous intima, arterial medial fibrosis, and arterial medial calcification.
Outcome & Measurements
Unassisted primary AVG survival (time to first intervention) and frequency of AVG interventions.
Results
55 patients (72%) underwent interventions and 148 graft interventions occurred during 89.9 years of follow-up (1.65 interventions per graft-year). Unassisted primary AVG survival was not significantly associated with arterial intimal thickness (HR, 0.72; 95% CI, 0.40-1.27; p=0.3), venous intimal thickness (HR, 0.64; 95% CI, 0.37-1.10; p=0.1), severe arterial medial fibrosis (HR, 0.58; 95% CI, 0.32-1.06; p=0.6), or severe arterial calcification (HR, 0.68; 95% CI, 0.37-1.31; p=0.3). The frequency of AVG interventions per year was inversely associated with arterial intimal thickness (relative risk [RR], 1.99; 95% CI, 1.16-3.42; p<0.001 for thickness <10 vs >25 μm); venous intimal thickness (RR, 2.11; 95% CI, 1.39-3.20; p<0.001 for thickness <5 vs >10 μm); arterial medial fibrosis (RR, 3.17; 95% CI, 1.96-5.13; p<0.001 for fibrosis <70% vs ≥70%), and arterial calcification (RR, 2.12; 95% CI, 1.31-3.43; p=0.001 for <10% vs ≥10% calcification).
Limitations
Single center study. Study may be underpowered to demonstrate differences in unassisted primary AVG survival.
Conclusions
Pre-existing vascular pathologic abnormalities in CKD patients may not be significantly associated with unassisted primary AVG survival. However, vascular intimal hyperplasia, arterial medial fibrosis, and arterial calcification may be associated with a decreased frequency of AVG interventions.
doi:10.1053/j.ajkd.2013.03.040
PMCID: PMC3778052  PMID: 23746379
14.  Population Ancestry and Genetic Risk for Diabetes and Kidney, Cardiovascular, and Bone Disease: Modifiable Environmental Factors May Produce the Cures 
Variable rates of disease observed between members of different continental population groups may be mediated by inherited factors, environmental exposures, or their combination. This manuscript provides evidence in support of differential allele frequency distributions that underlie the higher rates of non-diabetic kidney disease in the focal segmental glomerulosclerosis spectrum of disease and lower rates of coronary artery calcified atherosclerotic plaque and osteoporosis in populations of African ancestry. With recognition that these and other common complex diseases are affected by biologic factors comes the realization that targeted manipulation of environmental exposures and pharmacologic treatments will have different effects based on genotype. The current era of precision medicine will couple one’s genetic make-up with specific therapies to reduce rates of disease based on presence of disease-specific alleles.
doi:10.1053/j.ajkd.2013.05.024
PMCID: PMC3840048  PMID: 23896482
ancestry; APOL1; cardiovascular disease; diabetes mellitus; genetics; kidney disease
15.  Comparison of Associations of Urine Protein-Creatinine Ratio Versus Albumin-Creatinine Ratio With Complications of CKD: A Cross-sectional Analysis 
Background
Urine albumin-creatinine ratio (ACR) and protein-creatinine ratio (PCR) are important markers of kidney damage and are utilized for prognosis in persons with chronic kidney disease (CKD). Despite how commonly these measurements are done in clinical practice, relatively few studies have directly compared the performance of these two measures with regard to associations with clinical outcomes, which may inform clinicians about which measure of urinary protein excretion is best. We studied the association of ACR and PCR with common complications of CKD.
Study Design
Cross-sectional study.
Setting & Participants
3,481 participants with CKD in the Chronic Renal Insufficiency Cohort (CRIC) study.
Predictors
ACR and PCR.
Outcomes
We examined the association between ACR and PCR with measures of common CKD complications: serum hemoglobin, bicarbonate, parathyroid hormone, phosphorus, potassium and albumin.
Measurements
Restricted cubic spline analyses adjusted for estimated glomerular filtration rate (eGFR; calculated by the MDRD [Modification of Diet in Renal Disease] Study Equation) were performed to study the continuous association with our predictors with each outcome.
Results
Mean eGFR was 43 ± 13 (SD) ml/min/1.73 m2 and median levels of PCR and ACR were 140 and 46 mg/g, respectively. In continuous analyses adjusted for eGFR, higher ACR and PCR were comparable and both were associated with lower levels of serum hemoglobin, bicarbonate, and albumin and higher levels of parathyroid hormone, phosphorus, and potassium. Across all outcomes, the associations of ACR and PCR were comparable with only small, absolute differences in the outcome measure. Similar associations were seen in patients with diabetes mellitus.
Limitations
Participants largely had moderate CKD with low levels of ACR and PCR, so results may not be generalizable to all CKD populations.
Conclusions
In persons with CKD, ACR and PCR are relatively comparable in their associations with common complications of CKD. Thus routine measurement of PCR may provide similar information as ACR in managing immediate complications of CKD.
doi:10.1053/j.ajkd.2013.07.013
PMCID: PMC3840083  PMID: 24041612
16.  Income Level and Kidney Disease Severity and Progression Among Children and Adolescents With CKD: A Report From the Chronic Kidney Disease in Children (CKiD) Study 
Background
Among adults, lower socioeconomic status (SES) is a risk factor for chronic kidney disease (CKD), progression to end stage renal disease, and poor health outcomes, but the effect among young people with CKD is not well known.
Study Design
Prospective cohort study.
Settings & Participants
572 children and adolescents aged 1 to 16 years with mild to moderate CKD residing in the United States and Canada who were enrolled in the Chronic Kidney Disease in Children (CKiD) Study, a multicenter prospective cohort.
Predictor
Self-reported annual household income category as a proxy measure for SES: ≥$75,000 (high income), $30,000 to <$75,000 (middle income) and<$30,000 (low income).
Outcomes & Measurements
Clinical characteristics and CKD severity at baseline (GFR; comorbidities related to disease severity and management) and longitudinally (GFR decline; changes in blood pressure z scores and height z scores per year).
Results
At baseline, low and middle household incomes, compared to high income, were associated with minority race (39% and 20% vs. 7%), lower maternal education (28% and 5% vs. 1%), abnormal birth history (34% and 32% vs. 21%), and having at least one clinical comorbidity (66% and 64% vs. 55%).Baseline median GFRs were similar across income categories(between 43 and 45 ml/min/1.73m2). After adjusting for baseline differences, the average GFR declines per year for the high, middle and low income categories were −1.9%, −2.7%, and −2.3%, respectively, and were not statistically significantly different between groups. Blood pressure control tended to improve in all groups (z score, between −0.10 and −0.04), but this was not associated with income. Height deficits diminished over time for subjects from high income families but not among subjects from low income families(z scores for height per year, 0.05 and −0.004, respectively; P = 0.03 for comparison of high and low income).
Limitations
Statistical power to detect associations by income level is limited; income is an imperfect measure for SES; CKiD participants are not representative of children and adolescents with CKD who are uninsured or not receiving care.
Conclusions
GFR decline and blood pressure control were comparable across income groups. Children and adolescents with CKD from lower income households are at higher risk of impaired growth.
doi:10.1053/j.ajkd.2013.06.013
PMCID: PMC3840111  PMID: 23932090
socioeconomic status; children; adolescents; chronic kidney disease; progression; growth
17.  Association of a Reduction in Central Obesity and Phosphorus Intake With Changes in Urinary Albumin Excretion: The PREMIER Study 
Background
Excess adiposity and dietary factors may be important determinants of urinary albumin excretion (UAE).
Study Design
Observational analysis of PREMIER, a randomized trial designed to lower blood pressure using behavioral interventions (counseling on weight loss, healthy diet, and exercise).
Setting & Participants
481 participants with normal kidney function who provided adequate 24-hour urine collections at baseline and 6 months.
Predictors
Change in waist circumference, 24-hour urine sodium, potassium, phosphorus, and protein intake estimated from urea nitrogen.
Outcomes & Measurements
The primary outcome was change in log-transformed 24-hour UAE over 6 months.
Results
After 6 months, the proportion of individuals with UAE ≥10 mg/d decreased from 18.7% to 12.7% (p<0.001). Changes in mean waist circumference (−4.2±6.6 [SD] cm), 24-hour excretion of sodium (−28.2±71.7 mmol/d), potassium (+8.4±27.8 mmol/d), phosphorus (−27.7±314.1 mg/d), and protein intake(−1.7±19.4 g/d) were observed. After adjustment for relevant covariates, the following variables were significantly associated with reduction in ln(UAE) in separate models: decrease in waist circumference (p=0.001), decrease in 24-hour urine phosphorus (p<0.001), and decrease in protein intake (p=0.01). In a multivariable model including these three predictors, decreases in waist circumference (p=0.002) and 24-hour urine phosphorus (p=0.03), but not change in protein intake (p=0.5), remained significantly associated with reduction in ln(UAE). These associations remained significant even after adjustment for changes in blood pressure and insulin resistance. Baseline UAE and metabolic syndrome modified the relationship of waist circumference with ln(UAE); specifically, individuals with higher UAE and baseline metabolic syndrome experienced greater reductions in ln(UAE) from decreases in waist circumference.
Limitations
Observational study with potential for confounding.
Conclusions
In adults with normal kidney function, decreases in waist circumference and 24-hour urine phosphorus are associated with reductions in UAE. These findings support the rationale for clinical trials to determine whether reducing dietary phosphorus or waist circumference could prevent CKD or slow its progression.
doi:10.1053/j.ajkd.2013.04.022
PMCID: PMC3809322  PMID: 23810691
weight loss; waist circumference; protein; phosphorus; urinary albumin excretion
18.  Gastrointestinal Phosphate Handling in CKD and Its Association With Cardiovascular Disease 
Increases in the serum concentrations of parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), and ultimately phosphate and decreases in 1,25-dihydroxyvitamin D are thought to play a central role in the progressive nature of kidney disease and the development of cardiovascular disease in patients with CKD. The initial changes in PTH and FGF-23 are adaptive to maintain the serum concentration of phosphate and the phosphate load within defined levels by increasing the urinary excretion of phosphate. Less well appreciated is the unanticipated finding that the absorption of phosphate from the gastrointestinal tract is not down-regulated in CKD. This maladaptive response maintains higher levels of phosphate absorption thereby contributing to the phosphate burden. Moreover, in response to a low phosphate diet, as is often prescribed to such patients, gut phosphate absorption may be enhanced, undermining the potential beneficial effects of this intervention. Given the poor response to limiting phosphate intake and the use of phosphate binders, we suggest that research efforts be oriented toward a better understanding of the factors that affect the absorption of phosphate in the gastrointestinal tract and the development of agents that directly inhibit the phosphate transporters in the small intestine and/or their associated binding proteins.
doi:10.1053/j.ajkd.2013.04.013
PMCID: PMC3779494  PMID: 23769135
Gastrointestinal absorption of phosphate in CKD; Phosphate burden; Treatment strategies in CKD
19.  Comparison of Life Participation Activities Among Adults Treated by Hemodialysis, Peritoneal Dialysis, and Kidney Transplantation: A Systematic Review 
Background
A comprehensive assessment of the association of patients’ renal replacement therapy (RRT) modality on their participation in life activities (physical function, travel, recreation, freedom, work) is needed.
Study Design
Systematic review of peer-reviewed published studies.
Setting & Population
Adults undergoing RRT (hemodialysis, peritoneal dialysis, or transplantation).
Selection Criteria for Studies
We searched PubMed, Cochrane Library, and EMBASE from January 1980 through April 2012 for English-language articles that compared participation in life activities among patients receiving 1) hemodialysis compared with peritoneal dialysis, 2) hemodialysis compared with kidney transplantation, or 3) peritoneal dialysis compared with kidney transplantation.
Predictor
RRT modality.
Outcomes
Reported rates of physical function, travel, recreation, freedom, and work-related activities by RRT modality.
Results
A total of 46 studies (6 prospective cohort, 38 cross-sectional, and 2 pre-post transplantation) provided relevant comparisons of life participation activities among patients treated with hemodialysis, peritoneal dialysis, and kidney transplantation. Studies were conducted from 1985 to 2011 among diverse patient populations in 16 distinct locations. A majority of studies reported greater life participation rates among patients with kidney transplants compared to patients receiving either hemodialysis or peritoneal dialysis. In contrast, a majority of studies reported no differences in outcomes between patients receiving hemodialysis and patients receiving peritoneal dialysis. These results were consistent throughout the study period, across diverse populations, and among the subset of studies that performed appropriate adjustments for potential confounding factors.
Limitations
Many studies included in the review had significant design weaknesses.
Conclusions
Evidence suggests patients with kidney transplants may experience better rates of life participation compared to patients receiving dialysis, while patients receiving hemodialysis and patients receiving peritoneal dialysis may experience similar rates of life participation. Rigorously performed studies are needed to better inform patients about the association of RRT on these important patient reported outcomes.
doi:10.1053/j.ajkd.2013.03.022
PMCID: PMC3809150  PMID: 23725972
dialysis; ESRD treatment; kidney transplantation; physical functioning; quality of life; social participation
20.  Association of Serum Bicarbonate With Risk of Renal and Cardiovascular Outcomes in CKD: A Report From the Chronic Renal Insufficiency Cohort (CRIC) Study 
Background
The purpose of this study is to evaluate serum bicarbonate as a risk factor for renal outcomes, cardiovascular events and mortality in patients with chronic kidney disease (CKD).
Study Design
Observational cohort study.
Setting & Participants
3939 participants with CKD stages 2-4 who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 - December 2008.
Predictor
Serum bicarbonate.
Outcomes
Renal outcomes, defined as end-stage renal disease (either initiation of dialysis or kidney transplantation) or 50% reduction in eGFR; atherosclerotic events (myocardial infarction, stroke, peripheral arterial disease); congestive heart failure events; and death.
Measurements
Time to event.
Results
The mean eGFR was 44.8 ± 16.8 (SD) mL/min/1.73 m2, and the median serum bicarbonate was 24 (IQR, 22-26) mEq/L. During a median follow-up of 3.9 years, 374 participants died, 767 had a renal outcome, and 332 experienced an atherosclerotic event and 391 had a congestive heart failure event. In adjusted analyses, the risk of developing a renal endpoint was 3% lower per mEq/L increase in serum bicarbonate (HR, 0.97; 95% CI, 0.94-0.99; p=0.01). The association was stronger for participants with eGFR> 45ml/min/1.73m2 (HR, 0.91; 95%CI, 0.85-0.97; p=0.004). The risk of heart failure increased by 14% (HR, 1.14; 95%CI, 1.03-1.26; p=0.02) per mEq/L increase in serum bicarbonate over 24 mEq/L. Serum bicarbonate was not independently associated with atherosclerotic events (HR, 0.99; 95%CI, 0.95-1.03; p=0.6) and all-cause mortality (HR, 0.98; 95%CI, 0.95-1.02; p=0.3).
Limitations
Single measurement of sodium bicarbonate.
Conclusions
In a cohort of participants with CKD, low serum bicarbonate was an independent risk factor for kidney disease progression, particularly for participants with preserved kidney function. The risk of heart failure was higher at the upper extreme of serum bicarbonate. There was no association between serum bicarbonate and all-cause mortality or atherosclerotic events.
doi:10.1053/j.ajkd.2013.01.017
PMCID: PMC3701754  PMID: 23489677
metabolic acidosis; serum bicarbonate; chronic kidney disease; cardiovascular morbidity
21.  Prognostic Importance of Serum Alkaline Phosphatase in CKD Stages 3–4 in a Clinical Population 
Background
Elevated total serum alkaline phosphatase (ALP) levels have been associated with mortality in the general population and in dialysis patients.
Study Design
Retrospective cohort study.
Setting & Participants
28,678 patients with chronic kidney disease (CKD) stages 3 and 4 (estimated glomerular filtration rate [eGFR], 15–59 ml/min/1.73 m2) were identified using the Cleveland Clinic Chronic Kidney Disease Registry. CKD was defined as two eGFR values <60 ml/min/1.73 m2 drawn >90 days apart using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation.
Predictor
ALP levels measured using the calorimetric assay was examined as quartiles (quartile 1, <66 U/L; Q2, 66–81 U/L; Q3, 82–101 U/L; and Q4, ≥102 U/L) and as a continuous measure.
Outcomes & Measurements
All-cause mortality and ESRD were ascertained using the Social Security Death Index and US Renal Data System.
Results
After a median follow up of 2.2 years, 588 patients progressed to ESRD and 4,755 died. There was a graded increase in the risk for mortality with higher ALP quartiles (Q2, Q3, Q4) when compared to the reference quartile (Q1) after adjusting for demographics, comorbid conditions, use of relevant medications and liver function tests. The highest quartile of ALP was associated with a hazard ratio for ESRD of 1.38 (95% CI, 1.09–1.76). Each 1-standard deviation (42.7 U/L) higher ALP level was associated with 15% (95% CI, 1.09–1.22) and 16% (95% CI, 1.14–1.18) increased risk of ESRD and mortality respectively.
Limitations
Single center observational study, lack complete data including PTH for all study participants and attrition bias.
Conclusions
Higher serum ALP levels in CKD stages 3–4 were independently associated with all-cause mortality and ESRD.
doi:10.1053/j.ajkd.2013.04.012
PMCID: PMC3783514  PMID: 23769134
alkaline phosphatase; end-stage renal disease; mortality; chronic kidney disease
22.  CKD and Cardiovascular Disease in the Atherosclerosis Risk in Communities (ARIC) Study: Interactions With Age, Sex, and Race 
Background
Estimated glomerular filtration rate (eGFR) and albuminuria are central for diagnosis, staging, and risk evaluation in chronic kidney disease (CKD). Universal thresholds regardless of age, sex, and race are recommended, but relatively little is known about how these demographic factors alter the relationship of eGFR and albuminuria to cardiovascular outcomes.
Study Design
Observational cohort study.
Setting & Participants
11,060 whites and blacks aged 52–75 years in the Atherosclerosis Risk in Communities (ARIC) Study with median follow-up of 11.2 years.
Predictors
eGFR by the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation (reference, 95 ml/min/1.73 m2) and urinary albumin-creatinine ratio (ACR) (reference, at 5 mg/g).
Outcomes
Cardiovascular events (coronary disease, stroke, and heart failure) and all-cause mortality.
Measurements
Adjusted HRs associated with eGFR and ACR in subgroups according to age, sex and race.
Results
Cardiovascular risk significantly increased at eGFR <70 ml/min/1.73 m2 in all subgroups according to age (< 65 vs. ≥65 years), sex, and race (P for interaction >0.2 for these subgroups; e.g., at eGFR 30 ml/min/1.73 m2, the adjusted HR was 2.19 [95% CI, 1.10–4.35] at age 52–64 years vs. 2.23 [95% CI, 1.33–3.72] at age 65–75 years). Results were similar for mortality. Log(ACR) was linearly associated with cardiovascular risk without threshold effects in all subgroups, with some quantitative interactions. HRs according to ACR tended to be lower in men vs. women (e.g., at ACR 40 mg/g, 1.18 [95% CI, 0.98–1.41] vs. 1.77 [95% CI, 1.45–2.15]) and in older vs. younger population (1.24 [95% CI, 1.04–1.49] vs. 1.73 [95% CI, 1.42–2.12]) (P for interaction <0.01 for sex and age). Less evident interactions were observed for mortality.
Limitations
Single measurement of eGFR with creatinine and ACR and relatively narrow age range.
Conclusions
The associations of eGFR and ACR with cardiovascular events were largely similar, with some quantitative interactions, among age, sex, and racial subgroups, generally supporting universal thresholds of GFR and ACR for CKD definition/staging.
doi:10.1053/j.ajkd.2013.04.010
PMCID: PMC3783539  PMID: 23769137
Chronic kidney disease; estimated glomerular filtration rate (eGFR); urinary albumin-creatinine ratio (ACR); cardiovascular disease; all-cause mortality
23.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. Urine creatinine is correlated with muscle mass, and low muscle mass is also associated with CVD. Whether low urine creatinine in the denominator of the ACR contributes to the association of ACR with CVD is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
6,770 community-living individuals without CVD.
Predictors
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Outcome
Incident CVD events.
Results
During a mean of 7.1 years’ follow-up, 281 CVD events occurred. Geometric means for spot urine creatinine, urine albumin and ACR were 95 ± 2 (SD) mg/dl, 0.7 ± 3.7 mg/dl and 7.0 ± 3.1 mg/g. Adjusted HRs per 2-fold higher increment in each urinary measures with CVD events were similar (1/UCr: 1.07 [95% CI, 0.94-1.22]; urine albumin: 1.08 [95% CI, 1.01-1.14]; and ACR: 1.11 [95% CI, 1.04-1.18]). Urine creatinine was lower in older, female, and low weight individuals. ACR ≥10 mg/g was more strongly associated with CVD events in individuals with low weight (HR for lowest vs. highest tertile: 4.34 vs. 1.97; p for interaction=0.006). Low weight also modified the association of urine albumin with CVD (p for interaction=0.06), but 1/urine creatinine did not (p for interaction=0.9).
Limitations
We lacked 24-hour urine data.
Conclusions
While ACR is more strongly associated with CVD events among persons with low body weight, this association is not driven by differences in spot urine creatinine. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin and less by urine creatinine.
doi:10.1053/j.ajkd.2013.05.010
PMCID: PMC3783582  PMID: 23830183
24.  Outcomes of Patients Receiving Maintenance Dialysis Admitted Over Weekends 
Background
Hospital admissions over weekends have been associated with worse outcomes in different patient populations. The etiology of this difference in outcomes remains unclear; however different staffing patterns over weekends have been speculated to contribute. We evaluated outcomes in patients on maintenance dialysis admitted over weekends using a national database.
Study Design
Retrospective cohort study.
Setting & Participants
We included non-elective admissions of adult patients (≥18 years) on maintenance dialysis (n=3,278,572) identified using appropriate ICD-9-CM codes for years 2005-2009 using Nationwide Inpatient Sample database.
Predictor
Weekend vs weekday admission.
Outcomes
Primary outcome measure was all cause in-hospital mortality. Secondary outcomes included mortality by day three of admission, length of hospital stay, time to death and discharge disposition.
Measurements
We adjusted for patient and hospital characteristics, payer, year, comorbidities and primary discharge diagnosis common to maintenance dialysis patients.
Results
There were estimated 704,491 admissions over weekends vs 2,574,081 over weekdays. Unadjusted all cause in-hospital mortality was 40,666 (5.8%) for weekend admissions in comparison to 138,517 (5.4%) for weekday admissions (p<0.001). In multivariable model, patients admitted over weekends had higher all cause in-hospital mortality (OR, 1.06; 95% CI, 1.01-1.10) in comparison to those admitted over weekdays and higher mortality during first three days of admission (OR, 1.18; 95% CI, 1.10-1.26). Patients admitted over weekends were less likely to be discharged home, had longer hospital stay and shorter time to death compared to those admitted over weekdays on adjusted analysis.
Limitations
Use of ICD-9-CM codes to identify patients, defining weekend as midnight Friday to midnight Sunday.
Conclusions
Maintenance dialysis patients admitted over weekends have increased mortality rates and longer length of stay as compared to those admitted over weekdays. Further studies are needed to identify the reasons for worse outcomes for weekend admissions in this patient population.
doi:10.1053/j.ajkd.2013.03.014
PMCID: PMC3783620  PMID: 23669002
dialysis; admissions; mortality
25.  Association of Dialysate Bicarbonate Concentration With Mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS) 
Background
Most hemodialysis patients worldwide are treated with bicarbonate dialysis using sodium bicarbonate as the base. Few studies have assessed outcomes of patients treated with different dialysate bicarbonate levels, and the optimal concentration remains uncertain.
Study Design
The Dialysis Outcomes and Practice Patterns Study (DOPPS) is an international prospective cohort study.
Setting & Participants
This study included 17,031 patients receiving thrice-weekly in-center hemodialysis from 11 DOPPS countries (2002–2011).
Predictor
Dialysate bicarbonate.
Outcomes
All-cause and cause-specific mortality and first hospitalization, using Cox regression to estimate the effects of dialysate bicarbonate concentration, adjusting for potential confounders.
Measurements
Demographics, comorbid conditions, laboratory values, and prescriptions were abstracted from medical records.
Results
Mean dialysate bicarbonate was 35.5 ± 2.7 (SD) mEq/L, ranging from 32.2 ± 2.3 mEq/L in Germany to 37.0 ± 2.6 mEq/L in the US. Prescription of high dialysate bicarbonate (≥38 mEq/L) was most common in the US (45% of patients). Approximately 50% of DOPPS facilities used a single dialysate bicarbonate concentration. 3,913 patients (23%) died during follow-up. Dialysate bicarbonate concentration was positively associated with mortality (adjusted HR, 1.08 per 4 mEq/L higher [95% CI, 1.01–1.15]; HR for dialysate bicarbonate ≥38 vs. 33–37 mEq/L, 1.07 [95% CI, 0.97–1.19]). Results were consistent across levels of pre-dialysis session serum bicarbonate and between facilities that used a single dialysate bicarbonate concentration and those that prescribed different concentrations to individual patients. The association of dialysis bicarbonate with mortality was stronger in patients with longer dialysis vintage.
Limitations
Due to the observational nature of the current study, we cannot rule out that the reported associations may be biased by unmeasured confounders.
Conclusions
High dialysate bicarbonate, especially prolonged exposure, may contribute to adverse outcomes, likely through development of post-dialysis metabolic alkalosis. Additional studies are warranted to identify the optimal dialysate bicarbonate concentration.
doi:10.1053/j.ajkd.2013.03.035
PMCID: PMC3832240  PMID: 23707043
hemodialysis; outcomes; statistics; DOPPS; observational

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