American Journal of Nephrology (Am J Nephrol)

Publications in this journal

• Article: Inequalities in Transplant Waiting List Activation across Italian Dialysis Centers.

  Luca Neri, Maurizio Gallieni, Lisa Allegra Rocca Rey, Silvio Volmer Bertoli, Vittorio Andreucci, Diego Brancaccio
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  ABSTRACT: Background: The demand for kidney transplant exceeds organ supply; therefore, understanding patient-related and contextual factors associated with waiting list activation is key in ensuring that organ allocation is efficient and equitable. We sought to assess whether inequalities in wait-listing probability exist across centers and evaluate correlates of wait-listing in Italy. Methods: We linked the MigliorDialisi dataset (1,238 patients enrolled in 54 Italian hemodialysis centers) to administrative data concerning the activity of each participating center and contextual information abstracted from the Italian Institute of Statistics. We modeled the odds of waiting list activation for patients on dialysis by the subjects' sociodemographic, biomedical and psychosocial factors along with center-related and contextual factors. Results: The crude enlistment rate was 26% (95% CI 9-54) distributed as follows: 21, 34 and 33% in northern, central, and southern Italy, respectively (p < 0.01). Older patients with poorer health conditions and lower expectations toward transplantation outcomes were less likely to be wait-listed in multilevel multivariable logistic regression. In the fully adjusted model there was not a statistically significant variation in wait-listing across northern, central, and southern regions. However, the variance explained by center-related factors accounted for 12% (p < 0.01) of total variability in enlistment likelihood (20% in patients >65 years, p < 0.01). Conclusions: Our results showed that inter-center variation exists after adjusting for case mix. Additionally, we identified individual modifiable factors associated with wait-listing inequalities.
  American Journal of Nephrology 06/2013; 37(6):575-585.
• Article: Effects of Three Times Weekly Eight-Hour Nocturnal Hemodialysis on Volume and Nutritional Status.

  Cenk Demirci, Mehmet Ozkahya, Meltem Sezis Demirci, Gulay Asci, Timur Kose, Taskin Colak, Soner Duman, Huseyin Toz, Pinar Ergin, Siddik Momin Adam, Ercan Ok
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  ABSTRACT: Background: This prospective cohort study compared the changes in body water composition and nutritional parameters measured with multifrequency bioimpedance analysis between 8-hour three times weekly nocturnal hemodialysis (NHD) and 4-hour conventional hemodialysis (CHD) patients. Patients and Methods: 55 patients on CHD and 57 patients on NHD were included in the study. Multifrequency bioimpedance analysis was performed at baseline and at the 12th month. The primary outcomes of the study were changes in extracellular water (ECW), fat mass, dry lean mass and phase angle. Secondary outcomes of the study included changes in blood pressure and biochemical parameters related to nutrition and inflammation. Results: ECW/height values decreased in the NHD group, while they increased in the CHD group. Fat mass, dry lean mass, and serum albumin increased and high sensitive CRP decreased in the NHD group but did not change in the CHD group. When changes in parameters from baseline to the 12th month between the groups were compared, NHD was associated with improvement in volume parameter including ECW/height (difference -0.44 l/m, p < 0.001). Change in blood pressure was not different between the groups, however requirement for antihypertensive medication decreased from 26.5 to 8.5% in the NHD group (p = 0.002). NHD was also associated with increases in fat mass (difference 1.8 kg, p < 0.001), dry lean mass (difference 0.6 kg, p = 0.006), serum albumin (difference 0.19 g/dl, p < 0.001) and cholesterol (difference 18.8 mg, p < 0.001). Phase angle values decreased in the CHD group but did not change in the NHD group (difference between the groups 0.37°, p = 0.04). Conclusion: This study revealed that longer HD facilitates volume control and improves nutritional status.
  American Journal of Nephrology 05/2013; 37(6):559-567.
• Article: Prevalence of 25-OH Vitamin D Deficiency in a Population of Hemodialysis Patients and Efficacy of an Oral Ergocalciferol Supplementation Regimen.

  Anna Porter, Cheryl Gilmartin, Usasiri Srisakul, Jose Arruda, Sanjeev Akkina
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  ABSTRACT: Background/Aims: Optimal dosing regimens for 25-OH vitamin D (VitD) deficiency are unknown in hemodialysis (HD) patients. Our aim was to evaluate the efficacy of prescribing ergocalciferol supplementation based on KDOQI guidelines for chronic kidney disease (CKD) stages III-IV in HD patients. Methods: We conducted a retrospective study of 96 urban, predominately African-American HD patients at a single-center dialysis unit with VitD insufficiency or deficiency treated with ergocalciferol. Patients were classified as either compliant or non-compliant with supplementation as determined by review of pharmacy records. The primary outcome was VitD levels 6 months after initiation of treatment and secondary outcomes were VitD levels at 11 months, bone/mineral and anemia parameters. Results: The population was predominately African-American (69%) and Hispanic (28%). There were 61 individuals in the compliant group and 35 individuals in the non-compliant group. The compliant group was older but otherwise similar in demographics and co-morbid conditions to the non-compliant group. After 6 months of treatment, the compliant group had a significant increase in VitD level (14.7 ± 6.0 to 28.7 ± 10.0 ng/ml, p < 0.0001) compared to the non-compliant group (14.7 ± 5.5 to 14.8 ± 7.1 ng/ml, p = 0.95). There were no differences in the incidence of hypercalcemia between the two groups. Except for a decrease in phosphorus in the compliant group (5.6 ± 1.6 to 4.9 ± 1.7 mg/dl, p = 0.004), there were no significant difference in bone/mineral or anemia parameters including dosing of darbepoetin. Conclusion: An ergocalciferol-prescribing strategy using the KDOQI guidelines for stage III-IV kidney disease in HD patients with VitD deficiency or insufficiency is inadequate to achieve repletion or maintenance of normal VitD levels.
  American Journal of Nephrology 05/2013; 37(6):568-574.
• Article: Cardiovascular Toxicity of Epoetin-Alfa in Patients with Chronic Kidney Disease.

  Peter A McCullough, Huiman X Barnhart, Jula K Inrig, Donal Reddan, Shelly Sapp, Uptal D Patel, Ajay K Singh, Lynda A Szczech, Robert M Califf
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  ABSTRACT: Background: Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin-alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation. Methods: We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis. Results: Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point. Conclusions: In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent.
  American Journal of Nephrology 05/2013; 37(6):549-558.
• Article: Novel TRPM6 Mutations in Familial Hypomagnesemia with Secondary Hypocalcemia.

  Zhen Zhao, Yu Pei, Xianglan Huang, Yaping Liu, Wei Yang, Jing Sun, Nuo Si, Xiaoping Xing, Mei Li, Ou Wang, Yan Jiang, Xue Zhang, Weibo Xia
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  ABSTRACT: Background: Familial hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease characterized by severe hypomagnesemia and hypocalcemia associated with neurological symptoms, including generalized seizures, tetany and muscle spasms, which are refractory to anticonvulsant treatment. The pathophysiological hallmarks of HSH are the impaired intestinal absorption of magnesium accompanied by renal magnesium wasting as a result of a reabsorption defect in the distal convoluted tubule. Mutations in TRPM6, the gene encoding the transient receptor potential cation channel subfamily member 6, have been found to be responsible for this disease. In the present study, we report a Chinese family with 2 sisters affected with severe HSH, and elucidate the characteristics of TRPM6 gene mutations in these 2 patients. Methods: We evaluated the clinical, laboratory, and radiographic findings. All 39 TRPM6 exons and flanking exon-intron junctions from genomic DNA were amplified and sequenced in 2 affected members suffering from HSH and their family. Results: We found two novel mutations in the family, one frameshift mutation (c.1196delC) and one non-sense mutation (c.4577G>A). These mutations were predicted to result in a complete loss of function of TRPM6. Both of the sisters were compound heterozygotes for these mutations. Conclusion: Our results suggested that the compound heterozygous mutations in TRPM6 were responsible for HSH in the Chinese family.
  American Journal of Nephrology 05/2013; 37(6):541-548.
• Article: Oral Activated Charcoal Adsorbent (AST-120) Ameliorates Chronic Kidney Disease-Induced Intestinal Epithelial Barrier Disruption.

  Nosratola D Vaziri, Jun Yuan, Mahyar Khazaeli, Yuichi Masuda, Hirohito Ichii, Shuman Liu
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  ABSTRACT: Background: Chronic kidney disease (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, TNF-α, 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.
  American Journal of Nephrology 05/2013; 37(6):518-525.
• Article: Evaluation of Mycophenolic Acid Exposure Using a Limited Sampling Strategy in Renal Transplant Recipients.

  Jun Li, Yanfeng Liu, Jiawen Huang, Qian Fu, E Chen, Longshan Liu, Rui Zhang, Min Huang, Changxi Wang
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  ABSTRACT: Background/Aims: While there are drug exposure equation models based on limited sampling times for mycophenolate mofetil (MMF), there are few for enteric-coated mycophenolate sodium (EC-MPS), and none that studied Chinese individuals. Our objective is to generate the optimal model equations for estimation of the mycophenolic acid (MPA) area under the plasma concentration-time curve from 0 to 12 h (MPA-AUC0-12h) with a limited sampling strategy (LSS) for renal transplant recipients receiving EC-MPS. Methods: The pharmacokinetics in 31 Chinese renal allograft recipients treated with EC-MPS in combination with tacrolimus and steroids were determined. The model equations were generated by multiple stepwise regression analysis for estimation of the MPA-AUC. Results: A total of 31 patients with an average age and weight of 37.58 ± 10.9 years and 60.9 ± 10.7 kg, respectively, were included. Mean serum creatinine and glomerular filtration rate were 112.2 ± 17.7 μmol/l and 65.6 ± 14.6 ml/min, respectively. The mean values of AUC0-12h, pre-dose MPA trough concentration (C0), maximum concentrations (Cmax), and time to reach Cmax (Tmax) were 61.17 ± 26.39 mg·h/l (range 22.9-123.0 mg·h/l), 4.98 ± 4.65 mg/l (range 0.13-20.04 mg/l), 17.54 ± 10.67 mg/l (range 4.08-42.36 mg/l), and 5.0 ± 2.6 h (range 1.0-10.5 h), respectively. The best predictive equation for estimation of MPA-AUC0-12h was -3.63 + 8.35 × C4 + 17.04 × C7 + 13.74 × C12 (r(2) = 0.7491), prediction bias (PE%) was 20.9 ± 20.37, and prediction precision (APE%) was 3.66 ± 29.20. Conclusions: This model provides an effective approach for estimation of full MPA-AUC0-12h in Chinese adult renal allograft recipients treated with EC-MPS and tacrolimus.
  American Journal of Nephrology 05/2013; 37(6):534-540.
• Article: Association between Dietary Sodium and Potassium Intake with Chronic Kidney Disease in US Adults: A Cross-Sectional Study.

  Shailendra Sharma, Kim McFann, Michel Chonchol, Ian H de Boer, Jessica Kendrick
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  ABSTRACT: 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 estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) or eGFR ≥60 ml/min/1.73 m(2) with albuminuria (>30 mg/g creatinine). Results: The mean (SE) age and eGFR of participants were 45.0 ± 0.4 years and 88.0 ± 0.60 ml/min/1.73 m(2), respectively. 2,333 (14.2%) had CKD: 1,146 (7.3%) had an eGFR <60 ml/min/1.73 m(2) and 1,514 (8.4%) had an eGFR ≥60 ml/min/1.73 m(2) and albuminuria. After adjustment for age, sex, race, BMI, diabetes, hypertension, cardiovascular disease and congestive heart failure, subjects in the highest quartile of sodium intake had lower odds of CKD compared to subjects in the lowest quartile (adjusted OR: 0.79; 95% CI: 0.66-0.96; p < 0.016). Compared to the highest quartile, the odds of CKD increased 44% for participants in the lowest quartile of potassium intake (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.
  American Journal of Nephrology 05/2013; 37(6):526-533.
• Article: Mycophenolate as Maintenance Therapy for Lupus Nephritis with Impaired Renal Function.

  F Rivera, M L Illescas, E López-Rubio, J Fulladosa, R Poveda, J Baltar, G Fernández-Juárez, J Ballarín, A Oliet, A Vigil, J Lucas, M Sierra, M A Frutos, P García-Frías, C Ramos, E Mérida, M Praga, A Segarra
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  ABSTRACT: Background: Mycophenolate (MF) is effective as a maintenance therapy after induction therapy in patients with lupus nephritis (LN). However, little is known about its role in patients with impaired renal function. The purpose of this study was to evaluate the efficacy and safety of MF as a maintenance therapy for LN and its association with renal function. Methods: Data were obtained for 56 Spanish patients who were receiving MF as a maintenance therapy for LN. Patients were classified into two groups according to renal function at the initiation of MF treatment: group 1 [estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m(2)] and group 2 (eGFR <60 ml/min/1.73 m(2)). The primary endpoints of the study were the rates of renal relapse and responses, and their relationship with baseline renal function. Secondary outcomes were the appearance of side effects during treatment. Results: At initiation of MF treatment, the only differences between the groups were for age, hemoglobin levels, anti-DNA antibody titer, proteinuria, and renal function. In group 1 (n = 38), the eGFR was 98 ± 34 ml/min/1.73 m(2) and in group 2 (n = 18) the eGFR was 43 ± 14 ml/min/1.73 m(2). Only 3 cases had an eGFR <30 ml/min/1.73 m(2). No significant differences were observed in the rate of relapse at 6 months (group 1: 20%; group 2: 23%) or at 12 months (group 1: 25%; group 2: 17%). Response rates were also similar in both groups. Side effects were unremarkable. Conclusions: MF is effective and safe as a maintenance therapy for LN both in patients with normal renal function and in those with renal impairment.
  American Journal of Nephrology 05/2013; 37(6):509-517.
• Article: The Association of Prevalent Kidney Stone Disease with Mortality in US Adults: The National Health and Nutrition Examination Survey III, 1988-1994.

  Jie Tang, Pam Mettler, Kim McFann, Michel Chonchol
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  ABSTRACT: Background: Kidney stone disease is associated with hypertension, diabetes, metabolic syndrome, kidney function decline, and increased cardiovascular (CV) events. However, its association with all-cause and CV mortality is unclear. Methods: We used the Third National Health and Nutrition Examination Survey, a large US population-based study with mortality data through 2006 determined via linkage to the National Death Index to examine kidney stone disease in relation to all-cause and CV mortality risks. Results: Among 14,879 men and women over 18 years of age who were eligible for analysis, 683 participants reported a history of kidney stones. There was a total of 3,590 all-cause and 1,608 CV deaths during a median follow-up of 14.9 years. Stone formers had a significantly higher risk for all-cause mortality [hazard ratio (HR): 1.95, 95% CI: 1.64-2.33, p < 0.0001) and CV mortality (HR: 2.05, 95% CI: 1.60-2.62, p < 0.0001) in unadjusted analyses. However, after multivariate adjustment for age, gender, race, and poverty, stone formers no longer had increased risk for all-cause mortality (HR: 1.08, 95% CI: 0.93-1.26, p = 0.3) and CV mortality (HR: 1.07, 95% CI: 0.84-1.36, p = 0.6). Results remain unchanged after further adjustment for other clinical variables including history of hypertension, diabetes, and CV disease. Conclusion: The increased risk of all-cause and CV mortality in kidney stone formers is likely a reflection of unique demographics and associated comorbidities. There is no independent association of prevalent kidney stone disease with all-cause and CV mortality.
  American Journal of Nephrology 05/2013; 37(5):501-506.
• Article: Mineralocorticoid Receptor Blockade Reduced Oxidative Stress in Renal Transplant Recipients: A Double-Blind, Randomized Pilot Study.

  Marcos Ojeda-Cervantes, Jonatan Barrera-Chimal, Josefina Alberú, Rosalba Pérez-Villalva, Luis Eduardo Morales-Buenrostro, Norma A Bobadilla
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  ABSTRACT: Background: Previous experimental studies from our laboratory have demonstrated that aldosterone plays a central role in renal ischemic processes. This study was designed to evaluate the effect of mineralocorticoid receptor blockade in renal transplant recipients from living donors. Methods: 20 adult kidney transplant recipients from living donors were included in a double-blind, randomized, placebo-controlled clinical pilot study that compared spironolactone and placebo. Placebo or spironolactone (25 mg) was administered 1 day before and 3 days posttransplantation. Renal function and urinary kidney injury molecule-1, interleukin-18, and heat shock protein 72 as well as urinary hydrogen peroxide (H2O2) levels were quantified. Results: No significant differences were seen between the groups studied regarding age, gender, indication for kidney transplantation, residual renal function, renal replacement therapy, or warm and cold ischemia periods. In contrast, spironolactone administration significantly reduced the oxidative stress assessed by the urinary H2O2 excretion, in spite of no differences in renal function or reduction in tubular injury biomarkers. Conclusions: The findings of this exploratory study strongly suggest that aldosterone promotes oxidative stress and that the administration of spironolactone reduces the production of urinary H2O2 as a result of lesser formation of surrogate reactive oxygen species secondary to the ischemia-reperfusion phenomenon.
  American Journal of Nephrology 04/2013; 37(5):481-490.
• Article: Effects of Losartan and Pentoxifylline on Renal Dimethylarginine Dimethylaminohydrolase-1 Expression in Proteinuric Nephropathy.

  Sun-Hee Park, Seung Hyea Hyun, Hye-Myung Ryu, Ji-Sun Ahn, Se-Hyun Oh, Eun-Joo Oh, Se-Hee Yoon, Ji-Young Choi, Jang-Hee Cho, Chan-Duck Kim, Yong-Lim Kim
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  ABSTRACT: Background/Aims: Circulatory asymmetric dimethylarginine (ADMA) is correlated with proteinuria and endothelial dysfunction in patients with proteinuric renal diseases. However, it is not known whether proteinuria itself affects expression of dimethylarginine dimethylaminohydrolase (DDAH), a degrading enzyme of ADMA, in kidney. The aim of this study is to evaluate the direct effects of losartan and/or pentoxifylline on expression of renal DDAH-1 and its relation to oxidative stress in the setting of albuminuria. Methods: Using NRK52E cells, DDAH-1 mRNA and protein were determined after exposure to albumin with losartan and/or pentoxifylline. Reactive oxygen species (ROS), PKC activity, and NOX-4 mRNA were also measured. In addition, the effect of losartan and/or pentoxifylline on renal expression of DDAH-1 and serum ADMA were evaluated in a rat model of proteinuric nephropathy. Results : Exposure to albumin resulted in increased release of N-acetyl-β-D-glucosaminidase along with an increase of TNF-α, 8-hydroxy-2'-deoxyguanosine, and angiotensin II in NRK52E cells. Losartan and pentoxifylline reversed albumin-induced decrease of DDAH-1 mRNA and protein expression and DDAH-1 activity. The effects of losartan and pentoxifylline on DDAH-1 mRNA were associated with reduction of ROS. In addition, treatment with losartan and pentoxifylline resulted in an attenuated change of renal DDAH-1 protein expression and serum ADMA levels in vivo. Conclusion: DDAH-1 was positively regulated by losartan and pentoxifylline with its antioxidative effect in albumin-exposed renal proximal tubular cells. Combined treatment with losartan and pentoxifylline has a direct beneficial effect on expression of renal DDAH-1, and, thus, at least in part, modulates the circulatory levels of ADMA in proteinuric nephropathy.
  American Journal of Nephrology 04/2013; 37(5):491-500.
• Article: Tonsillar CD4+CD25+ Regulatory T Cells from IgA Nephropathy Patients Have Decreased Immunosuppressive Activity in Experimental IgA Nephropathy Rats.

  Hongdong Huang, Youming Peng, Xi-Dai Long, Zhihua Liu, Xiaojun Wen, Meng Jia, Yumei Liang, Anlan Huang
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  ABSTRACT: Background/Aim: CD4+CD25+ regulatory T (Treg) cells are of critical importance for maintenance of tolerance. We showed that the number of CD4+CD25+ Treg cells was significantly lower in tonsils of patients with IgA nephropathy (IgAN); however, the function of tonsillar CD4+CD25+ Treg cells in IgAN has not been reported. The aim of this study was to investigate the effect of tonsillar CD4+CD25+ Treg cells of IgAN patients on experimental IgAN in rats. Methods: Tonsillar CD4+CD25+ Treg cells were isolated by magnetic beads. A total of 2 × 10(6) CD4+CD25+ Treg cells were transferred into rats that were previously orally immunized over a period of 14 weeks and subsequently received an injection of BSA into the tail vein on 3 consecutive days. Urine protein and erythrocytes were measured. Glomerular injury was assessed by histopathology. Plasminogen activator inhibitor type 1 (PAI-1), interleukin (IL)-6 and transforming growth factor (TGF)-β1 in mesangial cells of rats were examined by reverse transcription PCR. Serum IgA and C3 and supernatants of IL-2, IL-4 and IL-6 in splenic cells were analysed by ELISA. Transferred tonsillar CD4+CD25+ Treg cells were tracked by reverse transcription PCR and flow cytometry. Results: IgA deposition in the mesangial region and the glomerular planar area and the number of cells, levels of serum IgA and supernatant IL-2, IL-4 and IL-6 in splenic cells and PAI-1, IL-6 and TGF-β1 expression in renal mesangial cells of rats that received CD4+CD25+ Treg cells from IgAN patients were significantly higher than in rats that received CD4+CD25+ Treg cells from the control group, although they were dramatically lower compared with rats treated without CD4+CD25+ Treg cells. Transferred tonsillar CD4+CD25+ Treg cells migrated predominantly to secondary lymphoid organs but not to the kidneys. Conclusion: Dysfunction of tonsillar CD4+CD25+ Treg cells may be an important cause of IgAN progression.
  American Journal of Nephrology 04/2013; 37(5):472-480.
• Article: Hyperuricemia Is an Independent Risk Factor for Mortality Only if Chronic Kidney Disease Is Present.

  Wookyung Chung, Ae Jin Kim, Han Ro, Jae Hyun Chang, Hyun Hee Lee, Ji Yong Jung
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  ABSTRACT: Background/Aims: Hyperuricemia has been considered a risk factor for renal disease and cardiovascular disease. However, the potential contribution of hyperuricemia to mortality remains uncertain, and the results in the available literature vary according to kidney function. The aim of this study was to determine the association between hyperuricemia and mortality in patients undergoing percutaneous coronary intervention (PCI) across the interaction of kidney function. Method: We retrospectively reviewed patients who underwent PCI from 2003 to 2009. Propensity scores for hyperuricemia (>7 mg/dl for males and >6 mg/dl for females) were used to assemble a matched cohort of 693 pairs of patients with and without hyperuricemia for analysis from the 3,201 patients who fulfilled the inclusion criteria among the 4,842 patients who underwent PCI. Results: Of the 3,201 patients who underwent PCI and for whom data were available regarding their baseline serum uric acid level, 763 (23.8%) had hyperuricemia. The hyperuricemia-associated hazard ratios (HRs) [95% confidence intervals (CIs)] for all-cause mortality were 1.780 (1.270-2.495) in the unmatched cohort and 1.655 (1.109-2.468) in the matched cohort. The HRs (95% CI) for all-cause mortality among those with and without chronic kidney disease (CKD) were 2.080 (1.318-3.283) and 1.592 (0.778-3.256), respectively (p for interaction, 0.001). Conclusions: Hyperuricemia is an independent risk factor for all-cause mortality in those patients with CKD but not in those without CKD.
  American Journal of Nephrology 04/2013; 37(5):452-461.
• Article: Microalbuminuria in HIV Disease.

  Colleen Hadigan, Elizabeth Edwards, Alice Rosenberg, Julia B Purdy, Estee Fleischman, Lilian Howard, Joann M Mican, Karmini Sampath, Akinbowale Oyalowo, Antoinette Johnson, Alexandra Adler, Catherine Rehm, Margo Smith, Leon Lai, Jeffrey B Kopp
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  ABSTRACT: 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 (urine protein/creatinine ratio ≥0.5 g/g), elevated serum creatinine, diabetes, or chronic inflammatory conditions. Subjects completed three research visits within 9 months. Microalbuminuria was defined as the geometric mean ACR of 25-355 mg/g for females and 17-250 mg/g for males. 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.
  American Journal of Nephrology 04/2013; 37(5):443-451.
• Article: Association between Water Intake, Chronic Kidney Disease, and Cardiovascular Disease: A Cross-Sectional Analysis of NHANES Data.

  Jessica M Sontrop, Stephanie N Dixon, Amit X Garg, Inmaculada Buendia-Jimenez, Oriane Dohein, Shih-Han S Huang, William F Clark
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  ABSTRACT: Background: Evidence from animal and human studies suggests a protective effect of higher water intake on kidney function and cardiovascular disease (CVD). Here the associations between water intake, chronic kidney disease (CKD) and CVD were examined in the general population. Methods: We conducted a cross-sectional analysis of the 2005-2006 National Health and Nutrition Examination Survey. Non-pregnant adults with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m(2) who were not taking diuretics were included. Total water intake from foods and beverages was categorized as low (<2.0 l/day), moderate (2.0-4.3 l/day) and high (>4.3 l/day). We examined associations between low total water intake and CKD (eGFR 30-60 ml/min/1.73 m(2)) and self-reported CVD. Results: Of 3,427 adults (mean age 46 (range 20-84); mean eGFR 95 ml/min/1.73 m(2) (range 30-161)), 13% had CKD and 18% had CVD. CKD was higher among those with the lowest (<2.0 l/day) vs. highest total water intake (>4.3 l/day) (adjusted odds ratio (OR) 2.52; 95% confidence interval (CI) 0.91-6.96). When stratified by intake of (1) plain water and (2) other beverages, CKD was associated with low intake of plain water: adjusted OR 2.36 (95% CI 1.10-5.06), but not other beverages: adjusted OR 0.87 (95% CI 0.30-2.50). There was no association between low water intake and CVD (adjusted OR 0.76; 95% CI 0.37-1.59). Conclusions: Our results provide additional evidence suggesting a potentially protective effect of higher total water intake, particularly plain water, on the kidney.
  American Journal of Nephrology 04/2013; 37(5):434-442.
• Article: Ginseng Treatment Attenuates Chronic Cyclosporine Nephropathy via Reducing Oxidative Stress in an Experimental Mouse Model.

  Kyoung Chan Doh, Sun Woo Lim, Shang Guo Piao, Long Jin, Seong Beom Heo, Yu Fen Zheng, Soo Kyung Bae, Gyu Hyun Hwang, Kyoung Il Min, Byung Ha Chung, Chul Woo Yang
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  ABSTRACT: Background: This study was performed to investigate whether ginseng extract has a protective effect in an experimental mouse model of chronic cyclosporine (CsA) nephropathy. Methods: Mice were treated with CsA (30 mg/kg/day, subcutaneously) with or without Korean red ginseng extract (KRG) (0.2, 0.4 g/kg/day, orally) on a 0.01% salt diet for 4 weeks. The effect of KRG on CsA-induced renal injury was evaluated by assessing renal function and pathology, mediators of inflammation, tubulointerstitial fibrosis and apoptotic cell death. Using an in vitro model, we also examined the effect of KRG on CsA-treated proximal tubular cells (HK-2). Oxidative stress was measured by assessing 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in 24-hour urine, tissue sections, and culture media. Results: Four weeks of CsA treatment caused renal dysfunction, typical pathologic lesions and apoptotic cell death. KRG treatment reduced serum creatinine and blood urea nitrogen and histopathology and increased creatinine clearance. Proinflammatory and profibrotic molecules such as induced nitric oxide synthase, cytokines, transforming growth factor (TGF)-β1 and TGF-β1-inducible gene h3 and apoptotic cell death, also decreased with KRG treatment. Consistent with these results, in vitro studies showed that addition of KRG protected against CsA-induced morphological changes, cytotoxicity, inflammation, and apoptotic cell death as demonstrated by annexin V binding. These changes were accompanied by decrease in the level of 8-OHdG in urine and culture supernatant after KRG treatment. Conclusion: The results of our in vivo and in vitro studies demonstrate that KRG has a protective effect in CsA-induced renal injury via reducing oxidative stress.
  American Journal of Nephrology 04/2013; 37(5):421-433.
• Article: Using Hemoglobin A1c to Derive Mean Blood Glucose in Peritoneal Dialysis Patients.

  Junichi Hoshino, Rajnish Mehrotra, Connie M Rhee, Kunihiro Yamagata, Yoshifumi Ubara, Kenmei Takaichi, Csaba P Kovesdy, Miklos Z Molnar, Kamyar Kalantar-Zadeh
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  ABSTRACT: 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, 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 [adjusted R(2) (R(2)adj = 0.454)], (2) BG = 55.3 + 28.8 × HbA1c - 10.2 × albumin - 3.3 × Hb (R(2)adj = 0.457), and (3) BG = 69.5 + 28.7 × HbA1c - 10.1 × albumin - 3.7 × Hb - 0.1 × age + race/ethnicity (-10.1 African Americans, -5.4 other race/ethnicities; R(2)adj = 0.457). All models showed greater explanatory power of BG variation than previously established HbA1c-BG equation models defined within non-PD cohorts [R(2)adj = 0.446 for both the Diabetes Control and Complications Trial (DCCT) and the A1c-Derived Average Glucose (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 Hb values better estimate the HbA1c-BG relationship in PD patients compared to equations using HbA1c alone.
  American Journal of Nephrology 04/2013; 37(5):413-420.
• Article: Cinacalcet Upregulates Calcium-Sensing Receptors of Parathyroid Glands in Hemodialysis Patients.

  Keiichi Sumida, Michio Nakamura, Yoshifumi Ubara, Yuji Marui, Kiho Tanaka, Kenmei Takaichi, Shinji Tomikawa, Naoko Inoshita, Kenichi Ohashi
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  ABSTRACT: Background: Cinacalcet hydrochloride (cinacalcet), a calcimimetic, has been shown to upregulate calcium-sensing receptor (CaSR) expression in parathyroid glands of rats with chronic renal insufficiency. However, the effect of cinacalcet on the reduced CaSR expression in human parathyroid glands remains to be elucidated. Methods: Four normal parathyroid glands and 71 hyperplastic parathyroid glands from 18 hemodialysis patients with refractory secondary hyperparathyroidism (SHPT) treated with (n = 10; cinacalcet group) or without (n = 8; conventional group) cinacalcet were examined immunohistochemically with a specific antibody against CaSR. The expression level of CaSR was analyzed semiquantitatively. Results: Compared with normal glands, the immunohistochemical expression of CaSR was decreased significantly in both the cinacalcet and conventional groups. In the cinacalcet group, the expression of CaSR was increased significantly compared with that in the conventional group (1.83 ± 0.14 vs. 0.87 ± 0.15, p < 0.001), even though the proportion of patients using vitamin D sterols and the mean administered dose of calcitriol equivalents were not significantly different between the two groups. The expression of CaSR was significantly decreased in the larger glands (>500 mg) compared with that in the smaller glands (<500 mg) in both groups; furthermore, it was markedly decreased in areas of nodular hyperplasia compared with diffuse hyperplasia in the cinacalcet group. Conclusions: Our results indicate that cinacalcet upregulates the depressed expression of CaSR in hemodialysis patients with SHPT, and that insufficient expression of CaSR, especially in larger glands with advanced nodular hyperplasia, underlies the pathogenesis of SHPT in patients who are resistant to cinacalcet.
  American Journal of Nephrology 04/2013; 37(5):405-412.