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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.  Disparate Effects of Roscovitine on Renal Tubular Epithelial Cell Apoptosis and Senescence: Implications for Autosomal Dominant Polycystic Kidney Disease 
American Journal of Nephrology  2008;29(6):509-515.
Background/Aims
Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD. We asked how a single agent can be efficacious in both PKD and cancer.
Methods
Renal tubular epithelial cells were incubated at diverse roscovitine concentrations; apoptosis and senescence were measured. Subsequently, levels of pro- and antiapoptotic proteins were evaluated.
Results
Renal tubular epithelial cells exposed to ‘low’ concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21, and these cells became senescent. Conversely, cells exposed to ‘high’ levels of roscovitine became apoptotic. The mechanism of antiapoptosis and senescence with ‘low’-dose roscovitine involves augmentation of the antiapoptotic proteins.
Conclusions
Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD, and suggest that further study of this agent should focus on assessment of dose response. Furthermore, our discovery of senescence induced by a PKD effective drug suggests a new area of therapeutic investigation in this disease.
doi:10.1159/000184590
PMCID: PMC2818470  PMID: 19066425
Autosomal dominant polycystic kidney disease; p21; Apoptosis; Senescence
10.  Route of Epoetin Administration Influences Hemoglobin Variability in Hemodialysis Patients 
American Journal of Nephrology  2008;29(6):532-537.
Background
Compared to the intravenous route, subcutaneous administration of epoetin requires lower dose and will be an attractive option for cost containment when bundling for dialysis is implemented. Hemoglobin variability defined as fluctuation of hemoglobin over time has not been well studied with respect to the route of administration.
Methods
157 prevalent-hemodialysis subjects were analyzed from an open-label, randomized study that compared the intravenous to the subcutaneous route of epoetin with identical weight-based dosing algorithm. Hemoglobin variability was defined as the number of weeks hemoglobin is outside the target range of 10–11 g/dl. Sensitivity analysis was performed.
Results
78 subjects in the intravenous and 79 in the subcutaneous group entered the 24-week dose maintenance phase. Baseline covariates were similar in both groups except for the dose of epoetin (lower in subcutaneous) and dialysis vintage (longer in intravenous). Patients on subcutaneous epoetin were outside the target range more weeks (p = 0.04) and had higher standard deviation of hemoglobin (p = 0.01) compared to the intravenous group.
Conclusions
The subcutaneous route of epoetin was associated with modestly higher hemoglobin variability, probably reflecting greater sensitivity of the subcutaneous route and/or identical epoetin-dosing algorithm employed in both the arms. This study could serve as an important guide when bundling for dialysis services is implemented as switching from intravenous to subcutaneous administration is likely to occur.
doi:10.1159/000187649
PMCID: PMC2818471  PMID: 19088467
Hemoglobin variability; Anemia; Subcutaneous epoetin; Bundling of dialysis service
11.  Regional Expression of NAD(P)H Oxidase and Superoxide Dismutase in the Brain of Rats with Neurogenic Hypertension 
American Journal of Nephrology  2008;29(5):483-492.
Background
Single injection of small quantities of phenol into the kidney cortex causes hypertension which is mediated by renal afferent sympathetic pathway activation. This phenomenon can be prevented by superoxide dismutase (SOD) infusion in the lateral ventricle, suggesting the role of superoxide () in noradrenergic control of arterial pressure. Since NAD(P)H oxidase is a major source of , we tested the hypothesis that hypertension in this model may be associated with upregulation of NAD(P)H oxidase in relevant regions of brain.
Methods
NAD(P)H oxidase subunits, mitochondrial (MnSOD) and cytoplasmic (CuZnSOD) SOD were measured in rats 4 weeks after injection of phenol or saline in the left kidney cortex.
Results
Phenol-injected rats exhibited hypertension, upregulation of gp91phox, p22phox, p47phox and p67phox in the medulla, gp91phox and p22phox in pons and gp91phox in hypothalamus. This was associated with upregulation of MnSOD with little change in CuZnSOD.
Conclusions
Chronic hypertension in phenol-injected rats is associated with upregulation of NAD(P)H oxidase and hence increased production capacity in the key regions of the brain involved in regulation of blood pressure. Since reactive oxygen species can intensify central noradrenergic activity, the observed maladaptive changes may contribute to the genesis and maintenance of the associated hypertension.
doi:10.1159/000178817
PMCID: PMC2821947  PMID: 19047792
Hypertension; Sympathetic activity; NAD(P)H oxidase; Oxidative stress; Reactive oxygen species; Medulla; Brain stem; Pons
12.  Risk Factors for Chronic Kidney Disease among American Indians and Alaska Natives – Findings from the Kidney Early Evaluation Program 
American Journal of Nephrology  2008;29(5):440-446.
Background
American Indians and Alaska Natives (AIAN) have a high incidence of end-stage renal disease. Less is known about chronic kidney disease (CKD) among AIAN and whether risk factors differ for low estimated glomerular filtration rate (eGFR) versus albuminuria with a normal eGFR.
Methods
Cross-sectional study examining the associations of age, sex, smoking, obesity, diabetes, hypertension, family history, and geographic region with CKD among a screened population of AIAN participants in the Kidney Early Evaluation Program from 2000 to 2006. CKD was defined by the presence of either a low eGFR, <60 ml/min/1.73 m2, or albuminuria, a urine albumin/creatinine ratio ≥30 mg/g.
Results
The prevalence of any CKD was 29%, of low eGFR was 17%, and of albuminuria with a normal eGFR was 12%. Older age was the strongest predictor of low eGFR (61+ years OR 8.42, 95% CI 5.92–11.98), followed by hypertension (OR 2.38, 95% CI 1.74–3.26). In contrast, diabetes (OR 2.04, 95% CI 1.57–2.64) and hypertension (OR 2.63, 95% CI 1.93–3.59) were the only predictors of albuminuria among persons with a normal eGFR.
Conclusion
The burden of CKD was high among this screened population of AIAN, and different risk factor patterns were associated with low eGFR and albuminuria. Innovative programs and longitudinal research are needed to address CKD among AIAN.
doi:10.1159/000174857
PMCID: PMC2821946  PMID: 19011277
Chronic kidney disease; Risk factors; American Indians; Alaska Natives
13.  Analyzing Change: A Primer on Multilevel Models with Applications to Nephrology 
American journal of nephrology  2008;28(5):792-801.
The analysis of change is central to the study of kidney research. In the past 25 years, newer and more sophisticated methods for the analysis of change have been developed, however as of yet these newer methods are underutilized in the field of kidney research. Repeated measures ANOVA is the traditional model that is easy to understand and simpler to interpret, but it may not be valid in complex real-world situations. Problems with the assumption of sphericity, unit of analysis, lack of consideration for different types of change, and missing data, in the repeated measures ANOVA context are often encountered. Multilevel modeling, a newer and more sophisticated method for the analysis of change, overcomes these limitations and provides a better framework for understanding the true nature of change. The present article provides a primer on the use of multilevel modeling to study change. An example from a clinical study is detailed and the method for implementation in SAS is provided.
doi:10.1159/000131102
PMCID: PMC2613435  PMID: 18477842
Longitudinal data analysis; analysis of change; change over time; repeated measures; multilevel modeling; mixed effects models; random coefficient models; hierarchical linear models; unit of analysis
14.  Change in Cardiovascular Risk Factors with Progression of Kidney Disease 
American Journal of Nephrology  2008;29(4):334-341.
Background
Prior studies evaluating the relationship of kidney disease with cardiovascular risk factors have been limited by their cross-sectional design. We evaluated the change in lipids, inflammatory and procoagulant biomarkers with decline in kidney function in a nested case-cohort study in the Cardiovascular Health Study, a community-based study of adults aged >65 years.
Methods
Individuals with an increase in serum creatinine ≥0.3 mg/dl (baseline to 3 years later, n = 207) were matched to controls of similar age, race, gender, diabetes and baseline serum creatinine, but whose change in creatinine was <0.3 mg/dl. Baseline and change in risk factors were analyzed with conditional logistic regression.
Results
Changes in C-reactive protein were similar. In contrast, cases had larger increases in fibrinogen (OR 1.38 per standard deviation, 95% confidence interval 1.08–1.76) and factor VIII [1.38 (1.10–1.72)] and larger decreases in HDL [OR 0.80 (0.64, 1.00)]. Change in interleukin-6 was greater in cases than controls, but this did not persist after multivariate adjustment. However, in linear regression, change in interleukin-6 was correlated with change in creatinine.
Conclusion
Cardiovascular risk factors and kidney function may change concurrently. This could lead to an increased risk of cardiovascular disease as kidney function worsens.
doi:10.1159/000166598
PMCID: PMC2786019  PMID: 18948687
Cardiovascular risk factors; Chronic kidney disease; Disease progression; Inflammation; Lipids
15.  Correlates of N-Terminal Prohormone Brain Natriuretic Peptides in African Americans with Hypertensive Chronic Kidney Disease: The African American Study of Kidney Disease and Hypertension 
American Journal of Nephrology  2008;29(4):292-298.
Background/Aims
The N-amino-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) is a marker of cardiac stress and elevated levels are indicative of heart failure. Few correlates of NT-proBNP levels have been identified in persons with moderate chronic kidney disease (CKD), and data from those without heart failure and from African Americans are especially limited.
Methods
The African American Study of Kidney Disease and Hypertension (AASK) enrolled nondiabetic African Americans with hypertensive kidney disease (glomerular filtration rate [GFR] = 20–65 ml/min/1.73 m2) and no evidence of clinical heart failure. NT-proBNP was measured in 982 AASK participants.
Results
In unadjusted analyses, GFR (r = −0.39; p < 0.001), hematocrit (r = −0.21; p < 0.001) and body mass index (BMI; r = −0.07; p = 0.04) were inversely correlated, and systolic blood pressure (r = 0.30; p < 0.001) and log UPCR (r = 0.32; p < 0.001) were positively correlated with log NT-proBNP levels. After adjustment for potential confounders, lower GFR and hematocrit and higher systolic blood pressure and protein:creatinine ratio remained significantly associated with higher NT-proBNP.
Conclusion
Lower GFR and hematocrit, and higher urinary protein excretion may be associated with volume expansion in CKD. These results suggest that these processes are associated with increased NT-proBNP in CKD and may play a role in the development of heart failure.
doi:10.1159/000159276
PMCID: PMC2786020  PMID: 18824845
Natriuretic peptides; Epidemiology; Chronic kidney disease
16.  Early Detection of Chronic Kidney Disease: Results of the PolNef Study 
American Journal of Nephrology  2008;29(3):264-273.
Background
Continuous increase in the number of patients with end-stage renal disease demands early detection of chronic kidney disease (CKD). The aim of the present study was to diagnose CKD in its earliest stages in a randomly selected population using a diagnostic algorithm developed by the working group.
Methods
An algorithm for the diagnostic procedure was created to identify patients with CKD requiring further nephrological care. Randomly chosen adult inhabitants of a city with a population of 60,000 were invited to participate in this study. Screening procedures included a microalbuminuria dipstick test accompanied by blood pressure measurement and medical questionnaire. In further diagnosis of CKD, estimated glomerular filtration rate (eGFR), albumin concentration in urine, urinalysis and ultrasound examination were used according to the algorithm. Multivariate logistic regression was performed to identify associations between participants’ characteristics and albuminuria.
Results
Out of 9,700 invited subjects, 2,471 individuals participated in the PolNef study. Albuminuria was detected in 15.6% of the investigated population using the dipstick test and thereafter confirmed in 11.9% by the turbidimetric method. The modeling of multivariate logistic regression indicated the following independent predictors of albuminuria: male sex, diabetes, nocturia and hypertension. For people without diabetes and without hypertension, nocturia independently predicted detection of albuminuria. 481 people received a consultation with a nephrologist, and 96% of them were recognized as having CKD. At least 9% of patients with CKD had eGFR by MDRD <60 ml/min/1.73 m2. Six persons were referred for further treatment because of newly diagnosed kidney tumor.
Conclusions
CKD in early stages occurs frequently in the studied population. The proposed diagnostic algorithm seems to be a powerful tool to identify subjects at risk of CKD. The role of nocturia as an independent predictor of albuminuria, both in the general population and in people without diabetes or hypertension, should be further examined.
doi:10.1159/000158526
PMCID: PMC2786021  PMID: 18812692
Albuminuria; Chronic kidney disease; Diagnostic algorithm; Nocturia
17.  Effect of Exercise on Cardiac Tissue Oxidative and Inflammatory Mediators in Chronic Kidney Disease 
American Journal of Nephrology  2008;29(3):213-221.
Background
Chronic renal failure (CRF) results in diminished physical activity and increased risk of cardiovascular disease (CVD). CVD risk factors are raised by sedentary life style and ameliorated by physical fitness in the general population. Accordingly, exercise improves hypertension, endothelial dysfunction, insulin resistance, dyslipidemia, inflammation and oxidative stress in high-risk populations. This study was designed to explore the effect of exercise on oxidative and inflammatory mediators in the left ventricle (LV) of CRF rats.
Methods and Results
One week after 5/6 nephrectomy female rats were housed in either regular cages or cages equipped with running wheels for 4 weeks. Sham-operated rats housed in regular cages served as controls. Sedentary CRF rats exhibited azotemia, hypertension, anemia, oxidative stress, activation of NF-κB and upregulations of reactive oxygen species-generating enzyme, NAD(P)H oxidase, MCP-1, cyclooxygenase-2 (COX-2), and PAI-1 in LV. The CRF rats assigned to the exercise group ran 6.8 ± 0.7 km/day and 72 ± 8 min/day. Voluntary exercise reversed NF-κB activation and lowered NAD(P)H oxidase, PAI-1, MCP-1 and COX-2 abundance, increased LV mass by raising myofibrillar proteins and ameliorated anemia without affecting renal function or arterial pressure.
Conclusions
CRF resulted in upregulation of prooxidant/proinflammatory pathways in LV. These changes were ameliorated by exercise, which indicates the potential cardiovascular benefit of exercise in renal insufficiency.
doi:10.1159/000156715
PMCID: PMC2786024  PMID: 18797164
Cardiovascular disease; Oxidative stress; Inflammation; Renin-angiotensin system; Hypertension
18.  Long-Term Cinacalcet HCl Treatment Improved Bone Metabolism in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism 
American Journal of Nephrology  2008;29(3):230-236.
Background/Aims
Few clinical trials conducted with cinacalcet have thoroughly addressed its effects of on bone metabolism. We assessed the effects of cinacalcet on bone markers in Japanese hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT).
Methods
200 Japanese HD patients with intact PTH (iPTH) levels ≥300 pg/ml were enrolled. The dose of cinacalcet was titrated from 25 up to 100 mg/day to achieve iPTH levels ≤250 pg/ml for 52 weeks.
Results
At the end of the study visit, 57.8% of patients (115/199) had achieved iPTH levels ≤250 pg/ml. Serum Ca, phosphorus (P) and Ca × P levels decreased rapidly and were maintained throughout the study. At week 52, all bone metabolic markers levels had decreased significantly from baseline. Although bone resorption markers gradually decreased throughout the study period, bone alkaline phosphatase significantly increased during the first 4 weeks and then gradually decreased.
Conclusions
The time courses of changes in bone markers after cinacalcet treatment resembled those observed after surgical parathyroidectomy (PTx), sometimes described as the hungry bone syndrome, indicating that cinacalcet treatment induces a rapid recovery in bone response to calcium. In addition, long-term efficacy and safety of cinacalcet were also observed in Japanese patients undertaking long-term hemodialysis (167.0 ± 81.4 months).
doi:10.1159/000156717
PMCID: PMC2786022  PMID: 18797166
Osteodystrophy; Bone disease; Hyperparathyroidism; Parathyroid hormone; Calcium
19.  Low Serum Uric Acid Level Is a Risk Factor for Death in Incident Hemodialysis Patients 
American Journal of Nephrology  2008;29(2):79-85.
Background
A reverse epidemiology of classic cardiovascular risk factors was observed in hemodialysis patients with a high comorbidity burden. We hypothesized that uric acid, a novel cardiovascular risk factor, also has an altered association with survival in these patients.
Methods
A retrospective study was conducted on 168 consecutive outpatient hemodialysis patients over a 6-year period. Serum uric acid, albumin levels and relevant laboratory information were recorded monthly. The disease severity was assessed using Comorbidity Index (CoI) scores. Patients were stratified into 3 groups according to their serum uric acid concentrations: group I was the lowest quintile, group II was the middle 3 quintiles and group III was the highest quintile. The risks of death were calculated utilizing a Cox regression model.
Results
Using group II as a reference group, the hazard ratio of group I was 2.23 [95% confidence interval (CI) 1.21–4.11, p = 0.01] and group III was 0.89 (95% CI 0.47–1.71, p = 0.74). The serum uric acid levels correlated inversely with CoI scores (r = −0.31, 95% CI −0.44 to −0.17, p < 0.0001) and positively with serum albumin levels (r = 0.35, 95% CI 0.21–0.48, p < 0.0001).
Conclusion
Low serum uric acid is a mortality risk factor in incident hemodialysis patients with a high comorbidity burden and hypoalbuminemia.
doi:10.1159/000151292
PMCID: PMC2786018  PMID: 18689987
Hypoalbuminemia; Hemodialysis, comorbidity; Serum uric acid, mortality
20.  Chronic Kidney Disease Is Often Unrecognized among Patients with Coronary Heart Disease: The REGARDS Cohort Study 
American Journal of Nephrology  2008;29(1):10-17.
Introduction
Individuals with kidney disease are at increased risk for coronary heart disease (CHD) and CHD is associated with an increased prevalence of chronic kidney disease (CKD). Awareness of CKD may potentially influence diagnostic decisions, life-style changes and pharmacologic interventions targeted at modifiable CHD risk factors. We describe here the degree to which persons with CHD are aware of their CKD.
Methods
The Reasons for Geographical and Racial Difference in Stroke (REGARDS) cohort study, a population-based sample of US residents aged 45 and older. We included in our analyses 28,112 REGARDS participants recruited as of June 2007. We estimated GFR (eGFR) using the MDRD equation, defined CKD as a GFR <60 ml/min/1.73 m2, and ascertained awareness of chronic kidney disease and coronary heart disease through self-report. We used the odds ratio to compare the association between awareness of kidney disease, as measured by GFR <60 ml/min/1.73 m2, among individuals with and without self-reported CHD by both the presence of CKD and the severity of impaired kidney function.
Results
Coronary heart disease was reported by 3,803 (14.1%) of subjects, and 11.3% of subjects had CKD by eGFR. Among all individuals with a GFR <60 ml/min/ 1.73 m2, 9.6% reported having been told by a physician that they had kidney disease. Among those with CHD and CKD, 5.0% were aware of their CKD compared to 2.0% in those without CHD [OR (95% CI) = 2.57 (2.08, 3.28)]. This difference persisted after controlling for the level of kidney function [aOR (95% CI) = 1.87 (1.43, 2.41)].
Conclusion
There was a high prevalence of CKD and a low prevalence of awareness of kidney disease among older adults in the US population with or without coronary heart disease. These findings support recent recommendations that patients with cardiovascular disease be systematically screened for and educated about CKD.
doi:10.1159/000148645
PMCID: PMC2786017  PMID: 18663284
Screening; Cardiovascular disease; Chronic kidney disease
21.  5-Methyltetrahydrofolate Administration Is Associated with Prolonged Survival and Reduced Inflammation in ESRD Patients 
American Journal of Nephrology  2008;28(6):941-948.
Background
Hemodialysis (HD) patients have a greatly increased risk of cardiovascular morbidity and mortality. For this reason, attempts are often made to normalize hyperhomocysteinemia. This randomized prospective study sought to determine which risk factors are predictors of mortality and whether high doses of folates or 5-methyltetrahydrofolate (5-MTHF) could improve hyperhomocysteinemia and survival in HD patients.
Methods
341 patients were divided into two groups: group A was treated with 50 mg i.v. 5-MTHF, and group B was treated with 5 mg/day oral folic acid. Both groups received i.v. vitamin B6 and B12. By dividing patients into C-reactive protein (CRP) quartiles, group A had the highest survival for CRP <12 mg/l, whereas no survival difference was found for group B. CRP was the only predictive risk factor for death (RR 1.17, range 1.04–1.30, p = 0.02). Dialysis age, hyperhomocysteinemia, methylenetetrahydrofolate reductase polymorphism, albumin, lipoprotein (a) and folate did not influence mortality risk. Survival in group A was higher than that in group B, namely 36.2 ± 20.9 vs. 26.1 ± 22.2 months (p = 0.003).
Results
Our results suggest that CRP, but not hyperhomocysteinemia, is the main risk factor for mortality in HD patients receiving vitamin supplements. Intravenous 5-MTHF seems to improve survival in HD patients independent from homocysteine lowering.
doi:10.1159/000142363
PMCID: PMC2786016  PMID: 18587236
ESRD patients; ESRD, survival; C-reactive protein; Homocysteine; 5-Methyltetrahydrofolate
22.  Association Analysis of the Ephrin-B2 Gene in African-Americans with End-Stage Renal Disease 
American Journal of Nephrology  2008;28(6):914-920.
Background
Genome scans in African-Americans with end-stage renal disease (ESRD) identified linkage on chromosome 13q33 in the region containing the ephrin-B2 ligand (EFNB2) genes. Interactions between the ephrin-B2 receptor and ephrin-B2 ligand play essential roles in renal angiogenesis, blood vessel maturation, and kidney disease.
Methods
The EFNB2 gene was evaluated as a positional candidate for non-diabetic and diabetic ESRD susceptibility in 1,071 unrelated African-American subjects; 316 with non-diabetic etiologies of ESRD, 394 with type 2 diabetes-associated ESRD and 361 healthy controls. Single nucleotide polymorphism (SNP) genotyping was performed on the Sequenom Mass Array System. Statistical analyses were computed using Dandelion version 1.26, Snpaddmix version 1.4 and Haploview version 3.32.
Results
Twenty-eight HapMap tag SNPs were genotyped spanning the 39 kilobases (kb) of the EFNB2 coding region, with average spacing of 1.43 kb. Analysis of 710 ESRD patient samples and 361 controls provided no evidence of single SNP associations in either diabetic or non-diabetic ESRD; although nominal evidence of association with all-cause ESRD was observed with a two SNP (p = 0.022) and three SNP (p = 0.023) haplotype, both containing SNPs rs7490924 and rs2391335 in intron 1.
Conclusions
Although an attractive positional candidate gene, polymorphisms in the EFNB2 gene do not appear to contribute in a substantial way to non-diabetic, diabetic or all-cause ESRD susceptibility in African-Americans. Additional genes within the chromosome 13q33 linkage interval are likely contributors to African-American non-diabetic ESRD.
doi:10.1159/000141934
PMCID: PMC2786015  PMID: 18580054
African-Americans; End-stage renal disease; Ephrin; Genetics; Hypertensive nephrosclerosis
23.  WNK Kinases, Renal Ion Transport and Hypertension 
American Journal of Nephrology  2008;28(5):860-870.
Two members of a recently discovered family of protein kinases are the cause of an inherited disease known as pseudohypoaldosteronism type II (PHAII). These patients exhibit arterial hypertension together with hyperkalemia and metabolic acidosis. This is a mirror image of Gitelman disease that is due to inactivating mutations of the SLC12A3 gene that encodes the thiazide-sensitive Na+: Cl− cotransporter. The uncovered genes causing PHAII encode for serine/threonine kinases known as WNK1 and WNK4. Physiological and biochemical studies have revealed that WNK1 and WNK4 modulate the activity of several transport pathways of the aldosterone-sensitive distal nephron, thus increasing our understanding of how diverse renal ion transport proteins are coordinated to regulate normal blood pressure levels. Observations discussed in the present work place WNK1 and WNK4 as genes involved in the genesis of essential hypertension and as potential targets for the development of antihypertensive drugs.
doi:10.1159/000139639
PMCID: PMC2820349  PMID: 18547946
Diuretics; Distal convoluted tubule; Salt transport; Potassium excretion; Phosphorylation
24.  Analyzing Change: A Primer on Multilevel Models with Applications to Nephrology 
American Journal of Nephrology  2008;28(5):792-801.
The analysis of change is central to the study of kidney research. In the past 25 years, newer and more sophisticated methods for the analysis of change have been developed; however, as of yet these newer methods are underutilized in the field of kidney research. Repeated measures ANOVA is the traditional model that is easy to understand and simpler to interpret, but it may not be valid in complex real-world situations. Problems with the assumption of sphericity, unit of analysis, lack of consideration for different types of change, and missing data, in the repeated measures ANOVA context are often encountered. Multilevel modeling, a newer and more sophisticated method for the analysis of change, overcomes these limitations and provides a better framework for understanding the true nature of change. The present article provides a primer on the use of multilevel modeling to study change. An example from a clinical study is detailed and the method for implementation in SAS is provided.
doi:10.1159/000131102
PMCID: PMC2613435  PMID: 18477842
Longitudinal data analysis; Analysis of change; Change over time; Repeated measures; Multilevel modeling; Mixed effects models; Random coefficient models; Hierarchical linear models; Unit of analysis
25.  The Role of Anemia Management in Improving Outcomes for African-Americans with Chronic Kidney Disease 
American Journal of Nephrology  2008;28(5):732-743.
Chronic kidney disease (CKD) is a serious threat to African-American public health. In this population CKD progresses to end-stage renal disease (ESRD) at quadruple the rate in Caucasians. Factors fueling progression to ESRD include diabetes and hypertension, which show high prevalences and accelerated renal damage in African- Americans, as well as possible nutritional, socioeconomic, and genetic factors. Anemia, a common and deleterious complication of CKD, is more prevalent and severe in African-American than Caucasian patients at each stage of the disease. Proactive management of diabetes, hypertension, anemia, and other complications throughout the course of CKD can prevent or delay disease progression and alleviate the burden of ESRD for the African-American community. Currently, African-Americans with CKD are less likely than Caucasian patients to receive anemia treatment before and after the onset of dialysis. Although African-Americans often require higher doses of erythropoiesis-stimulating agents, this may result from late treatment initiation, lower hemoglobin levels, or the presence of comorbidities such as diabetes and inflammation, although racial differences in response cannot be excluded. This review explores racial-specific challenges and potential solutions in renal anemia management to improve outcomes in African-American patients.
doi:10.1159/000127981
PMCID: PMC2820347  PMID: 18434712
Anemia management; Diabetes mellitus; Hypertension; Chronic kidney disease; Dialysis

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