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26.  Preservation of blood pressure stability with hypertonic mannitol during hemodialysis initiation 
American journal of nephrology  2012;36(2):168-174.
Background
Intra-dialytic hypotensive events are common among hemodialysis patients and are associated with a variety of patient and procedure related factors, including intra-dialytic decline in plasma osmolality. Prior studies and practice have suggested that administration of osmotically active drugs may ameliorate blood pressure decline during chronic hemodialysis.
Methods
Clinical and treatment data was collected for 102 consecutive patients requiring initiation of renal replacement therapy in 2 major teaching hospitals. Routine administration of mannitol differed according to institutional protocols, allowing its examination as the primary exposure of interest. Generalized linear models were fit to estimate associations of mannitol use during dialysis initiation with intra-dialytic blood pressure, as assessed by: 1) intra-dialytic blood pressure decline; 2) nadir intra-dialytic blood pressure; 3) absolute systolic blood pressure <90mmHg or decline >20mmHg.
Results
Mean age was 62 years (±16), 70% were male and 44% were diabetic. Mean pre-dialysis and nadir systolic blood pressure were 142mmHg (±29) and 121mmHg (±26) respectively. Mannitol administration was associated with less decline in intra-dialytic blood pressure, a higher nadir blood pressure and fewer hypotensive events requiring intervention. No effect modification was evident according to diabetes or acuity of kidney disease (chronic vs acute).
Conclusions
Mannitol administration appears to preserve hemodynamic stability during hemodialysis initiation. Randomized controlled trials are needed to confirm these findings and identify optimal management strategies to prevent intra-dialytic hypotension.
doi:10.1159/000341273
PMCID: PMC3779621  PMID: 22846598
hemodialysis; intra-dialytic hypotension; mannitol; osmolality
27.  Intradialytic blood pressure abnormalities: the highs, the lows, and all that lies between 
American journal of nephrology  2015;42(5):337-350.
Background
Frequent blood pressure (BP) measurements are necessary to ensure patient safety during hemodialysis (HD) treatments. Intradialytic BPs are not optimal diagnostic tools for hypertension and cardiovascular risk stratification, but they do have critical clinical and prognostic significance. We present evidence associating intradialytic BP phenomena including fall, rise, and variability with adverse clinical outcomes and review related pathophysiologic mechanisms and potential management strategies.
Summary
Observational studies demonstrate associations between intradialytic hypotension, hypertension, and BP variability and mortality. Lack of consensus regarding diagnostic criteria has hampered data synthesis, and prospective studies investigating optimal management strategies for BP phenomena are lacking. Mechanistic data suggest that cardiac, gut, kidney, and brain ischemia may lie on the causal pathway between intradialytic hypotension and mortality, and endothelial cell dysfunction, among other factors, may be an important mediator of intradialytic hypertension and adverse outcomes. These plausible pathophysiologic links present potential therapeutic targets for future inquiry. The phenomenon of intradialytic BP variability has not been adequately studied, and practical clinical measures and treatment strategies are lacking.
Key Messages
Intradialytic BP phenomena have important prognostic bearing. Clinical practice guidelines for both intradialytic hypotension and hypertension exist, but their underlying evidence is weak overall. Further research is needed to develop consensus diagnostic criteria for intradialytic hypotension, hypertension and BP variability and to elucidate optimal treatment and prevention strategies for each BP manifestation.
doi:10.1159/000441982
PMCID: PMC4761237  PMID: 26584275
blood pressure; hemodialysis; intradialytic hypotension; intradialytic hypertension; blood pressure variability
28.  OXIDATIVE BALANCE SCORE AND CHRONIC KIDNEY DISEASE 
American journal of nephrology  2015;42(4):320-327.
Background
The Oxidative balance score (OBS) is a composite estimate of the overall pro- and antioxidant exposure status in an individual. The aim of this study was to determine the association between OBS and renal disease.
Methods
Using the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study, OBS was calculated by combining 13 a priori-defined pro- and antioxidant factors by using baseline dietary and lifestyle assessment. OBS was divided into quartiles (Q1–Q4) with the lowest, Q1 (predominance of pro-oxidants) as the reference. Multivariable logistic regression and cox proportional hazards models were used to estimate adjusted odds ratios (ORs) for albuminuria defined as urine albumin/creatinine ratio ≥ 30mg/g, macroalbuminuria defined as urine albumin/creatinine ratio >300mg/g and CKD defined as estimated glomerular filtration rate < 60ml/min/1.73m2 (CKD-EPI) and hazard ratios (HRs) for ESRD, respectively.
Results
Of the 19,461 participants analyzed, 12.9% had albuminuria, 10.1% had CKD at baseline; over a median follow-up of 3.5 years (range 2.14–4.32 years) 0.46% developed ESRD. Higher OBS quartiles were associated with lower prevalence of CKD (OR vs. Q1: Q2=0.93, (95% CI, 0.80–1.08); Q3=0.90, (95% CI, 0.77–1.04); and Q4= 0.79 (95% C.I 0.67–0.92), p for trend <0.01). The associations between OBS and albuminuria (p for trend 0.31) and incident ESRD (p for trend 0.56) were not significant in the fully adjusted models.
Conclusions
These findings suggest that higher OBS is associated with lower prevalence of CKD. Lack of association with ESRD incidence in the multivariable analyses indicates that temporal relation between OBS and renal damage remains unclear.
doi:10.1159/000441623
PMCID: PMC4689189  PMID: 26569393
Oxidative balance; pro-oxidant; antioxidant; CKD; ESRD; albuminuria
29.  A trial of lifestyle modification on cardiopulmonary, inflammatory, and metabolic effects among obese with chronic kidney disease 
American journal of nephrology  2015;42(4):274-281.
Background
The feasibility and benefits of lifestyle intervention in CKD patients who are obese is not well studied. We examined the early effects of an exercise plus weight loss intervention on body composition, exercise capacity, metabolic parameters and kidney function in obese subjects with CKD.
Methods
Nine subjects (median age: 57 years, BMI: 43.9 kg/m2) underwent a lifestyle intervention program that included supervised aerobic exercise (i.e. ~ 85% HRmax) and dietary counseling (500 kcal reduction in daily caloric intake). Body composition (iDXA), exercise capacity (VO2max), quality of life, insulin resistance (Matsuda Index), inflammation (hs-C-Reactive Protein), adipokines (leptin and total adiponectin) and kidney function (iothalamate GFR) were measured at baseline and after 12-weeks of the intervention. Changes in parameters were compared using Wilcoxon signed-rank test.
Results
After 12 weeks of intervention, there was a significant decrease in BMI and fat mass (median: −4.9 kg [25th–75th percentile: −5.9, −3.0]). There was a significant increase in exercise capacity (3.7 ml/kg/min [3.0, 4.7]), along with improvements in insulin sensitivity (0.55 [0.43, 1.2]), total adiponectin (780.9 μg/ml [262.1, 1497.1]) and leptin (−5.1 ng/ml [−14.5, −3.3]). There were improvements in biomarkers of kidney disease and quality of life measures, but kidney function remained unchanged.
Conclusion
Lifestyle modification is feasible in obese patients with CKD and produces weight loss that is related to improvements in exercise capacity, insulin resistance, and adipokines. Whether lifestyle-induced weight loss and fitness can be sustained and whether it will mediate improvements in kidney function over time merits further investigation.
doi:10.1159/000441155
PMCID: PMC4711270  PMID: 26495987
kidney disease; exercise; physical capacity; weight loss
30.  Association analysis of the reticulon 1 gene (RTN1) in end-stage kidney disease 
American journal of nephrology  2015;42(4):259-264.
Background
The reticulon 1 gene (RTN1) encodes reticulons, endoplasmic reticulum stress proteins recently implicated in kidney disease progression.
Methods
RTN1 single nucleotide polymorphisms (SNPs) were tested for association with type 2 diabetes-associated (T2D) end-stage kidney disease (ESKD) in African Americans (AAs) and European Americans (EAs), and AAs with non-diabetic ESKD. RTN1 SNPs that were associated with T2D-ESKD in AA cases compared to non-nephropathy controls were identified from a discovery genome-wide association study (N=1,797), then tested for replication in 1,847 additional AA T2D-ESKD cases and controls.
Results
Three intronic RTN1 variants were nominally associated with T2D-ESKD in both discovery and replication analyses: rs1952034, rs12431381, and rs12434215 (additive models); combined T2D-ESKD (discovery+replication) p-values were 0.015-3.0×10−4 (odds ratios [ORs] 0.67-0.77; minor alleles protective). In addition, rs12434215 was weakly associated with T2D-ESKD in 557 EA T2D-ESKD cases contrasted with 753 EA non-nephropathy controls (p=0.019; OR=0.69, dominant model). Nominal association extended to non-diabetic causes of ESKD in 1,459 additional AA cases (rs12431381 and rs12434215 p-values=0.014–0.015; OR=0.77). An all-cause ESKD association analysis contrasted the 3,594 AA ESKD cases with 1,489 AA non-nephropathy controls and detected association with rs12434215 (p=6.7×10−4, OR=0.73) and rs12431381 (p=7.5×10−4, OR=0.75) in dominant models. Of the three SNPs, only rs12434215 was weakly associated with T2D per se when contrasting T2D non-nephropathy cases with non-diabetic controls (additive model p=0.032 AAs; p=0.048 EAs).
Conclusions
These results suggest evidence of genetic association between common variants in RTN1 and ESKD in AAs and EAs.
doi:10.1159/000441199
PMCID: PMC4651726  PMID: 26496126
African Americans; chronic kidney disease; diabetes; diabetic kidney disease; genetics; reticulon 1
31.  Trends in anemia management in hemodialysis patients with cancer 
American journal of nephrology  2015;42(3):206-215.
BACKGROUND
Erythropoiesis-stimulating agents (ESAs), intravenous iron, and blood transfusion are used to treat anemia in both end-stage renal disease (ESRD) and cancer. However, anemia treatment patterns have not been described among ESRD patients undergoing hemodialysis with concurrent cancer, especially in the recent era of ESA-related safety concerns.
METHODS
We analyzed Medicare data from a cohort of hemodialysis patients diagnosed with incident cancer. We used multivariable generalized linear models to estimate trends and patterns in ESA use, iron use, transfusion use, epoetin alfa (EPO) dose, iron dose, and resulting hemoglobin levels (2000–2011).
RESULTS
Of 43,760 eligible patients, quarterly ESA use declined slightly from a peak of 94.1% to 90.0%. Quarterly EPO dose increased from 2000 to 2004, then declined; quarterly hemoglobin levels followed a similar pattern. Iron use increased rapidly from 46.9% to 79.3%. Iron dose increased until 2010, then declined. There was an increase in quarterly transfusion use (6.3% to 11.7%) and mean number of transfusion days per year (1.4 to 1.8). Anemia treatment patterns varied by demographic/clinical subgroups, especially among patients receiving chemotherapy, who required higher ESA use, EPO dose, and frequency of transfusions.
CONCLUSIONS
Despite safety concerns about ESAs in both the ESRD and cancer populations, the proportion of hemodialysis patients with cancer who used ESAs between 2000 and 2011 remained extremely common. EPO dose and hemoglobin levels increased then decreased. Iron use, iron dose, and transfusions increased substantially. Future research examining the risk-benefit profile of different anemia management strategies in the dialysis population with cancer is needed.
doi:10.1159/000440771
PMCID: PMC4618160  PMID: 26439712
erythropoietin; anemia; iron; blood transfusion; dialysis; end-stage renal disease; cancer
32.  IMPACT OF NON-ADHERENCE ON RENAL AND CARDIOVASCULAR OUTCOMES IN US VETERANS 
American journal of nephrology  2015;42(2):151-157.
Background
Adherence is paramount in treating hypertension; still, no gold standard method is available for non-adherence screening delineating high-risk patients. An ICD-9-CM non-adherence diagnostic code (V15.81) has been available for decades; however, its utility is poorly studied. We examined the association between V15.81 code assigned prior to initiation of antihypertensive drugs (AHD) and renal and cardiovascular outcomes.
Methods
This was a historical prospective cohort study involving 312,489 newly treated hypertensive individuals (mean age 53.8years, 90.9% males, 20.3% black, median follow-up 8.0 years). We used crude and Cox models adjusted for baseline socio, demographic characteristics, estimated glomerular filtration rate (eGFR), BMI, blood pressure, co-morbidities, and prospective AHD adherence (measured as proportion of days covered,PDC).
Results
In unadjusted analysis, V15.81 code was associated with higher risks for faster eGFR decline (HR1.22, [95% CI] 1.11-1.33), incident CKD (HR1.17 [1.09-1.27]), ESRD (HR2.53 [1.72-3.72]), incident coronary artery disease (CAD) (HR1.26 [1.15-1.38), and stroke (HR1.55 [1.38-1.73]). In adjusted model, V15.81 code remained predictive of increased risk of CKD (HR1.33 [1.22-1.45]), ESRD (HR1.81 [1.18-2.78]), incident CAD (HR1.26 [1.14-1.40]), and stroke (HR1.46 [1.29-1.65]). Additional adjustment for PDC did not alter adverse associations between V15.81 code and studied outcomes.
Conclusions
Assignment of V15.81 code prior to AHD therapy was associated with higher risks of renal and cardiovascular outcomes in incident hypertensive US veterans. Previous history of non-adherence is a poor prognostic marker in hypertensive individuals; therefore, patients with V15.81 code may require close monitoring. The observational nature of this study limits our ability to make firm recommendations for clinical practice.
doi:10.1159/000440685
PMCID: PMC4601642  PMID: 26398170
non-adherence; V15.81 code; chronic kidney disease; end-stage renal disease; coronary artery disease; stroke
33.  A Risk Score to Guide Cystatin C Testing to Detect Occult Reduced Estimated Glomerular Filtration Rate 
American journal of nephrology  2015;42(2):141-147.
Background/Aims
Persons with occult reduced eGFR (eGFR <60 ml/min/1.73m2 detected by serum cystatin C but missed by creatinine) have high risk for complications. Among persons with preserved kidney function by creatinine-based estimated glomerular filtration rate ((eGFRcreat) >60 ml/min/1.73m2), tools to guide cystatin C testing are needed.
Methods
We developed a risk score to estimate an individual's probability of reduced eGFR by cystatin C (eGFRcys<60 ml/min/1.73m2) in The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and externally validated in the Third National Health and Nutrition Examination Survey (NHANES III). We used logistic regression with Bayesian model averaging and variables available in practice. We assessed performance characteristics using calibration and discrimination measures.
Results
Among 24,877 adults with preserved kidney function by creatinine, 13.5% had reduced eGFRcys. Older and Black participants, current smokers, and those with higher BMI, lower eGFRcreat, diabetes, hypertension, and history of cardiovascular disease were more likely to have occult reduced eGFR (p <0.001). The final risk function had a c-statistic of 0.87 in REGARDS, and 0.84 in NHANES. By risk score, 72% of occult reduced eGFR cases were detected by screening only 22% of participants.
Conclusions
A risk score using characteristics readily accessible in clinical practice can identify the majority of persons with reduced eGFRcys that is missed by creatinine.
doi:10.1159/000439231
PMCID: PMC4589276  PMID: 26381887
kidney disease; Serum Cystatin C; Creatinine; Creatinine-based estimated glomerular filtration rate (eGFRcreat); Cystatin C-based estimated glomerular filtration rate (eGFRcys)
34.  Association of self–reported frailty with falls and fractures among patients new to dialysis 
American journal of nephrology  2015;42(2):134-140.
Background
Although frailty has been linked to higher risk of falls and fracture in the general population, few studies have examined the extent to which frailty is associated with these outcomes among patients with ESRD, who are at particularly high risk for these events.
Methods
1,646 patients beginning maintenance hemodialysis in 297 dialysis units throughout the United States from September 2005 to June 2007 were enrolled in the Comprehensive Dialysis Study (CDS), and 1053 Medicare beneficiaries were included in this study. Self-reported frailty defined by patients endorsing two or more of the following: poor physical functioning, exhaustion, or low physical activity. Falls and fractures requiring medical attention were identified through Medicare claims data. We examined the association between frailty and the time to first fall or fracture using the Fine-Gray modification of Cox proportional hazards regression, adjusted for demographics, Quételet’s (body mass) index (BMI), diabetes mellitus, heart failure, and atherosclerosis.
Results
Seventy-seven percent of patients were frail by self-report. The median length of follow up was 2.5 [1.0, 3.9] years. Crude rates of first medically urgent falls or fractures were 66 and 126 per 1000 person-years in non-frail and self-reported frail participants, respectively. After accounting for demographic factors, comorbidities and the competing risk of death, self-reported frailty was associated with a higher risk of falls or fractures requiring medical attention (hazard ratio 1.60, 95% confidence interval 1.16–2.20).
Conclusion
Participants reporting frailty experienced nearly twice the risk of medically urgent falls or fractures compared to participants who did not report frailty.
doi:10.1159/000439000
PMCID: PMC4596065  PMID: 26381744
Fracture; Frailty; Hemodialysis
35.  Re-sequencing of the APOL1-APOL4 and MYH9 gene regions in African Americans does not identify additional risks for CKD progression 
American journal of nephrology  2015;42(2):99-106.
Background
APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants.
Methods
Re-sequencing was performed across a ~275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant.
Results
Sequencing identified 3246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions (InDels). No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1571 AA ESKD cases and 1334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p=0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes (FIND) did not replicate this association.
Conclusion
Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.
doi:10.1159/000439448
PMCID: PMC4589514  PMID: 26343748
African Americans; APOL1; kidney disease; FSGS; genetics; DNA sequencing
36.  Race, Mineral Homeostasis and Mortality in Patients with End-Stage Renal Disease on Dialysis 
American journal of nephrology  2015;42(1):25-34.
Background
Abnormalities in mineral homeostasis are ubiquitous in patients on dialysis, and influenced by race. We determine the race-specific relationship between mineral parameters and mortality in patients initiating hemodialysis.
Methods
We measured fibroblast growth factor 23 (FGF23) and 25-hydroxyvitamin D (25D) in 184 African American and 327 non-African American hemodialysis patients who enrolled between 1995–1998 in the Choices for Healthy Outcomes in Caring for ESRD Study. Serum calcium, phosphorus, parathyroid hormone (PTH) and total alkaline phosphatase were averaged from clinical measurements during the first 4.5 months of dialysis. We evaluated the associated prospective risk of mortality using multivariable Cox proportional hazards models stratified by race.
Results
PTH and total alkaline phosphatase were higher, whereas calcium, phosphorus, FGF23 and 25D were lower in African Americans compared to non-African Americans. Higher serum phosphorus and FGF23 were associated with greater mortality risk overall, however phosphorus was only associated among African Americans (HR 5.38; 95% CI 2.14–13.55 for quartile 4 vs 1), but not among non-African Americans (p-interaction=0.04). FGF23 was associated with mortality in both groups, but more strongly in African Americans (HR 3.91; 95% CI 1.74–8.82 for quartiles 4 vs 1; p-interaction=0.09). Serum calcium, PTH, and 25D were not consistently associated with mortality. The lowest and highest quartiles of total alkaline phosphatase associated with higher mortality risk, but this did not differ by race (p-interaction= 0.97).
Conclusions
Aberrant phosphorus homeostasis, reflected by higher phosphorus and FGF23, may be a risk factor for mortality in patients recently initiating hemodialysis, particularly African Americans.
doi:10.1159/000438999
PMCID: PMC4562864  PMID: 26287973
Dialysis; end-stage renal disease; epidemiology; fibroblast growth factor 23; phosphorus; vitamin D
37.  Dialysis Facility Transplant Philosophy and Access to Kidney Transplantation in the Southeast 
American journal of nephrology  2015;41(6):504-511.
Background
Little is known about the impact of dialysis facility treatment philosophy on access to transplant. The aim of our study was to determine the relationship between dialysis facility transplant philosophy and facility-level access to kidney transplant waitlisting.
Methods
A 25-item questionnaire administered to Southeastern dialysis facilities (n=509) in 2012 captured facility transplant philosophy (categorized as “transplant is our first choice,” “transplant is a great option for some,” and “transplant is a good option, if the patient is interested”) .. Facility-level waitlisting and facility characteristics were obtained from the 2008-2011 Dialysis Facility Report. Multivariable logistic regression was used to examinethe association between dialysis facility transplant philosophy and facility waitlisting performance (dichotomized using the national median), where low performance was defined as less than 21.7% of dialysis patients waitlisted within a facility.
Results
Fewer than 25% (n=124) of dialysis facilities reported “transplant is our first option.” A total of 131 (31.4%) dialysis facilities in the Southeast were high-performing with respect to waitlisting. Adjusted analysis showed that facilities who reported “transplant is our first option” were twice (OR=2.0, 95% CI 1.0, 3.9) as likely to have high waitlisting performance compared to facilities who reported “transplant is a good option, if the patient is interested.”
Conclusions
Facilities with staff who had a more positive transplant philosophy were more likely to have better facility waitlisting performance. Future prospective studies are needed to further transplantation.
doi:10.1159/000438463
PMCID: PMC4560967  PMID: 26278585
dialysis; chronic kidney failure; kidney transplantation; patient education
38.  Do the Eyes Reveal More Than Scleral Icterus in Sickle Cell Disease? 
American journal of nephrology  2015;41(6):485-486.
doi:10.1159/000438679
PMCID: PMC4561010  PMID: 26277980
albuminuria; conjunctival velocity; sickle cell disease
39.  Changes in Conjunctival Hemodynamics Predict Albuminuria in Sickle Cell Nephropathy 
American journal of nephrology  2015;41(6):487-493.
Background
Albuminuria is an early manifestation of deterioration in renal function in subjects with sickle cell disease (SCD). Hyperfiltration may be an early mechanism for kidney damage in SCD. The purpose of the current study was to determine the association between conjunctival hemodynamics and albuminuria in SCD subjects with preserved glomerular filtration rate.
Methods
Conjunctival microcirculation imaging was performed to measure conjunctival diameter (D) and axial blood velocity (V) in 35 SCD and 10 healthy control subjects. Albuminuria, defined as albumin excretion ratio (AER) was obtained from the medical charts. Based on the 95% confidence interval of conjunctival V in control subjects (0.40 - 0.60 mm/s), SCD subjects were allocated to three groups: V1 < 0.40 mm/s (N = 7), V2 of 0.40 – 0.60 mm/s (N = 18), and V3 ≥ 0.60 mm/s (N = 10).
Results
Mean log(AER) measurements in the V1, V2, and V3 groups were 1.08 ± 0.67 mg/g creatinine, 1.39 ± 0.59 mg/g creatinine, and 2.00 ± 0.91 mg/g creatinine, respectively, and followed a positive linear trend from the V1 to V3 groups (p = 0.01). By multivariate linear regression analysis, conjunctival V significantly correlated with albuminuria (p = 0.01) independent of age, blood pressure, α-thalassemia, hematocrit, white blood cell count, and lactate dehydrogenase concentration.
Conclusions
Increased conjunctival velocity is associated with albuminuria in sickle cell subjects. Assessment of conjunctival microvascular hemodynamics may improve our understanding of the pathophysiology and clinical course of sickle cell nephropathy.
doi:10.1159/000438678
PMCID: PMC4561023  PMID: 26278102
Sickle cell disease; Bulbar Conjunctiva; Hemodynamics; Kidney; Albuminuria
40.  Serum potassium, end stage renal disease and mortality in chronic kidney disease 
American journal of nephrology  2015;41(6):456-463.
Background/Aims
Hypokalemia and hyperkalemia are often noted in chronic kidney disease (CKD) patients but their impact on mortality and end stage renal disease (ESRD) is less well understood. We aimed to study the associations between potassium disorders, and mortality and progression to ESRD in a CKD population.
Methods
Using our Electronic Health Record-based CKD registry, 36,359 patients with eGFR < 60 ml/min/1.73m2 and potassium levels measured from January 1, 2005 to September 15, 2009 were identified. We examined factors associated with hypokalemia (<3.5 mmol/l) and hyperkalemia (>5.0 mmol/l) using logistic regression models and associations between serum potassium levels (both as continuous and categorical variables) and all-cause mortality or ESRD using Cox-proportional hazards models.
Results
Serum potassium <3.5 mmol/l was noted among 3% and >5.0 mmol/l among 11% of the study population. In the multivariable logistic regression analysis, lower eGFR, diabetes and use of ACE inhibitors or Angiotensin-Receptor Blockers were associated with higher odds of having hyperkalemia. Heart failure and African American race were associated with higher odds of hypokalemia. After adjustment for covariates including kidney function, serum potassium <4.0 mmol/l and >5.0 mmol/l were significantly associated with increased mortality risk but there was no increased risk for progression to ESRD. Time-dependent repeated measures analysis confirmed these findings. When potassium was examined as a continuous variable, there was a U-shaped association between serum potassium levels and mortality.
Conclusion
In patients with stage 3–4 CKD, serum potassium level <4.0 mmol/l and >5.0 mmol/l are associated with higher mortality but not with ESRD.
doi:10.1159/000437151
PMCID: PMC4686260  PMID: 26228532
Potassium; mortality; ESRD; chronic kidney disease
41.  Electrochemical skin conductance in diabetic kidney disease 
American journal of nephrology  2015;41(6):438-447.
Background
There is a need to identify patients with diabetic kidney disease (DKD) using non-invasive, cost-effective screening tests. Sudoscan®, a device using electrochemical skin conductance (ESC) to measure sweat gland dysfunction, is valuable for detecting peripheral neuropathy. ESC was tested for association with DKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2) in 383 type 2 diabetes mellitus (T2D)-affected patients; diagnostic thresholds were determined in 540 patients.
Methods
Relationships between ESC with eGFR and urine albumin:creatinine ratio (UACR) were assessed in 202 European Americans (EA) and 181 African Americans (AA) with T2D.
Results
In 92 EA DKD cases and 110 T2D non-nephropathy controls, respectively, mean(SD) ages were 68.9(9.8) and 61.1(10.8) years, HbA1c 7.4(1.2) and 7.4(1.3)%, eGFR 29.5(12.2) and 87.7(14.1) ml/min/1.73m2, and UACR 1227(1710) and 7.6(5.9) mg/g. In 57 AA cases and 124 controls, respectively, mean (SD) ages were 64.0(12.0) and 59.5(9.7) years, HbA1c 7.4(1.3) and 7.6 (1.7)%, eGFR 29.7(13.3) and 90.2(16.2) ml/min/1.73m2, and UACR 1172(1564) and 7.8(7.1) mg/g. Mean(SD) ESC (μS) was lower in cases than controls (EA: case/control hands 49.3(18.5)/62.4(16.2); feet 62.2(18.0)/73.4(13.9), both p<5.8×10−7; AA: case/control hands 39.8(19.0)/48.5(17.1); feet 53.2(21.3)/63.5(19.4), both p≤0.01). Adjusting for age, sex, BMI and HbA1c, hands and feet ESC associated with eGFR <60 ml/min/1.73m2 (p≤7.2×10−3), UACR >30 mg/g (p≤7.0×10−3), UACR >300 mg/g (p≤8.1×10−3), and continuous traits eGFR and UACR (both p≤5.0×10−9). HbA1c values were not useful for risk stratification.
Conclusions
ESC measured using Sudoscan® is strongly associated with DKD in AA and EA. ESC is a useful screening test to identify DKD in patients with T2D.
doi:10.1159/000437342
PMCID: PMC4560993  PMID: 26228248
African Americans; albuminuria; diabetes mellitus; electrochemical skin conductance; European Americans; kidney disease
42.  BRODIFACOUM INDUCES EARLY HEMOGLOBINURIA AND LATE HEMATURIA IN RATS: NOVEL RAPID BIOMARKERS OF POISONING 
American journal of nephrology  2015;41(0):392-399.
Introduction
Brodifacoum (BDF) is a superwarfarin that is used primarily as a rodenticide. There have been increasing number of reports of human cases of accidental or intentional BDF ingestion with high mortality rate. Its broad availability and high lethality suggest that BDF should be considered a potential chemical threat. Currently, there is no biomarker for early detection of BDF ingestion in humans; patients typically present with severe coagulopathy. Since we demonstrated earlier that warfarin can induce acute kidney injury with hematuria, we tested whether BDF would also lead to change in urinary biomarkers.
Material and methods
BDF was administered to Sprague Dawley rats via oral gavage. N-acetylcysteine (NAC) was given per os in drinking water 24 hours prior to BDF. Urinalysis was performed at different times after BDF administration. Anticoagulation and serum creatinine levels were analyzed in the blood.
Results
We observed that within a few hours the animals developed BDF-dose-dependent transient hemoglobinuria, which ceased within 24 hours. This was accompanied by a transient decrease in hematocrit, gross hemolysis and an increase in free hemoglobin in the serum. At later times, animals developed true hematuria with red blood cells in the urine, which was associated with BDF anticoagulation. NAC prevented early hemoglobinuria, but not late hematuria associated with BDF.
Conclusions
We propose that transient early hemoglobinuria (associated with oxidative stress) with consecutive late hematuria (associated with anticoagulation) are novel biomarkers of BDF poisoning and they can be used in clinical setting or in mass-casualty with BDF to identify poisoned patients.
doi:10.1159/000433568
PMCID: PMC4514561  PMID: 26111556
Brodifacoum; superwarfarin; acute kidney injury; urinalysis; hematuria; hemoglobinuria; N-acetylcysteine
43.  Estimated pulmonary artery systolic pressure and self-reported physical function in patients on hemodialysis 
American journal of nephrology  2015;41(0):313-319.
Background/Aims
Patients on chronic hemodialysis have a high prevalence of heart disease and poor self-reported physical function. The association between structural heart disease and self-reported physical function in patients on hemodialysis is unknown.
Methods
We studied the association between elevated pulmonary artery systolic pressure (PASP) and self-reported physical function in ESRD in 253 patients in the USRDS ACTIVE/ADIPOSE study between 2009 and 2011. We used multivariate linear regression with PASP obtained from clinical echocardiogram reports as the primary predictor and the Physical Function (PF) subscale of the SF-36 as the primary outcome. To determine whether associations between PASP and PF were driven by fluid overload or left ventricular hypertrophy, we assessed whether PASP was associated with bioimpedance spectroscopy (BIS)-derived extracellular water(ECW) and with left ventricular posterior wall thickness.
Results
In a multivariable model, each 10 mmHg higher PASP was associated with 3.32-point lower PF score (95% CI: -5.95, -0.68). In a multivariable model that included BIS estimates, both left ventricular posterior wall thickness (LVPW, per 5 mm) and ECW were associated with higher PASP (left ventricular posterior wall thickness 4.21 mmHg, 95% 0.38-8.04; ECW 1.12 mmHg per liter, 95% CI 0.07-2.18). Higher LVPW and higher ECW were independently associated with lower PF score.
Conclusion
Left ventricular hypertrophy and elevated pulmonary pressure are associated with worse self-reported physical function in patients on hemodialysis. The role of chronic volume overload on PASP and PF score should be evaluated in a prospective manner.
doi:10.1159/000431334
PMCID: PMC4672989  PMID: 26089100
physical function; end-stage renal disease; echocardiography; volume status
44.  Hemodialysis Patient Outcomes: Provider Characteristics 
American journal of nephrology  2014;39(5):367-375.
Background/Aims
Physician characteristics are associated with differential performance on quality measures and patient outcomes in several medical fields. We aimed to determine whether characteristics of physicians who provide care to dialysis patients were associated with patient outcomes.
Methods
This cohort study used United States Renal Data System data for patients who initiated in-center hemodialysis October 1, 2003–September 30, 2006 (n = 91,276). Patient characteristics were defined and physicians identified from Part B Medicare claims for outpatient dialysis services submitted during months 4–6 of hemodialysis. Physician characteristics were obtained from the American Medical Association Physician Master File. Associations of physician characteristics with 1-year patient mortality and first hospitalization were determined using Cox proportional hazards analysis; associations with quality of care (defined by influenza vaccination and waitlisting for kidney transplant) were determined using logistic regression.
Results
Physician characteristics were not associated with patient mortality. After adjustment for patient and other provider characteristics, patients whose physicians had practiced longer or were in administrative, research, or teaching practices were more likely to be hospitalized; patients whose providers practiced in smaller metropolitan statistical areas (MSAs) were less likely. More years since training was associated with greater chance of waitlisting, and practicing in smaller MSAs with less chance. Graduation from a foreign medical school, practicing in smaller MSAs, and travelling farther from office to dialysis unit were associated with greater odds of influenza vaccination.
Conclusions
Several characteristics of physicians seeing incident outpatient hemodialysis patients were associated with hospitalization and quality of care, but none with mortality.
doi:10.1159/000362286
PMCID: PMC4901871  PMID: 24776789
Hemodialysis; patient outcomes; provider characteristics; quality of care
45.  Aortic stiffness and kidney disease in an elderly population 
American journal of nephrology  2015;41(0):320-328.
Background/Aims
The causes of chronic kidney disease (CKD) in older people are not well understood. Aortic stiffness increases with age and results in transmission of increased pulsatility into the kidney microvasculature, potentially contributing to CKD in older populations.
Methods
We utilized data from the Age, Gene/Environment, Susceptibility-Reykjavik Study, a community-based prospective cohort study of cardiovascular disease (CVD) in Iceland. Associations of carotid pulse pressure (CPP) and carotid femoral pulse wave velocity (CFPWV) with estimated glomerular filtration rate based on creatinine and cystatin C (eGFR) and urine albumin-creatinine ratio (ACR) were assessed using linear regression, adjusting for demographics and CVD risk factors.
Results
940 participants [mean (SD) age 75.8 (4.7) years, mean (SD) CFPWV 12.9 (4.2) m/s, mean (SD) CPP 69 (21) mm Hg, mean (SD) eGFR 68 (16) ml/min/1.73m2, and median (IQR) ACR 3 (2–6) mg/g) were studied. At CPP greater than 85 mmHg, higher CPP was associated with lower eGFR in unadjusted analyses but not after adjustment. CPP was significantly associated with higher ACR in fully adjusted models [β (95% CI)=0.14 (0.03, 0.24) ln mg/g per SD]. Higher CFPWV was associated with lower eGFR and higher ACR in unadjusted analyses but not after adjustment.
Conclusion
Greater aortic stiffness may be associated with modestly higher levels of albuminuria in the elderly. The association with lower eGFR may be confounded by age and CVD risk factors.
doi:10.1159/000431332
PMCID: PMC4514536  PMID: 26067356
albuminuria; aortic stiffness; chronic kidney disease; elderly; glomerular filtration rate
46.  Renal Function and Long-term Decline in Cognitive Function: The Baltimore Longitudinal Study of Aging 
American journal of nephrology  2015;41(0):305-312.
Background
Renal disease has been associated with greater risk of dementia and greater cognitive impairment. However, the relationship of lower renal function with long-term decline in specific domains of cognitive function remains unclear among community-dwelling, nondemented individuals.
Methods
Stroke- and dementia-free participants (n=2,116) were enrolled in the Baltimore Longitudinal Study of Aging (BLSA), a community-based, prospective, longitudinal study. Renal function was estimated by the inverse of serum creatinine adjusted for age, sex, and race, and (in sensitivity analyses) GFR estimated using the MDRD formula. Outcome measures were changes in scores on 6 cognitive tests encompassing a range of cognitive functions, measured at 2 year intervals. Mixed-effects regression models examined the longitudinal relations of renal function with cognitive functions, adjusting for demographics, co-morbidity, and other potential confounders.
Results
Mean age at initial testing was 53.9 (SD=17.1) years, 94 (4.4%) participants had eGFR<60 cc/min/1.73m2, and 18.5% had at least one co-morbidity. With increasing age, longitudinal increases in creatinine concentrations were associated with more rapid decline in performance on several cognitive measures, including the learning slope of the California Verbal Learning Test (CVLT; a test of verbal learning; p<.01) and the Benton Visual Retention Test (BVRT), a test of visual memory (p<.01). Associations were similar for changes in eGFRMDRD, which was also associated with rate of decline in verbal memory.
Conclusion
In a community-based adult population, declines in renal function independently associated with greater long-term declines in visual memory and verbal memory and learning.
doi:10.1159/000430922
PMCID: PMC4544717  PMID: 26201453
Kidney function; creatinine; estimated glomerular filtration rate; cognitive function; neuropsychology; longitudinal trajectories
47.  Predictors of Provider-Patient Visit Frequency During Hemodialysis 
American journal of nephrology  2013;38(2):91-98.
Background/Aims
In 2004, the Centers for Medicare & Medicaid Services tied reimbursement for outpatient hemodialysis services to number of times per month providers see their dialysis patients, resulting in increased provider-patient visit frequency. Greater provider-patient visit frequency is associated with lower hospitalization risk for hemodialysis patients. Determinants of visit frequency are uncertain. We aimed to identify patient, provider, and dialysis facility characteristics associated with provider visit frequency.
Methods
This retrospective cohort study used United States Renal Data System (USRDS) data for point-prevalent patients receiving in-center hemodialysis on January 1, 2006 (n = 144,860). Patient characteristics were defined January 1-June 30, 2006, and provider-patient visit frequency (< 4 vs. ≥ 4 visits/month) July 1-December 31, 2006. Patient characteristics were obtained from the USRDS. Provider data were obtained from the American Medical Association Physician Master File. We determined longitudinal associations between patient, provider, and facility characteristics and provider-patient visit frequency using logistic regression.
Results
Patient characteristics independently associated with greater provider-patient visit frequency included older age, African American race, longer dialysis duration, higher comorbidity score, Medicaid eligibility, urban residence, better compliance with dialysis, and more hospital days during run-in. Provider characteristics associated with greater provider-patient visit frequency included more years in practice, graduation from a foreign medical school, shorter distance between provider office and dialysis unit, and caring for more dialysis patients; facility characteristics included free-standing, independent status.
Conclusion
After the Medicare reimbursement policy change, several patient, provider, and facility characteristics were independently associated with greater dialysis provider-patient visit frequency.
doi:10.1159/000353565
PMCID: PMC4880355  PMID: 23867383
Hemodialysis; Medicare; nephrology
48.  Podocyte structural parameters do not predict progression to diabetic nephropathy in normoalbuminuric type 1 diabetic patients 
American journal of nephrology  2015;41(0):277-283.
Background
Podocyte injury has been implicated in diabetic nephropathy ranging from normoalbuminuria to proteinuria in both type 1 and type 2 diabetes.
Methods
To determine whether podocyte structural parameters predict diabetic nephropathy risk in initially normoalbuminuric long-standing type 1 diabetic patients, we performed a nested case-control study in sex, and diabetes duration-matched progressors (progression to proteinuria or ESRD; n = 10), non-progressors (normoalbuminuric at follow-up, n = 10), and non-diabetic controls (n = 10).
Results
HbA1c and diastolic blood pressure were higher in progressors versus non- progressors. Podocyte number per glomerulus, numerical density of podocyte per glomerulus, and foot process width were not different among groups. Glomerular basement membrane width was greater in progressors versus non-progressors or controls, and in non-progressors versus controls. As expected, mesangial fractional volume was greater in progressors and non-progressors versus controls, with no differences between progressors and non-progressors.
Conclusion
This study does not indicate that podocyte structural changes are preconditions for later diabetic nephropathy progression in initially normoalbuminuric type 1 diabetic patients. However, this does not preclude an important role for podocyte injury at later stage of diabetic nephropathy.
doi:10.1159/000381992
PMCID: PMC4514533  PMID: 26021523
nephropathy; normoalbuminuria; podocyte; type 1 diabetes
49.  Lifestyle Factors and Indices of Kidney Function in the Framingham Heart Study 
American journal of nephrology  2015;41(0):267-274.
Background and objectives
Lifestyle characteristics are modifiable factors that could be targeted as part of chronic kidney disease (CKD) prevention. We sought to determine the association of lifestyle characteristics with incident estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 and rapid eGFR decline in older adults in the United States.
Methods
Prospective cohort study of Framingham Offspring participants with baseline eGFR<60mL/min/1.73m2 (n=1802) who attended the seventh (1998–2001; baseline) and eighth (2005–2008; follow-up) examinations (mean age=59years, 54.8% women). Predictors included measures of diet quality, physical activity, alcohol intake, and current smoking status assessed during baseline. Outcomes were based on creatinine-based eGFR at baseline and follow-up and included incident eGFR<60mL/min/1.73m2 (at follow-up) and rapid eGFR decline (annual eGFR decrease≥3mL/min/1.73m2).
Results
Over 6.6 years average follow-up 9.5% (n=171) of participants developed incident eGFR<60. A trend was observed across quartiles of diet quality, with higher levels of diet quality associated with a decreased odds ratio [OR] of incident eGFR<60 (p-trend=0.045). Higher diet quality was associated with decreased odds of rapid eGFR decline (p-trend=0.03) and was attenuated with additional adjustment (p-trend=0.07). In sensitivity analysis for rapid eGFR decline using a secondary definition (annual eGFR decrease≥3 and incident eGFR<60), diet associations remained significant with additional adjustment (p-trend=0.04). No associations were observed with physical activity, smoking status, or alcohol intake with incident eGFR<60 or rapid eGFR decline (all p>0.19).
Conclusions
Higher diet quality may be associated with a decreased risk of incident eGFR<60mL/min/1.73m2, and rapid eGFR decline. Whether adherence to a healthy diet can prevent reduction in kidney function warrants further study.
doi:10.1159/000430868
PMCID: PMC4514559  PMID: 25998023
lifestyle factors; dietary quality; physical activity; smoking; alcohol intake; chronic kidney disease; epidemiology
50.  High titer Anti-Basement Membrane Antibodies in a Subset of Patients with Pediatric Systemic Lupus Erythematosus 
American journal of nephrology  2015;41(3):241-247.
Background/Aims
There is a critical need for more non-invasive biomarkers for nephritis in patients with SLE. Recent studies in a model mouse and an adult SLE patient cohort suggest that anti-basement membrane antibody levels correlate well with lupus activity and kidney injury. The purpose of this study was to assess anti- basement membrane reactivity in pediatric SLE (pSLE) patients with or without nephritis.
Methods
Auto-antibodies to basement membrane antigens were assessed using an anti-matrigel ELISA. End-point titers were measured in pSLE patients and healthy children, as well as in autoimmune and non-immune mice, with good reproducibility. Findings were also analyzed with respect to presence or absence of nephritis, dsDNA antibodies, and other manifestations of pSLE.
Results
MRL/lpr mice developed high-titer anti-matrigel antibodies, whereas C57BL/6 mice did not. In a cohort of 21 pSLE patients and 22 pediatric controls, high-titer anti-matrigel IgG, IgM and IgA antibody levels were specific for pSLE. High-titer anti-matrigel IgG3 levels could distinguish with good sensitivity the 13 pSLE patients with a history of nephritis from the 8 non-renal pSLE patients. High-titer anti-matrigel IgG, IgA, IgM or IgG3 did not correlate with positive anti-double stranded DNA, but defined an overlapping subset of patients.
Conclusion
The addition of anti-basement membrane antibody testing to serologic testing in pSLE may help to monitor disease activity or to define important subsets of patients with risks for specific disease manifestations.
doi:10.1159/000381965
PMCID: PMC4441865  PMID: 25926050
glomerulonephritis; pediatrics; inflammation

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