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1.  Dietary acid load: A novel nutritional target in chronic kidney disease? 
Nonvolatile acid is produced from the metabolism of organic sulfur in dietary protein, and the production of organic anions during the combustion of neutral foods. Organic anion salts that are found primarily in plant foods are directly absorbed in the gastrointestinal tract and yield bicarbonate. The difference between endogenously produced nonvolatile acid and absorbed alkali precursors yields the dietary acid load, technically known as the net endogenous acid production, and must be excreted by the kidney to maintain acid-base balance. Although typically around 1 mEq/kg/day, dietary acid load is lower with greater intake of fruits and vegetables. In the setting of chronic kidney disease, a high dietary acid load invokes adaptive mechanisms to increase acid excretion despite reduced nephron number, such as increased per nephron ammoniagenesis and augmented distal acid excretion mediated by the renin-angiotensin system and endothelin-1. These adaptations may promote renal injury. Additionally, high dietary acid loads produce low-grade, subclinical acidosis that may result in bone and muscle loss. Early studies suggest that lowering the dietary acid load can improve subclinical acidosis, preserve bone and muscle, and slow decline of glomerular filtration rate in animal models and humans. Studies focusing on hard clinical outcomes are needed.
PMCID: PMC3604792  PMID: 23439373
chronic kidney disease; nutrition; metabolic acidosis; net endogenous acid production
2.  Choices in kidney transplantation in type 1 diabetes: Are there skeletal benefits of the endocrine pancreas? 
Kidney international  2013;83(3):356-358.
Traditionally, recipients of a simultaneous pancreas-kidney (SPK) versus kidney transplant alone (KTA) were thought to have higher fracture risk. Using a large US registry, Nikkel et al observed lower rates of fracture hospitalization among patients with type 1 diabetes after SPK compared to KTA, particularly among men. It is not known whether the apparent benefit of SPK is due to improved bone strength or fewer falls, but these findings may influence transplant decision making.
PMCID: PMC3589985  PMID: 23446255
3.  Inhibitors of mTOR and Risks of Allograft Failure and Mortality in Kidney Transplantation 
Data on long-term outcomes of users of inhibitors of the mammalian target of rapamycin (mTORI) are lacking in kidney transplantation. In an analysis of 139,370 US kidney transplant recipients between 1999 through 2010, we compared clinical outcomes among users of mTORIs versus calcineurin inhibitors (CNI) in their primary immunosuppresive regimen. During the first 2 years post-transplantation, primary use of mTORIs without CNIs (N=3,237) was associated with greater risks of allograft failure and death compared with a CNI-based regimen (N=125,623); the hazard ratio [HR] of the composite outcome ranged from 3.67 (95% confidence interval [CI], 3.12 – 4.32) after discharge to 1.40 (95%CI 1.26 – 1.57) by year 2. During years 2–8, primary use of mTORIs without CNIs was independently associated with greater risks of death (HR 1.25; 95%CI, 1.11 – 1.41) and the composite (HR 1.17; 95%CI, 1.08 – 1.27) in fully adjusted analyses. The results were qualitatively unchanged in subgroups defined by medical history, immunological risk and clinical course during the index transplant hospitalization. In a propensity-score matched cohort, use of mTORIs was associated with significantly worse outcomes during the first 2 years and greater risks of death (HR 1.21; 95%CI, 1.05 – 1.39) and the composite (HR 1.18; 95%CI, 1.08 – 1.30) in years 2–8. Compared with CNI-based regimens, use of an mTORI-based regimen for primary immunosuppression in kidney transplantation was associated with inferior recipient survival.
PMCID: PMC3777734  PMID: 23025566
kidney transplantation; allograft failure; mortality; mTOR inhibitors
4.  Fibroblast growth factor 23 is not associated with and does not induce arterial calcification 
Kidney international  2013;83(6):1159-1168.
Elevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease. As a potential mediating mechanism, FGF23 induces left ventricular hypertrophy; however, its role in arterial calcification is less clear. In order to study this we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331 to 420 days) of baseline. Baseline plasma FGF23 was not associated with prevalence or severity of coronary artery calcium after multivariable adjustment. In contrast, higher serum phosphate levels were associated with prevalence and severity of coronary artery calcium, even after adjustment for FGF23. Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium. We could not detect mRNA expression of FGF23 or its co-receptor, klotho, in human or mouse vascular smooth muscle cells, or normal or calcified mouse aorta. Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho. Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally. Hence, phosphate and FGF23 promote cardiovascular disease through distinct mechanisms.
PMCID: PMC3672330  PMID: 23389416
phosphate; fibroblast growth factor 23; vascular calcification; vascular smooth muscle; chronic kidney disease
5.  Trends in anemia management in US hemodialysis patients 2004–2010 
BMC Nephrology  2013;14:264.
There have been major changes in the management of anemia in US hemodialysis patients in recent years. We sought to determine the influence of clinical trial results, safety regulations, and changes in reimbursement policy on practice.
We examined indicators of anemia management among incident and prevalent hemodialysis patients from a medium-sized dialysis provider over three time periods: (1) 2004 to 2006 (2) 2007 to 2009, and (3) 2010. Trends across the three time periods were compared using generalized estimating equations.
Prior to 2007, the median proportion of patients with monthly hemoglobin >12 g/dL for patients on dialysis 0 to 3, 4 to 6 and 7 to 18 months, respectively, was 42%, 55% and 46% declined to 41%, 54%, and 40% after 2007, and declined more sharply in 2010 to 34%, 41%, and 30%. Median weekly Epoeitin alpha doses over the same periods were 18,000, 12,400, and 9,100 units before 2007; remained relatively unchanged from 2007 to 2009; and decreased sharply in the patients 3–6 and 6–18 months on dialysis to 10,200 and 7,800 units, respectively in 2010. Iron doses, serum ferritin, and transferrin saturation levels increased over time with more pronounced increases in 2010.
Modest changes in anemia management occurred between 2007 and 2009, followed by more dramatic changes in 2010. Studies are needed to examine the effects of declining erythropoietin use and hemoglobin levels and increasing intravenous iron use on quality of life, transplantation rates, infection rates and survival.
PMCID: PMC3866613  PMID: 24289058
Anemia; Erythropoietin stimulating agents; Hemodialysis
6.  Plant Protein Intake Is Associated with Fibroblast Growth Factor 23 and Serum Bicarbonate in Patients with CKD: The Chronic Renal Insufficiency Cohort Study 
Journal of Renal Nutrition  2012;22(4):379-388.e1.
Protein from plant, as opposed to animal, sources may be preferred in chronic kidney disease (CKD), due to lower bioavailability of phosphate and lower nonvolatile acid load.
Study Design
Observational cross-sectional study.
Setting & Participants
2938 participants with chronic kidney disease and information on dietary intake at the baseline visit in the Chronic Renal Insufficiency Cohort Study.
Percentage of total protein from plant sources (% plant protein) was determined by scoring individual food items from the National Cancer Institute Diet History Questionnaire (DHQ).
Metabolic parameters, including serum phosphate, bicarbonate (HCO3), potassium, and albumin, plasma fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), and hemoglobin.
We modeled the association between % plant protein and metabolic parameters using linear regression. Models were adjusted for age, sex, race, diabetes, body mass index, eGFR, income, smoking, total energy intake, total protein intake, 24 hour urinary sodium, use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers and use of diuretics.
Higher % plant protein was associated with lower FGF23 (p=0.05) and higher HCO3 (p=0.01), but not with serum phosphate or PTH (p=0.9 and 0.5, respectively). Higher % plant protein was not associated with higher serum potassium (p=0.2), lower serum albumin (p=0.2) or lower hemoglobin (p=0.3). The associations of % plant protein with FGF23 and HCO3 did not differ by diabetes status, sex, race, CKD stage (2/3 vs. 4/5) or total protein intake (≤ 0.8 g/kg/d vs. >0.8 g/kg/d) (p-interaction > 0.10 for each).
Cross-sectional study; Determination of % plant protein using the DHQ has not been validated.
Consumption of a higher percentage of protein from plant sources may lower FGF23 and raise HCO3 in patients with CKD.
PMCID: PMC3383455  PMID: 22480598
chronic kidney disease; nutrition; mineral metabolism; acidosis
7.  Net endogenous acid production is associated with a faster decline in GFR in African Americans 
Kidney international  2012;82(1):106-112.
Increased acid excretion may promote renal injury. To evaluate this in African Americans with hypertensive nephrosclerosis, we studied the association between the net endogenous acid production and progression of kidney disease in 632 patients in the AASK trial. Protein and potassium intakes were estimated from 24-hour urea nitrogen and potassium excretion, and used to estimate net endogenous acid production, averaged over 2 years, approximating routine intake. The link between net endogenous acid production and the I125iothalamate glomerular filtration rate (iGFR) and time to end stage renal disease or doubling of serum creatinine was analyzed using mixed models and Cox proportional hazards regressions. The trend in higher net endogenous acid production was significantly associated with a faster decline in iGFR over a median of 3.2 years. After adjustment for age, body mass index, baseline iGFR, urine protein to creatinine ratio and randomized treatment group, the trend in higher net endogenous acid production remained significantly associated with a faster decline in iGFR at a rate 1.01 mL/min/1.73 m2 per year faster in the highest to the lowest quartile. However, in time to event analyses over a median of 7.7 years, the adjusted hazard ratio (1.10) for composite renal events per 25 mEq/day higher net endogenous acid production was not significant. Hence, our findings implicate endogenous acid production as a potential modifiable risk factor for progressive kidney disease.
PMCID: PMC3540413  PMID: 22475819
8.  Comparative effectiveness studies to improve clinical outcomes in end stage renal disease: the DEcIDE patient outcomes in end stage renal disease study 
BMC Nephrology  2012;13:167.
Evidence is lacking to inform providers’ and patients’ decisions about many common treatment strategies for patients with end stage renal disease (ESRD).
The DEcIDE Patient Outcomes in ESRD Study is funded by the United States (US) Agency for Health Care Research and Quality to study the comparative effectiveness of: 1) antihypertensive therapies, 2) early versus later initiation of dialysis, and 3) intravenous iron therapies on clinical outcomes in patients with ESRD. Ongoing studies utilize four existing, nationally representative cohorts of patients with ESRD, including (1) the Choices for Healthy Outcomes in Caring for ESRD study (1041 incident dialysis patients recruited from October 1995 to June 1999 with complete outcome ascertainment through 2009), (2) the Dialysis Clinic Inc (45,124 incident dialysis patients initiating and receiving their care from 2003–2010 with complete outcome ascertainment through 2010), (3) the United States Renal Data System (333,308 incident dialysis patients from 2006–2009 with complete outcome ascertainment through 2010), and (4) the Cleveland Clinic Foundation Chronic Kidney Disease Registry (53,399 patients with chronic kidney disease with outcome ascertainment from 2005 through 2009). We ascertain patient reported outcomes (i.e., health-related quality of life), morbidity, and mortality using clinical and administrative data, and data obtained from national death indices. We use advanced statistical methods (e.g., propensity scoring and marginal structural modeling) to account for potential biases of our study designs. All data are de-identified for analyses. The conduct of studies and dissemination of findings are guided by input from Stakeholders in the ESRD community.
The DEcIDE Patient Outcomes in ESRD Study will provide needed evidence regarding the effectiveness of common treatments employed for dialysis patients. Carefully planned dissemination strategies to the ESRD community will enhance studies’ impact on clinical care and patients’ outcomes.
PMCID: PMC3554422  PMID: 23217181
9.  Soluble P-Selectin Levels Are Associated with Cardiovascular Mortality and Sudden Cardiac Death in Male Dialysis Patients 
American Journal of Nephrology  2011;33(3):224-230.
P-selectin is released by activated platelets and endothelium contributing to inflammation and thrombosis. We evaluated the association between soluble P-selectin and atherosclerotic cardiovascular disease (ASCVD) in dialysis patients.
We measured soluble P-selectin in serum from 824 incident dialysis patients. Using Cox proportional hazards models, we modeled the association of P-selectin levels with ASCVD events, cardiovascular mortality and sudden cardiac death.
After adjustment for demographics, comorbidity and traditional cardiovascular risk factors, higher P-selectin levels were associated with increased risk of ASCVD and cardiovascular mortality among males (p = 0.02 and p = 0.01, respectively), but not females (p = 0.52 and p = 0.31, respectively; p interaction = 0.003), over a median of 38.2 months. Higher P-selectin was associated with a greater risk of sudden cardiac death among males (p = 0.05). The associations between increasing P-selectin and cardiovascular mortality as well as sudden cardiac death in males persisted after adjustment for C-reactive protein, interleukin-6, serum albumin and platelet count (p = 0.01 and p = 0.03, respectively). The risk for sudden cardiac death was more than 3 times greater for males in the highest tertile of soluble P-selectin compared with the lowest tertile after adjustment (HR: 3.19; 95% CI: 1.18 – 8.62; p = 0.02).
P-selectin is associated with ASCVD, cardiovascular mortality and sudden cardiac death among male dialysis patients.
PMCID: PMC3064942  PMID: 21346329
Cardiovascular disease; Dialysis; End-stage renal disease; Inflammation; Sudden cardiac death; P-selectin
10.  Patterns in blood pressure medication use in US incident dialysis patients over the first 6 months 
BMC Nephrology  2013;14:249.
Several observational studies have evaluated the effect of a single exposure window with blood pressure (BP) medications on outcomes in incident dialysis patients, but whether BP medication prescription patterns remain stable or a single exposure window design is adequate to evaluate effect on outcomes is unclear.
We described patterns of BP medication prescription over 6 months after dialysis initiation in hemodialysis and peritoneal dialysis patients, stratified by cardiovascular comorbidity, diabetes, and other patient characteristics. The cohort included 13,072 adult patients (12,159 hemodialysis, 913 peritoneal dialysis) who initiated dialysis in Dialysis Clinic, Inc., facilities January 1, 2003-June 30, 2008, and remained on the original modality for at least 6 months. We evaluated monthly patterns in BP medication prescription over 6 months and at 12 and 24 months after initiation.
Prescription patterns varied by dialysis modality over the first 6 months; substantial proportions of patients with prescriptions for beta-blockers, renin angiotensin system agents, and dihydropyridine calcium channel blockers in month 6 no longer had prescriptions for these medications by month 24. Prescription of specific medication classes varied by comorbidity, race/ethnicity, and age, but little by sex. The mean number of medications was 2.5 at month 6 in hemodialysis and peritoneal dialysis cohorts.
This study evaluates BP medication patterns in both hemodialysis and peritoneal dialysis patients over the first 6 months of dialysis. Our findings highlight the challenges of assessing comparative effectiveness of a single BP medication class in dialysis patients. Longitudinal designs should be used to account for changes in BP medication management over time, and designs that incorporate common combinations should be considered.
PMCID: PMC3840675  PMID: 24219348
Blood pressure medication; Dialysis; Medication use patterns

Results 1-10 (10)