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1.  Acute Kidney Injury and Mortality in Hospitalized Patients 
American Journal of Nephrology  2012;35(4):349-355.
Background
The objective of this study was to determine the incidence of acute kidney injury (AKI) and its relation with mortality among hospitalized patients.
Methods
Analysis of hospital discharge and laboratory data from an urban academic medical center over a 1-year period. We included hospitalized adult patients receiving two or more serum creatinine (sCr) measurements. We excluded prisoners, psychiatry, labor and delivery, and transferred patients, ‘bedded outpatients’ as well as individuals with a history of kidney transplant or chronic dialysis. We defined AKI as (a) an increase in sCr of ≥0.3 mg/dl; (b) an increase in sCr to ≥150% of baseline, or (c) the initiation of dialysis in a patient with no known history of prior dialysis. We identified factors associated with AKI as well as the relationships between AKI and in-hospital mortality.
Results
Among the 19,249 hospitalizations included in the analysis, the incidence of AKI was 22.7%. Older persons, Blacks, and patients with reduced baseline kidney function were more likely to develop AKI (all p < 0.001). Among AKI cases, the most common primary admitting diagnosis groups were circulatory diseases (25.4%) and infection (16.4%). After adjustment for age, sex, race, admitting sCr concentration, and the severity of illness index, AKI was independently associated with in-hospital mortality (adjusted odds ratio 4.43, 95% confidence interval 3.68–5.35).
Conclusions
AKI occurred in over 1 of 5 hospitalizations and was associated with a more than fourfold increased likelihood of death. These observations highlight the importance of AKI recognition as well as the association of AKI with mortality in hospitalized patients.
doi:10.1159/000337487
PMCID: PMC3362180  PMID: 22473149
Acute kidney injury; Chronic kidney disease; Mortality; Health services
2.  Impact of Race on Predialysis Discussions and Kidney Transplant Preemptive Wait-Listing 
American Journal of Nephrology  2012;35(4):305-311.
Background/Aims
US registry data have consistently shown that blacks are less likely than whites to be wait-listed before beginning dialysis.
Methods
The Comprehensive Dialysis Study (CDS) was a special study conducted by the US Renal Data System (USRDS) in which a national cohort of patients who began maintenance dialysis therapy in 2005–2007 were asked whether kidney transplantation (KT) had been discussed with them before they started dialysis. Using responses from black and white CDS participants and information from the USRDS, we investigated preemptive wait-listing as a function of patient-reported predialysis KT discussion.
Results
Among those reporting early KT discussion, 31.0% of patients preemptively wait-listed were black, compared to 27.5% of those not preemptively wait-listed. Two thirds of preemptively wait-listed patients had received nephrology care more than 12 months before starting dialysis and reported that KT was discussed with them 12 months or more before dialysis. Early KT discussion and higher serum albumin and hemoglobin levels remained significant predictors of preemptive wait-listing in an adjusted logistic regression analysis. Among those preemptively wait-listed, 33% of blacks and 60% of whites had received a transplant by September 30, 2009 (study end date).
Conclusion
Early KT discussion appeared to reduce barriers to black patients' waiting list placement before the start of dialysis, which in turn may facilitate earlier access to a deceased donor organ transplant.
doi:10.1159/000336891
PMCID: PMC3362182  PMID: 22414927
Education; Kidney transplantation; Preemptive wait-listing; Race; United States Renal Data System
3.  Elevated Plasma Levels of Endostatin Are Associated with Chronic Kidney Disease 
American Journal of Nephrology  2012;35(4):335-340.
Background/Aims
Angiogenesis may play an important role in the renal repair process after injury. We investigated the association between plasma endostatin, an endothelial-specific antiangiogenic factor, and chronic kidney disease (CKD).
Methods
We compared plasma endostatin levels in 201 CKD patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or presence of albuminuria (≥30 mg/24 h).
Results
After adjustment for established CKD risk factors, the median (interquartile range) of plasma endostatin was 276.7 ng/dl (199.3–357.5) in patients with CKD and 119.4 ng/dl (103.7–134.6) in controls without CKD (p < 0.0001 for group difference). log-transformed plasma endostatin was significantly and inversely correlated with eGFR (r = −0.83, p < 0.0001) and positively correlated with log-transformed urine albumin (r = 0.66, p < 0.0001) in the study participants. In addition, one standard deviation increase in log-transformed plasma endostatin (0.55 ng/dl) was associated with a decline in eGFR of −26.2 ml/min and an increase in urine albumin of 3.26 mg/ 24 h after adjusting for multiple covariables. Furthermore, the multivariable-adjusted odds ratio for CKD comparing the highest tertile (≥131.4 ng/dl) to the two lower tertiles of plasma endostatin was 21.6 (95% CI: 10.2–45.5; p < 0.0001).
Conclusion
These data indicate that elevated plasma endostatin is strongly and independently associated with CKD. Prospective cohort studies and clinical trials are warranted to further examine the causal relationship between endostatin and risk of CKD and to develop novel interventions targeting circulating endostatin aimed at reducing CKD risk.
doi:10.1159/000336109
PMCID: PMC3362190  PMID: 22456114
Albuminuria; Antiangiogenic factor; Chronic kidney disease; Endostatin; Estimated glomerular filtration rate
4.  Incidence and Risk Factors for Acute Kidney Injury in HIV Infection 
American Journal of Nephrology  2012;35(4):327-334.
Background/Aims
Although HIV-infected persons are at higher risk for acute kidney injury (AKI) during hospitalization compared with their uninfected counterparts, risk factors for AKI are not well-defined. We aimed to describe the evolving incidence of AKI among HIV-infected individuals and to identify important AKI risk factors.
Methods
We conducted a prospective cohort study of 56,823 HIV-infected persons in the Department of Veterans Affairs Clinical Case Registry. Outcomes were: AKI (acute in-hospital serum creatinine increase of ≥0.3 mg/dl, or a relative increase by 50% or greater), and dialysis-requiring AKI. We used proportional hazards regressions to identify risk factors.
Results
From its peak in 1995 at 62 per 1,000 person-years, the incidence of AKI declined after the introduction of highly active antiretroviral therapy (HAART) in 1996 to a low point of 25 per 1,000 person-years in 2006. Incidence of dialysis-requiring AKI declined in the early 1990s, but doubled between 2000 and 2006. Using multivariate proportional hazard regression, we identified the following strong risk factors for AKI: chronic kidney disease (eGFR <60 ml/min/1.73 m2) (5.38, 95% CI: 5.11–5.67), proteinuria (1.78, 1.70–1.87), low serum albumin (<3.7 mg/dl) (5.24, 4.82–5.71), low body mass index (<18.5 kg/m2) (1.69, 1.54–1.86), cardiovascular disease (1.77, 1.66–1.89), low CD4 count (<200 cells/mm3) (2.54, 2.33–2.77), and high viral load (≥100,000 copies/ml) (2.51, 2.28–2.75). In addition, there was substantial heterogeneity in the strengths of risk factors for dialysis-requiring AKI before and after the introduction of HAART.
Conclusions
Although AKI incidence has decreased during the HAART era, it remains common in HIV-infected persons and appears attributable to both kidney- and HIV-related factors.
doi:10.1159/000337151
PMCID: PMC3362304  PMID: 22456100
Acute kidney injury; HIV; Chronic kidney disease; Proteinuria; Hypoalbuminemia
5.  5/6 Nephrectomy as a Validated Rat Model Mimicking Human Warfarin-Related Nephropathy 
American Journal of Nephrology  2012;35(4):356-364.
Background/Aims
We previously reported that patients with chronic kidney disease (CKD) receiving warfarin therapy and whose international normalized ratio increases to >3.0 may develop acute kidney injury (AKI) as a result of glomerular hemorrhage and formation of obstructive red blood cell (RBC) casts. We named this condition warfarin-related nephropathy (WRN). We also previously reported that acute excessive anticoagulation with brodifacoum (superwarfarin) induces AKI in 5/6 nephrectomy (5/6NE) rats. Limitations of the brodifacoum model precluded a careful assessment of dose-response relationships.
Methods
Warfarin treatment was used in 5/6NE.
Results
Herein we report that warfarin treatment of 5/6NE rats resulted in a dose-dependent increase in serum creatinine (SC). The increase in SC following warfarin treatment was greater at 3 and 19 weeks after the ablative surgery, than that observed 8 weeks after the ablative surgery. The SC increase was correlated with the prothrombin time increase. Morphologically, 5/6NE, but not control rats, had acute tubular injury with RBC and RBC casts in the tubules. Treatment with vitamin K prevented SC increase and morphologic changes in the kidney associated with warfarin treatment. A single episode of WRN did not affect the progression of CKD in 5/6NE.
Conclusion
(1) The 5/6NE model of CKD is an appropriate animal model to study the pathogenesis of WRN. (2) The pharmacokinetics of warfarin is better suited to the study of WRN than that of brodifacoum. (3) The more advanced stages of 5/6NE are more susceptible to WRN than the earlier stages. (4) Vitamin K treatment prevents WRN.
doi:10.1159/000337918
PMCID: PMC3487141  PMID: 22473220
Warfarin-related nephropathy; Acute kidney injury; Coagulation; 5/6 Nephrectomy
6.  Renal Adaptation to Gentamicin-Induced Mineral Loss 
American Journal of Nephrology  2012;35(3):279-286.
Background
Gentamicin, a well-known nephrotoxic drug, affects calcium and magnesium homeostasis. Although gentamicin induces urinary calcium and magnesium wasting immediately, it rarely causes significant hypocalcemia or hypomagnesemia clinically.
Methods
We conducted an animal study to investigate the renal adaptation in calcium and magnesium handling after gentamicin treatment and effects on the expression of calcium and magnesium transport molecules in distal tubule. Gentamicin (40 mg/kg) was injected daily in male Sprague-Dawley rats (220–250 g) for up to 7 days.
Results
This treatment did not affect serum creatinine, calcium, or magnesium levels. Gentamicin induced significant hypercalciuria (14-fold) and hypermagnesiuria (10-fold) in 6 h, which was associated with upregulation of TRPV5 (175 ± 3%), TRPV6 (170 ± 4%), TRPM6 (156 ± 4%) and calbindin-D28k (174 ± 3%; all p < 0.05 vs. control). This gene upregulation was maintained with daily injection of gentamicin for 7 days. The gentamicin-induced urinary calcium loss was reduced by 80% at days 3 and 7, while magnesium loss was reduced by 52 and 57% at days 3 and 7, respectively. On the other hand, urinary loss of potassium became worse on day 7 (2-fold), and phosphorus loss worse from day 3 to day 7 (3-fold).
Conclusion
There is a rapid adaptation to gentamicin-induced hypercalciuria and hypermagnesiuria. The upregulation of distal tubule transport molecules, TRPV5, TRPV6, TRPM6 and calbindin-D28k occurs within 6 h of gentamicin treatment. This renal adaptation prevents further mineral loss due to gentamicin treatment.
doi:10.1159/000336518
PMCID: PMC3357145  PMID: 22378246
Renal adaptation; Calcium; Magnesium; Gentamicin
7.  Autologous Creatinine Clearance in a Case of Necrotizing Fasciitis and Anuria 
American Journal of Nephrology  2012;35(3):225-229.
Necrotizing fasciitis can present with concomitant acute kidney injury. The etiology of acute kidney injury is often multifactorial; potential sources include volume depletion, abdominal compartment syndrome, rhabdomyolysis, and acute tubular necrosis (which may be related to hemodynamic instability, medications, or sepsis/infection). Kidney injury, defined via changes in serum creatinine, portends increased morbidity and mortality. Thus, it is crucial to accurately diagnose and assess the severity of kidney injury. We present the case of a patient with necrotizing fasciitis who endured 31 consecutive days of complete anuria. His serum creatinine decreased over this interval without the use of extracorporeal hemofiltration or dialysis. The explanation for this novel phenomenon lies in massive daily sero-sanguineous discharge and insensible losses with subsequent volume resuscitation. The patient's own convective clearance was substantial enough to maintain a modest creatinine clearance of 15 ml/min during sustained anuria. Our case emphasizes the importance of employing the creatinine, estimated glomerular filtration rate, and urine output portions of the Acute Kidney Injury Network (AKIN) or Risk Injury Failure Loss End stage (RIFLE) criteria in assessing the severity of kidney injury. It further reinforces the imperfection in using serum creatinine as a primary measure of glomerular filtration rate.
doi:10.1159/000336309
PMCID: PMC3711005  PMID: 22343604
Necrotizing soft tissue infection; Fasciitis; Acute renal failure; Burn; Debridement
8.  Iron Sucrose Promotes Endothelial Injury and Dysfunction and Monocyte Adhesion/Infiltration 
American Journal of Nephrology  2011;35(2):114-119.
Background/Aims
Intravenous (IV) iron preparations are widely used in the management of anemia in ESRD populations. Recent changes in reimbursement policy have dramatically increased the use of IV iron to lower the use of costly erythropoiesis-stimulating agents. These preparations are frequently administered with insufficient attention to the total body iron stores or presence of inflammation which is aggravated by excess iron. Endothelial injury and dysfunction are critical steps in atherosclerosis, thrombosis and cardiovascular disease. IV iron preparations raise plasma non-transferrin-bound iron which can promote oxidative stress, endothelial damage and dysfunction. We explored the effect of an IV iron preparation on endothelial cells, monocytes and isolated arteries.
Methods
Primary cultures of human aortic endothelial cells (HAEC) were treated with pharmacologically relevant concentrations of iron sucrose (10–100 μg/ml) for 4–24 h. Endothelial cell morphology, viability, and monocyte adhesion were tested. Endothelial function was assessed by measuring the vasorelaxation response to acetylcholine in normal rat thoracic aorta rings preincubated with iron sucrose (200 μg/ml).
Results
In contrast to the control HAEC which showed normal cobblestone appearance, cells treated with iron sucrose (50–100 μg/ml) for 4 h showed loss of normal morphological characteristics, cellular fragmentation, shrinkage, detachment, monolayer disruption and nuclear condensation/fragmentation features signifying apoptosis. HAEC exposure to iron sucrose (10–100 μg/ml) increased monocyte adhesion 5- to 25-fold. Incubation in media containing 200 μg/ml iron sucrose for 3 h caused marked reduction in the acetylcholine-mediated relaxation in phenylephrine-precontracted rat aorta.
Conclusion
Pharmacologically relevant concentration of iron sucrose results in endothelial injury and dysfunction and marked increase in monocyte adhesion.
doi:10.1159/000334939
PMCID: PMC3265804  PMID: 22212390
Iron sucrose; Endothelial function; Atherosclerosis; End-stage renal disease; Cardiovascular disease; Oxidative stress
9.  Is Awareness of Chronic Kidney Disease Associated with Evidence-Based Guideline-Concordant Outcomes? 
American Journal of Nephrology  2012;35(2):191-197.
Background
Awareness of chronic kidney disease (CKD) is low. Efforts are underway to increase recognition of CKD among patients, assuming that such an increase will lead to better outcomes through greater adherence to proven therapies. Few studies have tested this assumption.
Methods
CKD awareness, defined by a ‘yes’ answer to ‘Have you ever been told by a healthcare provider you have weak or failing kidneys?’, was assessed among 2,404 adults with CKD stages 1–4, who participated in the 2003–2008 National Health and Nutrition Examination Surveys. Odds of blood pressure (BP) control, self-reported use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), and glycemic control, were determined among those aware vs. unaware of their CKD.
Results
Optimal BP control, ACEI/ARB use and glycemic control were low in the US adult population with CKD, although there was a recent increase in attainment of guideline-concordant BP control. Odds of BP control and ACEI/ARB use were not different among individuals aware of their CKD compared to those unaware (adjusted odds ratio (AOR) 0.91; 95% CI 0.52–1.58 and AOR 0.75; 0.44–1.30, respectively). CKD awareness among diabetic participants was not associated with glycemic control (AOR 0.41; 95% CI 0.14–1.18).
Conclusion
Awareness of CKD is not associated with more optimal BP control, ACEI/ARB use or glycemic control. Future efforts in this area should further explore the measurement of CKD awareness and behaviors associated with CKD awareness.
doi:10.1159/000335935
PMCID: PMC3326277  PMID: 22286715
Chronic kidney disease; Awareness; National Health And Nutrition Examination Survey (NHANES); Guidelines
10.  Troponin I Levels and Postoperative Myocardial Infarction following Renal Transplantation 
American Journal of Nephrology  2012;35(2):175-180.
Background
The relationship of routine postoperative troponin I (TnI) monitoring in kidney transplant recipients and in-hospital myocardial infarction (MI) is not known.
Methods
This observational study evaluated the prevalence of abnormal postoperative TnI (Ortho Clinical Diagnostics assay) in 376 consecutive kidney or kidney/pancreas transplant recipients. In-hospital MI was adjudicated using the universal definition. Rates of death and coronary revascularizations at 1 year were studied. Logistic regression analysis was performed to identify independent predictors of abnormal TnI.
Results
Ninety-five (25%) recipients had abnormal TnI (>0.04 ng/ml) following transplantation. Abnormal TnI levels were more common in older (mean age: 52.2 ± 13.4 vs. 48.3 ± 13.2 years, p = 0.01), diabetic (57.9 vs. 45.6%, p = 0.04), and prior coronary artery disease (31.6 vs. 20.3%, p = 0.02) patients. In-hospital MI occurred in 6 patients (1.6%). All subsequent in-hospital cardiovascular events occurred in the abnormal postoperative TnI group; most in those with TnI levels >1 ng/ml. Previous coronary artery disease was the only independent predictor of a postoperative TnI level >1 ng/ml in multivariate analysis (odds ratio 4.61, 95% confidence interval 1.49–14.32). At 1 year there was no significant difference in death (3.2 vs. 1.8%, p = 0.42) and borderline significant difference in coronary revascularization (5.3 vs. 1.4%, p = 0.049) in abnormal versus normal TnI groups.
Conclusions
In-hospital MI was infrequent, but abnormal TnI highly prevalent following renal transplantation. Normal TnI levels following renal transplantation had a high negative predictive value in excluding patients likely to develop subsequent postoperative MI. The role of a higher TnI cut-off for screening for postoperative MI in high-risk subgroups deserves future prospective evaluation.
doi:10.1159/000335679
PMCID: PMC3326278  PMID: 22286592
Troponin; Transplant; Myocardial infarction; Postoperative
11.  Depletion of Macrophages and Dendritic Cells in Ischemic Acute Kidney Injury 
American Journal of Nephrology  2012;35(2):181-190.
Background
Inflammation is thought to play a role in ischemic acute kidney injury (AKI). We have demonstrated that macrophage and dendritic cell depletion, using liposome-encapsulated clodronate (LEC), is protective against ischemic AKI.
Methods
To determine whether macrophages or dendritic cells or both play a role in ischemic AKI, we performed ischemic AKI in CD11b-DTR mice that have a diphtheria toxin (DT)-induced depletion of CD11b cells (macrophages) and CD11c-DTR mice that have a DT-induced depletion of CD11c cells (dendritic cells).
Results
While LEC-treated animals had a significant functional protection from AKI, CD11b-DTR and CD11c-DTR mice were not protected against AKI despite a similar degree of renal macrophage and dendritic cell depletion. Proinflammatory cytokines are known to play a role in ischemic AKI. To determine the possible reasons for the lack of protection in CD11b-DTR and CD11c-DTR mice compared to LEC-treated mice, 32 cytokines/chemokines were measured in these mice. Of the cytokines/chemokines measured, IL-6, MCP-1, GMCSF, IL-1β and CXCL1 (also known as IL-8 in humans or KC in mice) showed significant differences in the LEC-treated, CD11b-DTR and CD11c-DTR mice. MCP-1 and CXCL1 (known mediators of AKI), and also GMCSF and IL-1β were increased in AKI and decreased in LEC-treated AKI but not AKI in CD11b-DTR or CD11c-DTR mice. Conclusions: These findings suggest that LEC-mediated protection from AKI is not simply mediated by depletion of renal macrophage or dendritic cell subpopulations. Protection against AKI in LEC-treated compared to CD11b-DTR or CD11c-DTR mice may be partially explained by differences in proinflammatory cytokine profiles.
doi:10.1159/000335582
PMCID: PMC3326279  PMID: 22286667
Macrophages; Dendritic cells; Ischemia; Acute kidney injury
12.  Structural Equation Modeling Highlights the Potential of Kim-1 as a Biomarker for Chronic Kidney Disease 
American Journal of Nephrology  2012;35(2):152-163.
Background
Chronic kidney disease (CKD) is a major public health problem, and despite continued research in the field, there is still a need to identify both biomarkers of risk and progression, as well as potential therapeutic targets. Structural equation modeling (SEM) is a family of statistical techniques that has been utilized in the fields of sociology and psychology for many years; however, its utilization in the biological sciences is relatively novel. SEM's ability to investigate complex relationships in an efficient, single model could be utilized to understand the progression of CKD, as well as to develop a predictive model to assess kidney status in the patient.
Methods
Fischer 344 rats were fed either an ad libitum diet or a calorically restricted diet, and a time-course study of kidney structure and function was performed. EQS, a SEM software package, was utilized to generate five CKD models of the Fisher 344 rat and identify relationships between measured variables and estimates of kidney damage and kidney function.
Results
All models identified strong relationships between a biomarker for CKD, kidney injury molecule-1 (Kim-1) and kidney damage, in the Fischer 344 rat CKD model. Models also indicate a strong relationship between age and renal damage and dysfunction.
Conclusion
SEM can be used to model CKD and could be useful to examine biomarkers in CKD patients.
doi:10.1159/000335579
PMCID: PMC3326283  PMID: 22269876
Chronic kidney disease; Kidney injury molecule-1; Structural equation modeling
13.  Mortality Associated with Dose Response of Erythropoiesis-Stimulating Agents in Hemodialysis versus Peritoneal Dialysis Patients 
American Journal of Nephrology  2012;35(2):198-208.
Background
Several studies have shown an association between erythropoietin-stimulating agent (ESA) responsiveness and mortality in chronic kidney disease (CKD) patients. In our present study, we examined the association between prescribed ESA dose and mortality in peritoneal dialysis (PD) and hemodialysis (HD) patients. We hypothesized that PD patients received lower ESA dose for the same achieved hemoglobin compared to HD patients and that ESA dose-mortality associations were different between PD and HD patients.
Methods
We compared the prescribed doses of ESA between 139,103 HD and 10,527 PD patients treated in DaVita dialysis clinics from 7/2001 through 6/2006 using adjusted Poisson regression and examined mortality-predictability of prescribed ESA dose and ESA responsiveness index (ESA/hemoglobin) in PD and HD with follow-up through 6/2007 using Cox regression models.
Results
Poisson adjusted ratio of ESA dose of HD to PD was 3.6 (95% CI 3.5–3.7). In PD patients, adjusted all-cause death hazard ratios (HR) for ESA doses of 3,000–5,999, 6,000–8,999 and ≥9,000 U/week (reference <3,000 U/week) were 0.97 (0.87–1.07), 0.85 (0.76–0.95) and 1.08 (0.98–1.18), respectively; whereas in HD patients across commensurate ESA dose increments of 10,000–19,999, 20,000–29,999 and ≥30,000 U/week (reference <10,000 U/week) were 1.14 (1.11–1.17), 1.54 (1.50–1.58) and 2.15 (2.10–2.21), respectively. In PD and HD patients, the adjusted death HR of the 4th to 1st quartile of ESA responsiveness index were 1.14 (1.04–1.26) and 2.37 (2.31–2.43), respectively.
Conclusions
Between 2001 and 2006, most PD patients received substantially lower ESA dose for same achieved hemoglobin levels, and low ESA responsiveness was associated with higher mortality in both HD and PD patients.
doi:10.1159/000335685
PMCID: PMC3326284  PMID: 22286821
Anemia; Hemoglobin; Erythropoietin-stimulating agent therapy; Peritoneal dialysis; Hemodialysis; Mortality; Cardiovascular mortality
14.  Increased Presence of Cognitive Impairment in Hemodialysis Patients in the Absence of Neurological Events 
American Journal of Nephrology  2011;35(2):120-126.
Background/Aims
Cognitive impairment (CI) is highly prevalent among hemodialysis (HD) patients and is associated with increased morbidity and mortality. The aim was to compare cognitive function in HD patients with no history of stroke or dementia and well-matched controls. Studies are required to determine the impact of HD and chronic kidney disease-specific risks on CI.
Methods
76 outpatients (50 receiving outpatient HD and 26 with normal kidney function matched for age and comorbidity) underwent a cross-sectional observational study. HD patients were well dialyzed and had optimal hemoglobin levels. A battery of eight neuropsychological tests was used. Outcomes included assessment scores of neurocognitive testing and prevalence and subtype of CI.
Results
Compared to controls, HD subjects had significantly lower composite scores for each tested cognitive domain. In each domain except memory, the percentage of subjects with impairment was significantly higher in HD subjects than controls. Differences between the groups were independent of vascular and dementia risk factors. 82% of HD subjects met criteria for CI versus 50% of controls. Non-amnestic subtype of CI was more prevalent in both groups.
Conclusion
Well-dialyzed HD patients with optimized hemoglobin levels and with no history of stroke or dementia performed significantly worse on multiple measures of cognition compared to controls. A higher prevalence of non-memory impairment may suggest an underlying vascular versus neurodegenerative mechanism. HD and chronic kidney disease-specific risk factors may contribute to early CI not readily detected by routine screening methods.
doi:10.1159/000334871
PMCID: PMC3711004  PMID: 22212437
Cognitive impairment; Chronic kidney disease; Hemodialysis
15.  Pretransplant Physical Activity Predicts All-Cause Mortality in Kidney Transplant Recipients 
American Journal of Nephrology  2011;35(1):17-23.
Background
Low physical activity (PA) has been associated with higher rates of cardiovascular disease (CVD) and mortality in the general population. Despite the benefits of kidney transplantation, kidney transplant recipients (KTRs) remain at elevated risk for CVD and mortality compared to individuals without kidney disease.
Methods
A prospective cohort of 507 adult KTRs from three academic centers completed the Physical Activity Scale for the Elderly (PASE) at transplantation. PASE scores were divided into tertiles.
Results
PA was lower with older age, history of CVD, smoking, and diabetes. During the median 8-year follow-up period, 128 individuals died, among whom 101 had a functioning allograft. In multivariable Cox regression for all-cause mortality, greater PA was strongly associated with better survival (HR: 0.52 for most active vs. inactive tertiles, 95% CI: 0.31–0.87, p = 0.01). Secondary analyses, in which (1) death with a functioning graft was the primary outcome, and (2) PASE scores were converted to the metabolic equivalent of task, revealed similar results. We did not find an association between change of PA after transplantation and mortality.
Conclusions
PA at the time of kidney transplantation is a strong predictor of all-cause mortality and death with graft function. Evaluation of PA level among kidney transplant candidates may be a useful method to risk-stratify patients for survival after kidney transplantation. Kidney transplant candidates and recipients should also be encouraged to be physically active.
doi:10.1159/000334732
PMCID: PMC3251242  PMID: 22156548
Kidney transplantation; Mortality; Physical activity
16.  Arginine and Asymmetric Dimethylarginine in Puromycin Aminonucleoside-Induced Chronic Kidney Disease in the Rat 
American Journal of Nephrology  2011;35(1):40-48.
Background/Aims
Reduced renal L-arginine (L-Arg) synthesis/transport, induction of arginases and increased endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) will inhibit NO production. This study investigated pathways of L-Arg synthesis/uptake/utilization, ADMA degradation and oxidant/antioxidants in puromycin aminonucleoside (PAN) chronic kidney disease (CKD).
Methods
Rats were given low- (LD) or high-dose (HD) PAN and followed for 11 weeks for proteinuria. BP was measured and blood and tissues were harvested and analyzed for abundance of argininosuccinate synthase (ASS) and lyase (ASL), arginase, cationic amino acid transporter (CAT1) and dimethylargininedimethylaminohydrolase (DDAH) in kidney, cortex, aorta and liver. Arginase and DDAH activity, plasma L-Arg and ADMA, renal pathology and creatinine clearances were also measured.
Results
PAN caused dose-dependent kidney damage and hypertension and creatinine clearance fell in HD-PAN. Renal ASS fell in HD-PAN, renal cortex and aortic ASL and membrane CAT1 fell in both PAN groups. There was no activation of renal arginase, but aortic arginase increased in LD-PAN. Renal DDAH activity fell moderately in LD-PAN and markedly in HD-PAN where hepatic DDAH activity also fell. Plasma L-Arg was unchanged while ADMA rose moderately and dose-dependently with PAN. There were several indices of oxidative stress which was most prominent in HD-PAN.
Conclusion
Reduction in renal ASS/ASL and loss of renal cortex CAT1 compromises renal L-Arg synthesis and release. Loss of aortic CAT1 impairs L-Arg uptake. Increased plasma ADMA was associated with progressive loss of renal DDAH activity. However, loss of renal clearance and falls in hepatic DDAH activity in HD-PAN did not have additive effects on plasma ADMA.
doi:10.1159/000334740
PMCID: PMC3251243  PMID: 22179117
Argininosuccinate synthase; Argininosuccinate lyase; Arginase; Cationic amino acid transporter, CAT1; Dimethylarginine dimethylaminohydrolase, DDAH; Hypertension; Proteinuria; Creatinine clearance; Nitric oxide
17.  Cognitive Function and the Risk of Death in Chronic Kidney Disease 
American Journal of Nephrology  2011;35(1):49-57.
Background and Aims
Cognitive impairment is a risk factor for death in dialysis patients and the general population. We sought to determine if cognitive impairment is associated with death in people with non-dialysis-dependent chronic kidney disease (CKD), and if so, whether this relationship is greater in the CKD population compared to the general population.
Methods
National Health and Nutrition Examination Survey-III participants older than 60 years were asked to subtract 3 from 20 five times and to perform immediate and delayed recall of three items. A cognitive score of 0–11 was assigned based on the number of correct responses. Participants were categorized according to cognitive score (11, 9–10, 6–9, and 0–5) and CKD status. Survival analyses were conducted using Cox models.
Results
Within the CKD subpopulation, those in the lowest cognitive score group had a twofold increased hazard of death compared to those with maximum score. Within the non-CKD subpopulation, those in the lowest cognitive score group had a 46% increased hazard of death compared to those with maximum score. However, the difference in the hazards of death in the CKD and non-CKD subpopulations with the lowest cognitive score was not significant (p = 0.99).
Conclusions
Low cognitive score is associated with an increased risk of death in elderly individuals with and without CKD; however, there was no interaction of CKD and low cognitive score in this analysis.
doi:10.1159/000334872
PMCID: PMC3254030  PMID: 22189005
Cognitive function; Cognitive score; Chronic kidney disease; Mortality
18.  Living Donor Kidney Donation: Another Form of White Coat Effect 
American Journal of Nephrology  2011;35(1):75-79.
Background/Aims
Living donor nephrectomy can be associated with increases in blood pressure several years following the procedure, but the best method to assess blood pressure during the living donor evaluation process is unclear.
Methods
Living kidney donors underwent casual clinic and ambulatory blood pressure monitoring (ABPM) and measurement of central aortic pressures at baseline and 6 months following donor nephrectomy.
Results
There was a significant decline in clinic systolic blood pressure (SBP; p = 0.001) and central aortic systolic pressure (p = 0.011) during the study period. However, average ABPM was unchanged and other measures of central arterial pressures and Augmentation Index were unchanged at 6 months compared to baseline.
Conclusions
The remarkable differences between clinic SBP and ambulatory SBP prior to donation, and the disappearance of these differences 6 months later, suggest a substantial white coat effect on SBP associated with living kidney donor evaluation. Also, ABPM represents a better way to assess blood pressure prior to kidney donation.
doi:10.1159/000335070
PMCID: PMC3254031  PMID: 22189100
Ambulatory blood pressure monitoring; Blood pressure; Living donors; Hemodynamics; Transplantation
19.  Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway 
American Journal of Nephrology  2011;35(1):90-100.
Background/Aims
The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics.
Methods
Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks.
Results
Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin.
Conclusions
Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.
doi:10.1159/000335079
PMCID: PMC3316484  PMID: 22205374
Cadherin; Megalin; β-NAG; Proteinuria
20.  Kidney Function Decline in the Elderly: Impact of Lipoprotein-Associated Phospholipase A2 
American Journal of Nephrology  2011;34(6):512-518.
Background: Whether lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with kidney function decline has not been well studied. Methods: We investigated associations of Lp-PLA2 antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m2 per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m2). Results: Mean age was 72 ± 5 years. Average eGFRcys decline was −1.79 ml/min/1.73 m2 (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA2 antigen, eGFRcys decline was faster among persons in the second, β −0.31 (95% CI −0.52, −0.10), third −0.19 (–0.41, 0.02) and fourth quartiles −0.26 (–0.48, −0.04) after full adjustment. Persons in the highest quartile of Lp-PLA2 antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA2 activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m2) at baseline. Conclusion: Higher levels of Lp-PLA2 antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.
doi:10.1159/000333045
PMCID: PMC3225232  PMID: 22056971
Chronic kidney disease; Elderly; Estimated GFR; Kidney decline; Lipoprotein-associated phospholipase A2
21.  Natural Recovery from Antiglomerular Basement Membrane Glomerulonephritis Is Associated with Glomeruli-Infiltrating CD8α+CD11c+MHC Class II+ Cells 
American Journal of Nephrology  2011;34(6):519-528.
Background/Aims: In an antiglomerular basement membrane glomerulonephritis (GN) model, GN-resistant Lewis (LEW) rats naturally recover from early glomerular inflammation (days 21–23). We have previously identified a glomeruli-infiltrating CD8α+CD11highMHC II+ cell (GIL CD8α+ cell) in GN-prone Wistar Kyoto (WKY) rats, which terminates glomerular inflammation through inducing T cell apoptosis prior to glomerular fibrosis at days 35–40. We investigated if GIL CD8α+ cells were also associated with the recovery in LEW rats. Methods: GIL CD8α+ cells in LEW rats were characterized; their infiltration was observed in connection with T cell apoptosis in glomeruli. Results: An influx of GIL CD8α+ cells into inflamed glomeruli was confirmed in the immunized LEW rats at days 17–22, which was much earlier than days 28–35 in WKY rats. Notably, LEW rats had a GIL CD8α+CD11high subpopulation after day 17, while WKY rats lacked this population until after day 30. Analyses further revealed a large number of clustered apoptotic CD4+ or CD3+ T cells in the glomeruli during recovery (day 23) in LEW rats, as compared to day 35 (transition to fibrosis) in WKY rats. Thus, infiltration of GIL CD8α+ cells coincided with decline of glomerular inflammation and T cell apoptosis during recovery in LEW rats. Isolated GIL CD8α+ cells were able to infiltrate glomeruli in both WKY and LEW rats at day 20. Conclusion: Our data revealed a strong association between GIL CD8a+ cells and recovery from early glomerular inflammation. It raises a possibility of involvement of GIL CD8a+ cells in the recovery.
doi:10.1159/000333004
PMCID: PMC3237105  PMID: 22068125
Glomerulonephritis; Immunosuppression; Animal models; Apoptosis
22.  Poor Outcomes in Elderly Kidney Transplant Recipients Receiving Alemtuzumab Induction 
American Journal of Nephrology  2011;34(6):534-541.
Introduction
Alemtuzumab and rabbit antithymocyte globulin (rATG) are being used with increasing frequency as induction agents in kidney transplantation. Using the US Renal Data Base System, we analyzed the safety profile of these agents in the elderly.
Methods
In a cohort of patients transplanted from January 2000 to July 2009 and followed through 2009, we assessed the effect of induction on allograft loss and death among elderly recipients. Recipients were censored at dates of allograft loss, death or the end of study. Independent associations between induction agents and allograft loss or death were examined using multivariate analysis with forward stepwise Cox regression.
Results
Among 130,402 patients with first transplants, 14,907 were age 65 years or older. 4,466 (30%), 3,049 (20.5%), 1,501 (10.1%), and 999 (6.7%) were induced with thymoglobulin, basiliximab, daclizumab, and alemtuzumab, respectively. After adjusting for baseline differences, induction with alemtuzumab was associated with an increased risk of graft loss and death, with an adjusted hazard ratio (AHR) of 1.26 (95% CI 1.08–1.48). Risk was also present at other age cutoffs [age >60 (AHR 1.16; 95% CI 1.03–1.31; p = 0.014), age >70 (AHR 1.43; 95% CI 1.13–1.81; p = 0.003) and age >75 (AHR 1.68; 95% CI 1.07–2.63; p = 0.024)].
Conclusions
In the elderly, alemtuzumab is associated with an escalating risk of death and graft loss in recipients of kidney transplantations.
doi:10.1159/000334092
PMCID: PMC3237278  PMID: 22104284
Alemtuzumab; Kidney transplantation; Elderly recipients; Induction agents, complications; Kidney transplants, outcomes
23.  Use of Diffusion Tensor MRI to Identify Early Changes in Diabetic Nephropathy 
American Journal of Nephrology  2011;34(5):476-482.
Background/Aims
Currently available clinical indicators of kidney disease lack the sensitivity and/or specificity to identify early-stage diabetic nephropathy (DN). Quantitative diffusion magnetic resonance imaging (MRI), specifically diffusion tensor imaging (DTI), has been used to quantify pathophysiologic changes in other organs but has not been well studied in kidney diseases, including DN. The goal of this pilot study was to examine differences in kidney DTI parameters in diabetic subjects versus healthy controls.
Methods
16 diabetic and 5 healthy control subjects were recruited for this institutional review board-approved/Health Insurance Portability and Accountability Act-compliant study. Kidneys were scanned using DTI to generate apparent diffusion coefficient (ADC) and fractional anisotropy (FA) data. Mean cortical and medullary ADC and FA values were calculated by selecting multiple regions of interest. Diabetics were stratified by estimated glomerular filtration rate (eGFR) into 2 groups: eGFR ≥60 (n = 10) and eGFR <60 (n = 6) ml/min/1.73 m2. Mean diffusion parameters and eGFRs were compared between these groups of diabetic subjects and healthy controls.
Results
Medullary FA, ADC and cortical ADC values were significantly lower in diabetics with eGFR <60 compared to controls. Notably, both mean medullary FA and ADC were significantly lower in diabetics with eGFR ≥60 compared to controls (p = 0.001 and p = 0.042, respectively). For the study subjects in aggregate, medullary FA correlated significantly with eGFR (R = 0.69, p < 0.01); the other diffusion parameters showed no significant correlations.
Conclusions
This pilot study suggests that changes in medullary DTI assessments may serve as indicators of early DN. Further studies are needed to determine if these findings could serve as biomarkers to identify diabetics at risk of DN progression.
doi:10.1159/000333044
PMCID: PMC3214881  PMID: 22024476
Diabetic nephropathy; Chronic kidney disease; Magnetic resonance imaging; Diffusion parameters; Diffusion tensor imaging
24.  Amelioration of Albuminuria in ROCK1 Knockout Mice with Streptozotocin-Induced Diabetic Kidney Disease 
American Journal of Nephrology  2011;34(5):468-475.
Background
Although blockade of Rho kinase with pharmacologic inhibitors ameliorates renal fibrosis and diabetic kidney disease (DKD), the underlined mechanisms remain largely unclear. The present study tested the hypothesis that ROCK1 may regulate the early development of albuminuria via the megalin/cubilin-dependent mechanism.
Methods
A DKD model was induced in ROCK1 knockout and wild-type mice by streptozotocin (STZ). The effect of deleted ROCK1 on urinary albumin excretion and the expression of megalin/cubilin were examined. In addition, the effect of blocking ROCK activities with an inhibitor (Y-27632) on tubular albumin reabsorption was tested in a normal rat tubular epithelial cell line (NRK52E) under high-glucose conditions. Expression of transforming growth factor (TGF)-β1, interleukin-1β and collagen-1 was also been examined.
Results
Urinary albumin excretion was significantly increased in ROCK1 WT mice at 8 weeks after STZ injection. In contrast, mice lacking ROCK1 gene were protected against the development of albuminuria. This was associated with the protection against the loss of megalin/cubilin and an increase in TGF-β1, IL-1β, and fibrosis in the kidney. In vitro, we also found that blockade of Rho kinase with inhibitor Y-27632 prevented high-glucose-induced loss of megalin expression and an increase of TGF-β1, thereby increasing the absorption rate of FITC-labeled albumin by tubular epithelial cells.
Conclusion
ROCK1 may play a role in the development of albuminuria in DKD by downregulating the endocytosis receptors complex – megalin/cubilin.
Copyright © 2011 S. Karger AG, Basel
doi:10.1159/000332040
PMCID: PMC3691875  PMID: 21986457
Diabetic kidney disease; Tubular cells, albuminuria; ROCK; Megalin; Cubilin
25.  Trefoil Factor 3 Predicts Incident Chronic Kidney Disease: A Case-Control Study Nested within the Atherosclerosis Risk in Communities (ARIC) Study 
American Journal of Nephrology  2011;34(4):291-297.
Background
Early detection of individuals at high risk for chronic kidney disease (CKD) may aid prevention. Urinary levels of trefoil factor 3 (TFF3) are associated with acute kidney injury in animal models, but the association of TFF3 levels with incident CKD in humans is unknown.
Methods
We conducted a case-control study nested within the Atherosclerosis Risk in Communities (ARIC) Study and the ARIC Carotid MRI Study to determine whether urinary TFF3 levels predict incident CKD over 8.6 years of follow-up. A total of 143 participants with incident CKD (eGFR decreasing by ≥25% to <60 ml/min/1.73 m2) were matched on age, sex and race to 143 non-cases.
Results
Higher TFF3 levels at baseline were strongly associated with Black race, diabetes (both p = 0.002), and antihypertensive medication use (p = 0.02). Compared to participants with TFF3 levels in the lowest quartile, the odds ratio (OR) of incident CKD was 1.84 (95% confidence interval (CI): 0.80, 4.22) for individuals with TFF3 levels in the second quartile, 2.43 (95% CI: 1.06, 5.53) for the third quartile, and 2.77 (95% CI: 1.22, 6.28) for the fourth quartile (p trend = 0.02). Adjustment for covariates, including urinary albumin: creatinine ratio, did not markedly change the associations. Twofold higher TFF3 levels were strongly associated with incident CKD after adjustment for CKD risk factors (adjusted OR = 1.35; 95% CI: 1.11, 1.64).
Conclusions
Higher urinary TFF3 levels may indicate ongoing repair of damage in the kidney. Additional studies are needed to confirm whether TFF3 can be useful as a marker of increased risk for CKD.
doi:10.1159/000330699
PMCID: PMC3169359  PMID: 21829008
Kidney disease; Tubulointerstitual disease; Biomarkers

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