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1.  Evaluation of Genetic Association and Expression Reduction of TRPC1 in the Development of Diabetic Nephropathy 
American journal of nephrology  2008;29(3):244-251.
Background/Aims
The TRPC1 gene on chromosome 3q22–24 resides within the linkage region for diabetic nephropa-thy (DN) in type 1 (T1D) and type 2 diabetes mellitus (T2D). A recent study has demonstrated that TRPC1 expression is reduced in the kidney of diabetic ZDF- and STZ-treated rats. The present study aimed to evaluate the genetic and functional role of TRPC1 in the development of DN.
Methods
Genetic association study was performed with two independent cohorts, including 1,177 T1D European Americans with or without DN from GoKinD population and 850 African-American subjects with T2D-associated end-stage renal disease (ESRD), or with hypertensive (non-diabetic) ESRD, and nondiabetic controls. Seven tag SNP markers derived from HapMap data (phase II) were genotyped. TRPC1 gene expression was examined using real time RT-PCR.
Results
No significant association of TRPC1 DNA polymorphisms with DN or ERSD was found in GoKinD and African-American populations. TRPC1 gene mRNA expression in kidney was found to be trendily reduced in 12-week and significantly in 26-week-old db/db mice.
Conclusions
TRPC1 genetic polymorphism may not fundamentally contribute to the development of DN, while reduction of the gene expression in kidney may be a late phenomenon of DN as seen in diabetic animal models.
doi:10.1159/000157627
PMCID: PMC2698220  PMID: 18802326
TRPC1 gene; Single-nucleotide polymorphism; Diabetic nephropathy; End-stage renal disease; Diabetes types 1 and 2
2.  Tetracycline-Inducible Gene Expression in Conditionally Immortalized Mouse Podocytes 
American journal of nephrology  2008;29(3):153-163.
Background
Conditionally immortalized podocytes are valuable research tools but are difficult to efficiently transfect and do not provide graded transgene expression.
Methods
Conditionally immortalized mouse podocyte cell lines were established employing a tetracycline-inducible system. Glomerular cells, isolated from transgenic mice bearing two transgenes, NPHS2-reverse tetracycline-controlled transactivator, rtTA (A transgene) and H2-Kb-thermosensitive SV40 T, ts58A (I transgene), were cloned. One clone (AI podocytes) expressing WT1 and synaptopodin was transfected with pBI-EGFP (enhanced green fluorescent protein, G transgene) and separately with ptTS-Neo (transcriptional suppressor, T transgene) to produce stable transformants, AIG podocytes and AIT podocytes.
Results
AIG podocytes expressed EGFP at 33 and 37°C after doxycycline treatment, and retained podocin and rtTA mRNA expression and temperature-sensitive growth regulation. AIT podocytes, transiently transfected with luciferase-BI-EGFP (LG transgene), showed reduced background expression of EGFP and luciferase in the absence of doxycycline. In AITLG podocytes, generated by stable transfection of AIT podocytes with the LG transgene, luciferase expression was tightly regulated by doxycycline in a time- and concentration-dependent manner both at 33 and 37°C, although background expression was not entirely eliminated. These podocytes retained temperature-sensitive growth regulation and expression of podocyte differentiation markers.
Conclusion
Mouse podocytes expressed tetracycline-induced transgenes efficiently while retaining differentiation markers.
doi:10.1159/000151770
PMCID: PMC2698022  PMID: 18753740
Tetracycline-inducible system; Conditional immortalization; Transcription; Gene of interest
3.  Angiotensin II Infusion Induces Nephrin Expression Changes and Podocyte Apoptosis 
American journal of nephrology  2008;28(3):500-507.
Background/Aim:
In in vitro studies, angiotensin (Ang) II has been demonstrated to promote podocyte apoptosis. The present study evaluates the effects of Ang II infusion in rats on podocyte nephrin expression and apoptosis and the molecular mechanisms involved in Ang II-induced proteinuria and mesangial expansion.
Methods:
Sprague-Dawley rats were randomly assigned to receive either normal saline or Ang II (400 ng·kg−1·min−1) by means of a mini-osmotic pump for variable time periods. Systolic blood pressure and urinary protein and albumin excretion rate measurements were carried out on days 7, 14, 21, and 28. The animals were sacrificed on days 14 and 28 and evaluated for serum creatinine, renal pathological changes, podocyte apoptosis, renal nephrin mRNA, and protein expression.
Results:
The Ang II-infused rats developed hypertension and proteinuria. On day 14, the Ang II-infused rats showed narrowing of the slit diaphragm, an increase in podocyte nephrin mRNA and protein expression, and alterations in its distribution along the foot processes. On day 28, the Ang II-infused rats demonstrated the presence of apoptotic podocytes and decreased nephrin mRNA and protein expression. There was a negative correlation between nephrin expression and the numbers of apoptotic podocytes (r = −0.63, p < 0.05).
Conclusion:
These results suggest that changes in nephrin expression may play a role in the pathogenesis of Ang II-induced podocyte apoptosis.
doi:10.1159/000113538
PMCID: PMC2630486  PMID: 18204248
Angiotensin II; Proteinuria; Nephrin expression; Podocyte; Apoptosis
4.  Precision of Biomarkers to Define Chronic Inflammation in CKD 
American journal of nephrology  2008;28(5):808-812.
Background/Aims
Several inflammatory biomarkers have been found to be associated with cardiovascular disease or all-cause mortality in dialysis patients, but their usefulness in clinical practice or as surrogate endpoints is not certain. The purpose of the present study was to determine the intrapatient variation of C-reactive protein, IL-6, fetuin-A and albumin in a population of dialysis patients.
Methods
Apparently healthy dialysis patients with either a tunneled dialysis catheter or fistula had monthly assessments of these biomarkers for a total of four determinations, and the intraclass correlation coefficients were calculated as measures of intersubject variance.
Results
Our results showed large within-subject variation relative to the total variation in the measurements (31-46%). Having a tunneled catheter as opposed to a fistula was not significantly associated with mean levels, suggesting that chronic subclinical catheter infection does not explain the variation seen in the biomarkers. In contrast, there was a rapid change in these biomarkers with a clinically apparent acute infection.
Conclusion
These results suggest that these biomarkers have limitations for use as surrogate endpoints in clinical trials due to wide fluctuations, even in apparently clinically healthy individuals.
doi:10.1159/000135692
PMCID: PMC2574778  PMID: 18506106
Biomarkers, precision; Chronic inflammation; Chronic kidney disease; CKD stage 5D; Inflammatory biomarkers, intrapatient variance; Tunneled dialysis catheter
5.  Evaluation of Genetic Association and Expression Reduction of TRPC1 in the Development of Diabetic Nephropathy 
American Journal of Nephrology  2008;29(3):244-251.
Background/Aims
The TRPC1 gene on chromosome 3q22–24 resides within the linkage region for diabetic nephropathy (DN) in type 1 (T1D) and type 2 diabetes mellitus (T2D). A recent study has demonstrated that TRPC1 expression is reduced in the kidney of diabetic ZDF- and STZ-treated rats. The present study aimed to evaluate the genetic and functional role of TRPC1 in the development of DN.
Methods
Genetic association study was performed with two independent cohorts, including 1,177 T1D European Americans with or without DN from GoKinD population and 850 African-American subjects with T2D-associated end-stage renal disease (ESRD), or with hypertensive (non-diabetic) ESRD, and nondiabetic controls. Seven tag SNP markers derived from HapMap data (phase II) were genotyped. TRPC1 gene expression was examined using real time RT-PCR.
Results
No significant association of TRPC1 DNA polymorphisms with DN or ERSD was found in GoKinD and African-American populations. TRPC1 gene mRNA expression in kidney was found to be trendily reduced in 12-week and significantly in 26-week-old db/db mice.
Conclusions
TRPC1 genetic polymorphism may not fundamentally contribute to the development of DN, while reduction of the gene expression in kidney may be a late phenomenon of DN as seen in diabetic animal models.
doi:10.1159/000157627
PMCID: PMC2698220  PMID: 18802326
TRPC1 gene; Single-nucleotide polymorphism; Diabetic nephropathy; End-stage renal disease; Diabetes types 1 and 2
6.  Tetracycline-Inducible Gene Expression in Conditionally Immortalized Mouse Podocytes 
American Journal of Nephrology  2008;29(3):153-163.
Background
Conditionally immortalized podocytes are valuable research tools but are difficult to efficiently transfect and do not provide graded transgene expression.
Methods
Conditionally immortalized mouse podocyte cell lines were established employing a tetracycline-inducible system. Glomerular cells, isolated from transgenic mice bearing two transgenes, NPHS2-reverse tetracycline-controlled transactivator, rtTA (A transgene) and H2-Kb-thermosensitive SV40 T, ts58A (I transgene), were cloned. One clone (AI podocytes) expressing WT1 and synaptopodin was transfected with pBI-EGFP (enhanced green fluorescent protein, G transgene) and separately with ptTS-Neo (transcriptional suppressor, T transgene) to produce stable transformants, AIG podocytes and AIT podocytes.
Results
AIG podocytes expressed EGFP at 33 and 37°C after doxycycline treatment, and retained podocin and rtTA mRNA expression and temperature-sensitive growth regulation. AIT podocytes, transiently transfected with luciferase-BI-EGFP (LG transgene), showed reduced background expression of EGFP and luciferase in the absence of doxycycline. In AITLG podocytes, generated by stable transfection of AIT podocytes with the LG transgene, luciferase expression was tightly regulated by doxycycline in a time- and concentration-dependent manner both at 33 and 37°C, although background expression was not entirely eliminated. These podocytes retained temperature-sensitive growth regulation and expression of podocyte differentiation markers.
Conclusion
Mouse podocytes expressed tetracycline-induced transgenes efficiently while retaining differentiation markers.
doi:10.1159/000151770
PMCID: PMC2698022  PMID: 18753740
Tetracycline-inducible system; Conditional immortalization; Transcription; Gene of interest
7.  Precision of Biomarkers to Define Chronic Inflammation in CKD 
American Journal of Nephrology  2008;28(5):808-812.
Background/Aims
Several inflammatory biomarkers have been found to be associated with cardiovascular disease or all-cause mortality in dialysis patients, but their usefulness in clinical practice or as surrogate endpoints is not certain. The purpose of the present study was to determine the intrapatient variation of C-reactive protein, IL-6, fetuin-A and albumin in a population of dialysis patients.
Methods
Apparently healthy dialysis patients with either a tunneled dialysis catheter or fistula had monthly assessments of these biomarkers for a total of four determinations, and the intraclass correlation coefficients were calculated as measures of intersubject variance.
Results
Our results showed large within-subject variation relative to the total variation in the measurements (31–46%). Having a tunneled catheter as opposed to a fistula was not significantly associated with mean levels, suggesting that chronic subclinical catheter infection does not explain the variation seen in the biomarkers. In contrast, there was a rapid change in these biomarkers with a clinically apparent acute infection.
Conclusion
These results suggest that these biomarkers have limitations for use as surrogate endpoints in clinical trials due to wide fluctuations, even in apparently clinically healthy individuals.
doi:10.1159/000135692
PMCID: PMC2574778  PMID: 18506106
Biomarkers, precision; Chronic inflammation; Chronic kidney disease; CKD stage 5D; Inflammatory biomarkers, intrapatient variance; Tunneled dialysis catheter
8.  Angiotensin II Infusion Induces Nephrin Expression Changes and Podocyte Apoptosis 
American Journal of Nephrology  2008;28(3):500-507.
Background/Aim
In in vitro studies, angiotensin (Ang) II has been demonstrated to promote podocyte apoptosis. The present study evaluates the effects of Ang II infusion in rats on podocyte nephrin expression and apoptosis and the molecular mechanisms involved in Ang II-induced proteinuria and mesangial expansion.
Methods
Sprague-Dawley rats were randomly assigned to receive either normal saline or Ang II (400 ng·kg–1·min–1) by means of a mini-osmotic pump for variable time periods. Systolic blood pressure and urinary protein and albumin excretion rate measurements were carried out on days 7, 14, 21, and 28. The animals were sacrificed on days 14 and 28 and evaluated for serum creatinine, renal pathological changes, podocyte apoptosis, renal nephrin mRNA, and protein expression.
Results
The Ang II-infused rats developed hypertension and proteinuria. On day 14, the Ang II-infused rats showed narrowing of the slit diaphragm, an increase in podocyte nephrin mRNA and protein expression, and alterations in its distribution along the foot processes. On day 28, the Ang II-infused rats demonstrated the presence of apoptotic podocytes and decreased nephrin mRNA and protein expression. There was a negative correlation between nephrin expression and the numbers of apoptotic podocytes (r = −0.63, p < 0.05).
Conclusion
These results suggest that changes in nephrin expression may play a role in the pathogenesis of Ang II-induced podocyte apoptosis.
doi:10.1159/000113538
PMCID: PMC2630486  PMID: 18204248
Angiotensin II; Proteinuria; Nephrin expression; Podocyte; Apoptosis
9.  FATTY ACIDS AND OTHER RISK FACTORS FOR SUDDEN CARDIAC DEATH IN PATIENTS STARTING HEMODIALYSIS 
American journal of nephrology  2013;38(1):10.1159/000351764.
Background
Little is known about risk factors for sudden cardiac death in hemodialysis patients during the high-risk first year of dialysis. We therefore undertook to identify such risk factors in a nationally representative cohort and were able to include baseline levels of blood fatty acids, some of which influence arrhythmogenicity and sudden cardiac death risk.
Design
The study cohort included 100 patients who died of sudden cardiac during the first year of hemodialysis and 300 frequency-matched controls. Using the elastic net statistical method, numerous demographic and clinical characteristics were included with baseline total serum levels for eleven major fatty acids (Model 1) and with serum phospholipid fractions of these same fatty acids (Model 2). Final models included only covariates that had a non-zero coefficient.
Results
In Model 1, serum albumin (odds ratio (95% CI): 0.55(0.33,0.93), P=0.03) and total serum long chain n-3 docosapentaenoic acid (0.70(0.51,0.97), P=0.03) were inversely associated with odds of sudden cardiac death, while the total serum saturated fatty acid level had a direct association (1.01(1.00,1.02), P=0.03). In Model 2, serum albumin and docosapentaenoic acid remained inversely associated with sudden cardiac death in a similar manner as in model 1. Pulse pressure also had an inverse association (0.96(0.93,1.00), P<0.05).
Conclusions
Several factors, including blood content of docosapentaenoic acid and saturated fatty acids, were associated with odds of sudden cardiac death during year one of hemodialysis. These results raise the possibility that dietary modification may reduce sudden death risk.
doi:10.1159/000351764
PMCID: PMC3856432  PMID: 23816975
omega-3; fatty acids; sudden cardiac death; hemodialysis; incident; risk factors; nutrition; cardiovascular
10.  Oral activated charcoal adsorbent (AST-120) ameliorates CKD-induced intestinal epithelial barrier disruption 
American journal of nephrology  2013;37(6):518-525.
Back ground
CKD impairs intestinal barrier function which by allowing influx of noxious products causes systemic inflammation. We have recently shown that intestinal barrier dysfunction in CKD is due to degradation of epithelial tight junction (TJ) which is, in part, mediated by influx of urea and its conversion to ammonia by microbial urease. We hypothesized that by adsorbing urea and urea-derived ammonia, oral activated charcoal (AST-120) may ameliorate CKD-induced intestinal epithelial barrier disruption and systemic inflammation.
Methods
Rats were randomized to the CKD or control groups. The CKD group was fed a chow containing 0.7% adenine for 2 weeks. They were then randomized to receive a chow with or without AST-120 (4 g/kg/day) for 2 weeks. Rats consuming regular diet served as controls. Animals were then euthanized, colons were removed and processed for Western blot and immunohistology and plasma was used to measure endotoxin, and oxidative and inflammatory markers.
Results
Compared with the controls the untreated CKD rats showed elevated plasma endotoxin, IL-6, TNFα, MCP-1, CINC-3, L-selectin, ICAM-1, and malondialdehyde, and depletions of colonic epithelial TJ proteins; claudin-1, occludin, and ZO1. Administration of AST-120 resulted in partial restoration of the epithelial TJ proteins and reduction in plasma endotoxin and markers of oxidative stress and inflammation.
Conclusions
CKD animals exhibited depletion of the key protein constituents of the colonic epithelial TJ which was associated with systemic inflammation, oxidative stress and endotoxemia. Administration of AST-120 attenuated uremia-induced disruption of colonic epithelial TJ and the associated endotoxemia, oxidative stress and inflammation.
doi:10.1159/000351171
PMCID: PMC3777856  PMID: 23689670
Epithelial tight junction; Endotoxin; activated charcoal; ESRD; uremia
11.  Association between Dietary Sodium and Potassium Intake with Chronic Kidney Disease in U.S. Adults: A Cross-Sectional Study 
American journal of nephrology  2013;37(6):526-533.
Background/Aims
Clinical guidelines recommend a diet low in sodium and high in potassium to reduce blood pressure and cardiovascular events. Little is known about the relationship between dietary sodium and potassium intake and chronic kidney disease (CKD).
Methods
13,917 participants from the National Health and Nutrition Examination Survey (2001–2006) were examined. Sodium and potassium intake were calculated from 24-hour recall and evaluated in quartiles. CKD was defined as eGFR <60 mL/min, or eGFR ≥ 60mL/min with albuminuria (>30mg/g creatinine).
Results
The mean (SE) age and eGFR of participants was 45.0 ± 0.4 years and 88.0 ± 0.60 ml/min/1.73m2, respectively. 2333 (14.2%) had CKD: 1146 (7.3%) had an eGFR < 60 ml/min/1.73m2 and 1514 (8.4%) had an eGFR ≥ 60 ml/min/1.73 m2 and albuminuria. After adjustment for age, sex, race, body mass index, diabetes, hypertension, cardiovascular disease and congestive heart failure subjects in the highest quartile of sodium intake had a lower odds of CKD compared to subjects in the lowest quartile (adjusted OR 0.79, 95% CI, 0.66 to 0.96; p<0.016). Compared to the highest quartile, participants in the lowest quartile of potassium intake had a 44% increased odds of CKD (adjusted OR 1.44, 95% CI 1.16–1.79, p=0.0011).
Conclusions
Higher intake of sodium and potassium is associated with lower odds of CKD among US adults. These results should be corroborated through longitudinal studies and clinical trials designed specifically to examine the effects of dietary sodium and potassium intake on kidney disease and its progression.
doi:10.1159/000351178
PMCID: PMC3919025  PMID: 23689685
Chronic Kidney Disease; Dietary sodium intake; Dietary potassium intake
12.  Microalbuminuria in HIV Disease 
American journal of nephrology  2013;37(5):10.1159/000350384.
Background/Aims
Microalbuminuria is a marker for early kidney disease and cardiovascular risk. The purposes of this study were to determine the prevalence of microalbuminuria in an HIV-infected clinic population, to test the predictive value of a single urine albumin-creatinine ratio (ACR) to identify persistent microalbuminuria and to examine covariates of microalbuminuria.
Methods
We conducted a prospective cohort study of HIV-infected subjects (n=182) without proteinuria (P/C ratio ≥0.5 g/g), elevated serum creatinine, diabetes, or chronic inflammatory conditions. Subjects completed three research visits within nine months. Microalbuminuria was defined as the geometric mean ACR of 25–355 mg/g for women and 17–250 mg/g for men.
Results
The prevalence of microalbuminuria was 14%. The negative predictive value of a single urine ACR determination was 98%, whereas the positive predictive value was only 74%. Microalbuminuria was similar among Black (15%) and non-Black (14%) subjects (p=0.8). Subjects with microalbuminuria were more likely to have hypertension (p=0.02) and metabolic syndrome (p=0.03). While duration of HIV infection and the level of HIV viremia were similar between groups, those with microalbuminuria were more likely to have a CD4 count <200 cells/μL (p=0.0003). In a multivariate logistic regression analysis, the only significant independent predictors of microalbuminuria were low CD4 count (p=0.018) and current ritonavir exposure (p=0.04).
Conclusion
The prevalence of microalbuminuria in an HIV-infected clinic population was similar to earlier reports, and was associated with hypertension and impaired immune function. A single normal ACR determination effectively excludes microalbuminuria, whereas an elevated ACR requires confirmation.
doi:10.1159/000350384
PMCID: PMC3809894  PMID: 23615312
HIV infection; microalbuminuria; urinary albumin-creatinine ratio
13.  Iron Sucrose Impairs Phagocytic Function and Promotes Apoptosis in Polymorphonuclear Leukocytes 
American journal of nephrology  2012;36(1):50-57.
Background
With the recent implementation of bundling reimbursement policy the use of intravenous (IV) iron preparations for the management of anemia in the ESRD population has dramatically increased. Iron overload increases the risk of infections in individuals with or without kidney disease. IV iron administration in ESRD patients impairs bacteriocidal capacity of PMNs against Escherichia Coli. These preparations consist of an elemental iron core and a carbohydrate shell. In addition to the iron core the carbohydrate shell may affect PMNs. We therefore examined the effect of iron sucrose, a commonly used preparation, on phagocytic capacity of PMNs from a group of normal individuals against Gram positive (Staphylococcus Aureus) and Gram negative (E. Coli) bacteria.
Methods
Iron sucrose was added to heparinized blood samples at pharmacologically-relevant concentrations and incubated for 4 and 24 hours at 37° C to simulate in vivo condition. Blood samples mixed with equal volume of saline solution served as controls. To isolate the effects of the carbohydrate shell, blood samples were co-treated with the iron chelator, desferrioxamine.
Results
Iron sucrose caused significant PMN apoptosis and dose-dependent suppression of phagocytic function against both Gram positive and negative bacteria. These abnormalities were prevented by desferrioxamine which precluded contribution of the carbohydrate shell to the PMN dysfunction.
Conclusions
At pharmacologically-relevant concentrations iron sucrose promotes apoptosis and inhibits phagocytic activities of PMNs. The deleterious effect of iron sucrose is mediated by its elemental iron core, not its carbohydrate shell, and as such may be shared by other IV iron preparations.
doi:10.1159/000339285
PMCID: PMC3986045  PMID: 22722756
Iron; Infection; Inflammation; Immune deficiency; Anemia; End-stage renal disease; Dialysis
14.  Using Hemoglobin A1c to Derive Mean Blood Glucose in Peritoneal Dialysis Patients 
American journal of nephrology  2013;37(5):10.1159/000349929.
Background
Although hemoglobin A1c (HbA1c) has been widely used as a clinical assessment tool for outcome analyses related to glycemic control, the relationship between HbA1c and average blood glucose (BG) specific to peritoneal dialysis (PD) patients with diabetes has not been characterized. We sought to develop HbA1c-BG equation models for PD patients.
Methods
We examined associations between HbA1c and random serum BG values over time in a contemporary 5-year (2001–2006) cohort of DaVita PD patients with diabetes. We identified 850 patients (mean age 58±13 years old and 56% male) with 4,566 paired measurements of HbA1c and BG. The bootstrapping method was used to estimate average BG and corresponding HbA1c.
Results
Linear regression analyses yielded the following HbA1c-BG equations: (1) BG (mg/dL)=24.1 + 28.6 × HbA1c – 12.2 × Albumin (R2adj=0.454), (2) BG = 55.3+ 28.8 × HbA1c-10.2 × Albumin −3.3 × Hemoglobin (R2adj=0.457), (3) and BG =69.5 +28.7 × HbA1c- 10.1 × Albumin- 3.7 × Hemoglobin- 0.1 × Age+ Race/Ethnicity (−10.1 African-Americans, −5.4 other race/ethnicities; R2adj=0.457). All models showed greater explanatory power of BG variation than previously established HbA1c-BG equation models defined within non-PD cohorts (R2adj=0.446 for both the DCCT and the ADAG equations).
Conclusions
The association between HbA1c and BG in PD patients is different than that of patients with normal kidney function. Our analysis suggests that equations incorporating serum albumin and/or hemoglobin values better estimate the HbA1c-BG relationship in PD patients compared to equations using HbA1c alone.
doi:10.1159/000349929
PMCID: PMC3844668  PMID: 23594745
Hemoglobin A1c; blood glucose; equation model; glycemic control; albumin; hemoglobin; peritoneal dialysis; race
15.  Metabolic Syndrome, Vitamin D Deficiency and Hypoadiponectinemia among Non-Diabetic Patients Early after Kidney Transplantation 
American journal of nephrology  2013;37(5):10.1159/000349930.
Background and Aims
Metabolic syndrome (MetS) is common among kidney transplant patients. We studied the relationship between MetS, vitamin D deficiency/insufficiency and hypoadiponectinemia early post-transplantation and their impact on clinical outcomes.
Methods
Seventy-four previously non-diabetic kidney transplant patients were enrolled in a prospective cohort study between February and November 2008. Participants underwent a 2-hours oral glucose tolerance test (OGTT) and had their plasma levels of 25-hydroxyvitamin D (25[OH]D), adiponectin, insulin, intact parathyroid hormone and lipids measured at 11 weeks after transplantation. Clinical events including cardiovascular events, new onset diabetes after transplantation, acute rejection, graft loss and death were recorded during the follow-up to December 2012.
Results
Thirty-four study patients (45.9%) had MetS. Patients with MetS had lower plasma concentrations of 25[OH]D (20.5±7.2 vs. 24.8±11.1 ng/ml, p=0.049) and adiponectin (8.2±4.5 vs. 14.6±8.0 μg/ml, p<0.0001) early on, and higher composite clinical event rate (61.8% vs. 27.5%, p=0.003) during the follow-up. Multivariate analysis showed that the presence of MetS early after transplantation was independently associated with 25[OH]D insufficiency/deficiency (OR 14.0, 95% CI 1.8, 107.5, p=0.011), depressed plasma adiponectin levels (β -6.39, r2 0.195, p<0.0001) and increased risk for clinical events (OR 5.6, 95% CI 1.9, 16.5, p=0.002).
Conclusion
Kidney transplants patients with MetS early after transplantation had lower levels of 25[OH]D and adiponectin, and unfavorable clinical outcomes.
doi:10.1159/000349930
PMCID: PMC3816759  PMID: 23751485
adiponectin; clinical outcomes; kidney transplantation; metabolic syndrome; vitamin D deficiency
16.  Prevalence of pre-ESRD care and associated outcomes among urban, micropolitan, and rural dialysis patients 
American journal of nephrology  2013;37(3):274-280.
Background/aims
Pre-ESRD care associates with improved outcomes among patients receiving dialysis. It is unknown what proportion of US micropolitan and rural dialysis patients receive pre-ESRD care and benefit from such care when compared to urban.
Methods
A retrospective cohort study was performed using data from the US Renal Data System. Patients ≥18 years old who initiated dialysis in 2006 and 2007 were classified as rural, micropolitan, or urban and prevalence of pre-ESRD care (early nephrology care >6 months, permanent vascular access, dietary education) was determined using the medical evidence report. The association of pre-ESRD care with dialysis mortality and transplantation was assessed using Cox regression with stratification for geographic residence.
Results
Of 204,463 dialysis patients, 80% were urban, 10.2% were micropolitan, and 9.8% were rural. Overall attainment of pre-ESRD care was poor. After adjustment, there were no significant geographic differences in attainment of early nephrology care or permanent dialysis access. Receiving care reduced all-cause mortality and increased the likelihood of transplantation to a similar degree regardless of geographic residence. Both micropolitan and rural patients received less dietary education (RR 0.80 95% CI 0.76–0.84 and RR 0.85 95% CI 0.80–0.89, respectively).
Conclusion
Among patients who receive dialysis, the prevalence of early nephrology care and permanent dialysis access is poor and does not vary by geographic residence. Micropolitan and rural patients receive less dietary education despite an observed mortality benefit, suggesting that barriers may exist to quality dietary care in more remote locations.
doi:10.1159/000348377
PMCID: PMC3787839  PMID: 23548738
rural; disparity; chronic kidney disease
18.  Low Body Mass Index and Dyslipidemia in Dialysis Patients linked to Elevated Plasma Fibroblast Growth Factor 23 
American journal of nephrology  2013;37(3):183-190.
Background
Fibroblast growth factor 23 (FGF23) has been associated with death in dialysis patients. Since FGF23 shares structural features with FGF19-subfamily members that exert hormonal control of fat mass, we hypothesized that high circulating FGF23 concentrations would be associated with the development of a uremic lipid profile and lower body mass index.
Methods
This study was conducted among 654 patients receiving chronic hemodialysis. C-terminal FGF23 concentrations were measured in stored plasma samples. Linear regression was used to examine the cross-sectional associations of plasma FGF23 concentrations with body mass index (BMI), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG). Cox-proportional hazard models were used to examine the association between FGF23 concentrations and all-cause mortality.
Results
Participants had a mean age of 60 ± 11 years and a median [IQR] FGF23 concentration of 4212 [1411-13816] RU/mL. An increase per SD in log10 FGF23 was associated with lower BMI (β= −1.11; p=0.008), TC (β= −6.46; p=0.02), LDL-C (β= −4.73; p=0.04) and HDL-C (β= −2.14; p=0.03); after adjusting for age, gender, race, cardiovascular risk factors, serum albumin, markers of mineral metabolism, and use of lipid lowering drugs. The association of FGF23 with death was attenuated after adjustment for HDL-C (HR of highest quartile 1.53, 95% CI 1.06-2.20 compared to lowest quartile).
Conclusion
These results indicate that higher plasma FGF23 levels are associated with lower BMI and dyslipidemia in dialysis patients. The association between FGF23 and death may be mediated through unexplored metabolic risk factors unrelated to mineral metabolism.
doi:10.1159/000346941
PMCID: PMC3717381  PMID: 23428834
Hemodialysis; fibroblast growth factor 23; dyslipidemia; body mass index
19.  Impact of ultrasound-guided kidney biopsy simulation on trainee confidence and biopsy outcomes 
American journal of nephrology  2012;36(6):570-574.
Background/Aims
To improve procedural skill competence in real-time ultrasound-guided renal biopsy, we have developed an inexpensive simulation tool (a porcine kidney inserted under turkey breast) that mimics biopsy conditions in human patients in terms of kidney size, depth, echogenicity and overall structural characteristics. This study investigated the utility of this simulation tool for improving trainees’ confidence in performing renal biopsy and biopsy-associated bleeding complications.
Methods
We have quantitatively assessed the confidence level of renal fellows before and after their initial renal biopsy simulation training. Subsequently, we determined the effect of this simulation training on trainees’ procedural competence by comparing outcomes of clinical renal biopsies performed by fellows that did vs those who did not participate in the simulation training.
Resuts
We show that the renal biopsy simulation has improved the confidence level of trainees (23.4 pre-simulation to 70.3 post-simulation on a 0–100 scale; p=0.001; eta squared=0.69). The improvement in trainees’ confidence did not vary across their prior experience performing renal biopsies (eta squared=0.23, p=0.060). Additionally, fellows who participated in the simulation training demonstrated improved competence in performing the renal biopsy procedure in patients. Successful retrieval of renal tissue per pass was 94% (vs 73 % in fellows who did not participate in this simulation training; p=0.002) and procedure-related blood loss was reduced as indicated by smaller post-biopsy vs pre-biopsy hematocrit decline (1.18 vs 2.68; p=0.049).
Conclusion
Renal biopsy simulation training may improve trainees’ confidence and reduce the severity of biopsy-associated bleeding complications in patients.
doi:10.1159/000345305
PMCID: PMC3918883  PMID: 23221146
kidney biopsy; training; model; bleeding complications
20.  Healthy Behaviors, Risk Factor Control and Awareness of Chronic Kidney Disease 
American journal of nephrology  2013;37(2):135-143.
Background/Aims
The association between chronic kidney disease (CKD) awareness and healthy behaviors is unknown. We examined whether CKD self-recognition is associated with healthy behaviors and achieving risk-reduction targets known to decrease risk of cardiovascular morbidity and CKD progression.
Methods
CKD awareness, defined as a “yes” response to “Has a doctor or other health professional ever told you that you had kidney disease?”, was examined among adults with CKD (eGFR < 60 ml/min/1.73 m2) who participated in the REasons for Geographic and Racial Differences in Stroke study. Odds of participation in healthy behaviors (tobacco avoidance, avoidance of regular NSAID use, physical activity) and achievement of risk reduction targets (ACEI/ARB use, systolic blood pressure (SBP) control and glycemic control among those with diabetes) among those aware vs. unaware of their CKD were determined by logistic regression, controlling for socio-demographics, access to care and co-morbid conditions. SBP control was defined as < 130 mmHg (primary definition) or < 140 mmHg (secondary definition).
Results
Of 2,615 participants, only 6% (n=166) were aware of having CKD. Those who were aware had 82% higher odds of tobacco avoidance compared to those unaware [adjusted odds ratio =1.82, 95% CI (1.02–3.24)]. CKD awareness was not associated other healthy behaviors or achievement of risk-reduction targets.
Conclusions
Awareness of CKD was only associated with participation in one healthy behavior and was not associated with achievement of risk-reduction targets. To encourage adoption of healthy behaviors, a better understanding of barriers to participation in CKD-healthy behaviors is needed. Keywords: chronic kidney disease, awareness, behaviors, self-management
doi:10.1159/000346712
PMCID: PMC3649001  PMID: 23392070
Chronic kidney disease; awareness; self-management; behaviors
21.  Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in CKD 
Background
Chronic kidney disease (CKD) impairs intestinal barrier function which leads to endotoxemia and systemic inflammation. We have found depletion of intestinal epithelial tight junction (TJ) proteins in animals with CKD. We further showed that addition of ESRD patients' plasma to the culture medium provokes marked drop in transepithelial electrical resistance (TER) and depletion of TJ proteins in cultured human enterocytes. These effects were less severe with post- than pre-hemodialysis plasma suggesting the role of dialyzable agent(s). This study tested the hypothesis that intestinal barrier dysfunction in uremia may be due to diffusion of urea into the gut and its conversion to ammonia by microbial urease.
Methods
Human enterocytes (T84 cells) were seeded on Transwell plates and utilized when TER exceeded 1,000 Ω.cm2 to ensure full polarization and TJ formation. Confluent cells were then incubated for 24 hr in media containing zero, 42, or 74 mg/dl urea or urea plus urease to simulate presence of microbial flora.
Results
At clinically-relevant concentrations, urea caused a concentration-dependent fall in TER and the key TJ protein; cluadin-1, occludin, and ZO1. The effects of urea were dramatically amplified by urease causing cells detachment, dissipation of TER, and massive loss of TJ proteins.
Conclusions
uremia-induced disruption of intestinal TJ and barrier function is, in part, mediated by urea which is generally considered to be a nontoxic retained metabolite. These findings reveal a novel mechanism for salutary effect of urea-lowering strategies e.g. low protein diet and longer and more frequent dialysis regimens in advanced CKD.
doi:10.1159/000345969
PMCID: PMC3686571  PMID: 23258127
Endotoxin; Inflammation; Gastrointestinal pathology; End-stage renal disease; uremia; cardiovascular disease
22.  Relationship of Urine Dopamine with Phosphorus Homeostasis in Humans: The Heart and Soul Study 
American journal of nephrology  2012;35(6):10.1159/000338483.
Background
Urine dopamine (DA) is produced in the proximal tubule and has been found to increase in response to dietary phosphorus intake, and to contribute to greater urinary phosphorus excretion in animal models. Whether urine DA is associated with phosphorus homeostasis in humans is uncertain.
Methods
This was a cross-sectional study of 884 outpatients. DA was measured from 24-hour urine collections. We examined cross-sectional associations between urine DA and serum phosphorus, 24-hour urine phosphorus (as an indicator of dietary phosphorus absorption), fractional excretion of phosphorus (FEphos), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). Models were adjusted for age, sex, race, eGFR, albuminuria, hypertension, heart failure, tobacco use, body mass index, and diuretic use.
Results
Mean age was 66.6 ± 11 years and mean eGFR was 71 ± 21.3 ml/min/1.73 m2. The mean urine DA was 193 ± 86 µg/day, mean serum phosphorus was 3.6 ± 0.6 mg/dl, mean daily urine phosphorus excretion was 671 ± 312 mg/day, and mean FEphos was 17 ± 9%. In adjusted models, each standard deviation higher DA was associated with 78.4 mg/day higher urine phosphorus and 0.9% lower FEphos (p < 0.05 for both). There was no statistically significant association between urine DA, serum phosphorus, FGF-23 or PTH in adjusted models.
Conclusions
Higher dietary phosphorus absorption is associated with higher urine DA in humans, consistent with animal models. However, higher urine DA is not associated with FGF-23 or PTH, suggesting that known mechanisms of renal tubular handling of phosphorus may not be involved in the renal dopamine-phosphorus regulatory pathway in humans.
doi:10.1159/000338483
PMCID: PMC3873852  PMID: 22572568
Urine dopamine; Phosphorus; Kidney; Proximal tubule
23.  Association between Non-Alcoholic Liver Disease and Chronic Kidney Disease: An Ultrasound Analysis from NHANES 1988–1994 
American journal of nephrology  2012;36(5):466-471.
Background/ Aims
Non-alcoholic fatty liver disease (NAFLD) has been proposed to contribute to chronic kidney disease (CKD) independently of traditional cardiometabolic risk factors. We hypothesized that NAFLD is associated with CKD and that greater severity of NAFLD is associated with higher odds of CKD.
Methods
A cross-sectional analysis of 11,469 adults who participated in the National Health and Nutrition Examination Survey 1988–1994. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. CKD was defined as an estimated glomerular filtration rate of ≤60 mL/min/1.73 m2 or the presence of albuminuria in subjects with an estimated glomerular filtration rate of >60 mL/min/1.73 m2.
Results
2,891 (25.4%) patients in the cohort had CKD. The prevalence of NAFLD was higher in individuals with CKD compared to those without CKD (42.2% vs. 34.5%, p<0.0001). NAFLD was associated with CKD in unadjusted logistic regression analysis (odds ratio 1.47, 95% confidence interval 1.29–1.67, p<0.0001). Adjustment for demographics and components of metabolic syndrome attenuated this relationship (odds ratio 1.04, 95% confidence interval 0.88–1.23, p=0.64). Moderate and severe NAFLD on ultrasound were increasingly associated with prevalent CKD in unadjusted analysis but not after adjustment for metabolic syndrome components.
Conclusion
After adjusting for features of metabolic syndrome, ultrasound-diagnosed NAFLD is not associated with prevalent CKD among US adults. Aggressive public health efforts are needed to prevent and treat metabolic syndrome.
doi:10.1159/000343885
PMCID: PMC3563287  PMID: 23128368
chronic kidney disease; nonalcoholic fatty liver disease; NHANES
24.  Low Blood Levels of Long Chain n-3 Polyunsaturated Fatty Acids in U.S. Hemodialysis Patients: Clinical Implications 
American journal of nephrology  2012;36(5):451-458.
Background
Cardioprotective and other clinical benefits of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) are inversely related to dietary intake and hence blood content. We therefore investigated, in the first study of its kind, the blood content and distribution of these fatty acids in a large representative population of U.S. hemodialysis patients.
Methods
Frozen sera were obtained from 400 individuals who were part of a large, contemporary, representative cohort of U.S. incident hemodialysis patients. LC n-3 PUFA were measured in total serum lipids and in the neutral and polar serum fractions using gas chromatography and solid phase extraction techniques. Mean LC n-3 PUFA levels were compared to levels of other dialysis and non-dialysis populations from published reports.
Results
The study population was qualitatively similar to the overall U.S. hemodialysis population in terms of major clinical characteristics. LC n-3 PUFA were present in the serum polar fraction, with essentially none being detected in the neutral fraction (P<0.0001 for polar versus neutral fractions for all three LC n-3 PUFA). Mean serum LC n-3 PUFA levels (weight %(±SD): total-1.55±0.95, polar-3.99± 1.45) were low compared to non-dialysis and most other non-U.S. hemodialysis cohorts.
Conclusions
While U.S. hemodialysis patients have a blood distribution of LC n-3 PUFA that is similar to that in the general population, blood content is among the lowest recorded in the medical literature. This has implications for renal dietary recommendations and makes U.S. patients an ideal group in which to test the clinical effects of LC n-3 PUFA supplementation.
doi:10.1159/000343741
PMCID: PMC3784309  PMID: 23128302
omega-3; fatty acids; hemodialysis; cardiovascular; nutrition
25.  Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium 
American journal of nephrology  2012;36(5):438-443.
Back ground
CKD causes intestinal barrier dysfunction which by allowing influx of endotoxin and other noxious products contributes to the CKD-associated systemic inflammation and uremic toxicity. We have recently shown that intestinal barrier dysfunction in CKD animals is due to degradation of trans-cellular [claudin-1 and occludin] and intra-cellular [ZO1] constituents of epithelial tight junction (TJ). This study determined whether CKD-associated disruption of TJ is mediated by retained uremic toxins/metabolites and if so whether they are removed by hemodialysis.
Methods
The TJ-forming human enterocytes (T84 cells) were seeded on the Transwell plates and utilized when trans-epithelial electrical resistance (TER) exceeded 1000 mΩ/cm2 to ensure full polarization and TJ formation. The cells were then incubated for 24 hr in media containing 10% pre- or post-hemodialysis plasma from ESRD patients or healthy individuals. TER was then measured and cells were processed for Western blot and immunohistological analyses.
Results
Compared with the control plasma, incubation in media containing pre-dialysis plasma from ESRD patients resulted in a marked drop in TER pointing to increased epithelial permeability. This was accompanied by significant reductions in cluadin-1 (85%), occludin (15%), and ZO1 (70%) abundance. The severity of TJ damage and dysfunction was significantly less in cells exposed to the post-dialysis than per-dialysis plasma. These findings point to the presence of as-yet unidentified product(s) in the uremic plasma capable of depleting epithelial TJ.
Conclusions
Exposure to uremic milieu damages the intestinal epithelial TJ and impairs its barrier function, events which are mediated by agents which are partially removed by hemodialysis.
doi:10.1159/000343886
PMCID: PMC3725306  PMID: 23128155
Tight junction; inflammation; hemodialysis; ESRD; CKD

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