bims-fikidi 2018-05-27 papers

bims-fikidi

Biomed News

on Fibroblast growth factor 23 in chronic kidney disease

Issue of 2018–05–27
eleven papers selected by
Regina Goetz, New York University Langone Medical Center

Urinary mitochondrial DNA level in non-diabetic chronic kidney diseases.
Dietary Changes Involving Bifidobacterium longum and Other Nutrients Delays Chronic Kidney Disease Progression.
Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption.
Differential Determinants of Tubular Phosphate Reabsorption: Insights on Renal Excretion of Phosphates in Kidney Disease.
Association of Pre-End-Stage Renal Disease Hemoglobin with Early Dialysis Outcomes.
Kidney Disease in Women is Associated with Disadvantaged Childhood Socioeconomic Position.
Renal Pre-Competitive Consortium (RPC2): discovering therapeutic targets together.
Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study.
Change in kidney function after unilateral adrenalectomy in patients with primary aldosteronism: identification of risk factors for decreased kidney function.
Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction.
Risk factors of the peptic ulcer bleeding in aging uremia patients under regular hemodialysis.

Clin Chim Acta. 2018 May 17. pii: S0009-8981(18)30245-6. [Epub ahead of print]484 36-39

Urinary mitochondrial DNA level in non-diabetic chronic kidney diseases.

Pascal Zhongping Wei, Bonnie Ching-Ha Kwan, Kai Ming Chow, Phyllis Mei-Shan Cheng, Cathy Choi-Wan Luk, Ka-Bik Lai, Philip Kam-To Li, Cheuk Chun Szeto.

   BACKGROUND: Mitochondrial dysfunction plays an important role in the pathogenesis and progression of chronic kidney disease (CKD). We study the relation between urinary mitochondrial DNA (mtDNA) levels and renal dysfunction in non-diabetic CKD.
METHODS: We recruited 32 CKD patients (20 had hypertensive nephrosclerosis, 12 had IgA nephropathy). Urinary supernatant mtDNA level was measured and compared to baseline clinical and pathological parameters. The patients were followed 57.8 ± 30.5 months for renal function decline.
RESULTS: The average urinary supernatant mtDNA level was 222.0 ± 210.3 copy/μL. There was a modest but significant correlation between urinary mtDNA level and proteinuria (Spearman's r = 0.387, p = 0.035), but not any other baseline clinical or pathological parameter. Urinary mtDNA level had a significant inverse correlation with the slope of GFR decline (r = -0.402, p = 0.023). Urinary mtDNA level is a predictor of renal survival even after adjusting for baseline proteinuria with multivariate Cox analysis. In this model, every increase in urinary mtDNA by 100 copy/μL confers a 25.0% increase in risk of doubling of serum creatinine or need of dialysis (95%CI, 0.7% to 55.1%).
CONCLUSION: Mitochondrial DNA is readily detectable in the urinary supernatant of non-diabetic CKD, and its level correlates with the rate of renal function decline and predicts the risk of doubling of serum creatinine or need of dialysis. Further studies are needed to determine the value of urinary supernatant mtDNA level as a prognostic indicator of non-diabetic CKD.

Keywords:  CKD; Renal failure; Survival

DOI:  https://doi.org/10.1016/j.cca.2018.05.036
Am J Nephrol. 2018 May 18. 47(5): 325-332

Dietary Changes Involving Bifidobacterium longum and Other Nutrients Delays Chronic Kidney Disease Progression.

Yuko Iwashita, Masaki Ohya, Mitsuru Yashiro, Tomohiro Sonou, Kazuki Kawakami, Yuri Nakashima, Takuro Yano, Yu Iwashita, Toru Mima, Shigeo Negi, Kaoru Kubo, Koichi Tomoda, Toshitaka Odamaki, Takashi Shigematsu.

   BACKGROUND: Recent studies suggest that prebiotic and/or probiotic treatments ameliorate kidney function in humans and animals by improving the gut environment. However, the gut microbiota and kidney disease interactions remain to be determined. This study investigated whether synbiotics modulate the gut microbiota and ameliorate kidney function using a rat model of chronic kidney disease (CKD). As uremic toxins are associated with CKD-related mineral and bone disorder, the secondary aim was to evaluate the relationship between synbiotics and secondary hyperparathyroidism (SHPT).
METHODS: 5/6 nephrectomy (Nx) rats were developed as the CKD model. Sham-operated (sham) rats were used as the control. To investigate the effectiveness of prebiotics (glutamine, dietary fiber, and oligosaccharide) and probiotics (Bifidobacterium longum strain; GFOB diet), rats were randomly assigned to 4 groups: Nx group fed the GFOB diet (n = 10); Nx group fed the control (CON) diet (n = 10); sham group fed the GFOB diet (n = 5); and sham group fed the control diet (n = 5). Blood, feces, and kidney samples were collected and analyzed.
RESULTS: Serum creatinine (Cre) and blood urea nitrogen in the Nx GFOB group were significantly lower than those in the Nx CON group. Serum indoxyl sulfate in the Nx GFOB group was lower than that in the Nx CON group, and significantly correlated with serum Cre. Inorganic phosphorus and intact parathyroid hormone in the Nx GFOB group were significantly lower than those in the Nx CON group.
CONCLUSION: Improving the gut environment using synbiotics ameliorated kidney function and might be a pharmacological treatment for SHPT without any serious adverse events.

Keywords:  Chronic kidney disease; Chronic kidney disease progression; Gut microbiota; Prebiotics; Probiotics; Secondary hyperparathyroidism; Synbiotics

DOI:  https://doi.org/10.1159/000488947
Am J Nephrol. 2018 May 18. 47(5): 343-351

Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption.

Kenneth R Phelps, Darius L Mason.

   BACKGROUND: The serum phosphorus concentration ([P]s) is the sum of EP/Ccr and TRP/Ccr, where Ccr is creatinine clearance and EP and TRP are rates of excretion and reabsorption of phosphate. In chronic kidney disease (CKD), parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) mediate reduction of TRP/Ccr, and [PTH] and [FGF23] are linear functions of EP/Ccr. If controls and patients with CKD are considered together, TRP/Ccr is a hyperbolic function of EP/Ccr. Given these observations, we hypothesized that hyperbolas would describe relationships of phosphate reabsorption to [PTH] and [FGF23].
METHODS: We studied 30 patients and 28 controls with mean eGFR of 29.5 and 86.0 mL/min/1.73 m2, respectively. All analyses combined both subsets. We measured fasting [PTH] 1-84 and intact [FGF23], and determined contemporaneous EP/Ccr, TRP/Ccr, fractional excretion of phosphorus (FEP), and phosphate tubular maximum per volume of filtrate (TmP/GFR). We examined linear regressions of TRP/Ccr and TmP/GFR on 100/[PTH] and 100/[FGF23]; from linear equations we derived hyperbolic equations relating reabsorptive parameters to hormone concentrations.
RESULTS: TRP/Ccr and TmP/GFR were linear functions of 100/[PTH] and 100/[FGF23] and hyperbolic functions of [PTH] and [FGF23]. TRP/Ccr and TmP/GFR fell minimally over the ranges of EP/Ccr, [PTH], and [FGF23] seen in CKD. FEP rose with EP/Ccr despite stable phosphate reabsorption.
CONCLUSIONS: Hyperbolas describe relationships of TRP/Ccr and TmP/GFR to [PTH] and [FGF23] if subjects with normal and reduced GFR are analyzed together. Although FEP rises with [PTH] and [FGF23] as GFR falls, the simultaneous increments do not signify hormonally mediated reductions in phosphate reabsorption.

Keywords:  Fibroblast growth factor 23; Fractional excretion of phosphate; Parathyroid hormone; Phosphate; Tubular phosphate reabsorption

DOI:  https://doi.org/10.1159/000489270
Am J Nephrol. 2018 May 18. 47(5): 300-303

Differential Determinants of Tubular Phosphate Reabsorption: Insights on Renal Excretion of Phosphates in Kidney Disease.

Nahid Tabibzadeh, Romuald Mentaverri, Maïté Daroux, Rafik Mesbah, Alexia Delpierre, Jean-Gabriel Paul, Valérie Deken, Ziad A Massy, Pierre Bataille.

  We assessed the tubular reabsorption of phosphate (TRP) and maximal renal threshold for phosphate reabsorption to glomerular filtration rate (TmPi/GFR) and their determinants in 64 stages 2-4 chronic kidney disease (CKD) patients in order to define the early changes in phosphate metabolism in CKD. In multivariable analysis, TmPi/GFR correlates were estimated GFR (eGFR), intact parathyroid hormone (iPTH), and hemoglobin (R2 = 0.417), while TRP correlates were eGFR, iPTH, 24-h phosphaturia, and calcitriol (R2 = 0.72). This suggests that TmPi/GFR and TRP, respectively, assess hemoglobin-phosphate and bowel-kidney phosphate regulation axis. Iron supplementation based on TmPi/GFR or earlier phosphate restriction based on TRP should be investigated in view of modifying clinical outcomes in CKD.

Keywords:  Chronic kidney disease; Fibroblast growth factor 23; Mineral and bone disorders; Tubular phosphate reabsorption

DOI:  https://doi.org/10.1159/000488864
Am J Nephrol. 2018 May 18. 47(5): 333-342

Association of Pre-End-Stage Renal Disease Hemoglobin with Early Dialysis Outcomes.

Carola-Ellen Kleine, Melissa Soohoo, Omesh N Ranasinghe, Christina Park, Maria V Marroquin, Yoshitsugu Obi, Connie M Rhee, Hamid Moradi, Csaba P Kovesdy, Kamyar Kalantar-Zadeh, Elani Streja.

   BACKGROUND: Incident hemodialysis patients have a high mortality risk within the first months after dialysis initiation. Pre-end-stage renal disease (ESRD) factors like anemia management may impact early post-ESRD outcomes. Therefore, we evaluated the impact of pre-ESRD hemoglobin (Hgb) and pre-ESRD Hgb slope on post-ESRD mortality and hospitalization outcomes.
METHODS: The study included 31,472 veterans transitioning to ESRD. Using Cox and negative binomial regression models, we evaluated the association of pre-ESRD Hgb and Hgb slope with 12-month post-ESRD all-cause and cardiovascular mortality and hospitalization rates using 4 levels of hierarchical multivariable adjustment, including erythropoietin use and kidney decline in slope models.
RESULTS: The cohort was 2% female, 30% African-American, and on average 68 ± 11 years old. Compared to Hgb 10-< 11 g/dL, both low (< 10 g/dL) and high (≥12 g/dL) levels were associated with higher all-cause mortality after full adjustment (HR 1.25 [95% CI 1.15-1.35] and 1.09 [95% CI 1.02-1.18], respectively). Similarly, Hgb exhibited a U-shaped association with CV mortality, while only lower Hgb was associated with a higher hospitalization rate. Neither an annual pre-ESRD decline in Hgb nor increase was associated with higher post-ESRD mortality risk after adjustment for kidney decline. However, we observed a modest J-shaped association between pre-ESRD Hgb slope and post-ESRD hospitalization rate.
CONCLUSIONS: Lower and higher pre-ESRD Hgb levels are associated with a higher risk of early post-ESRD mortality, while there was no association between the pre-ESRD slope and mortality. An increase in pre-ESRD Hgb slope was associated with higher risk of post-ESRD hospitalization. Additional studies aimed at anemia management prior to ESRD transition are warranted.

Keywords:  Anemia; Chronic kidney disease; End-stage renal disease; Hemoglobin; Mortality

DOI:  https://doi.org/10.1159/000489223
Am J Nephrol. 2018 May 18. 47(5): 292-299

Kidney Disease in Women is Associated with Disadvantaged Childhood Socioeconomic Position.

Mark Canney, Siobhan Leahy, Siobhan Scarlett, Rose Anne Kenny, Mark A Little, Conall M O'Seaghdha, Cathal McCrory.

   BACKGROUND: Socioeconomic position (SEP) is an important determinant of health and it is dynamic across the entire lifespan. We sought to investigate the relationship between life-course SEP and chronic kidney disease (CKD) using 3 conceptual models: critical period, pathway and accumulation.
METHODS: Cross-sectional analysis of 4,996 participants from The Irish Longitudinal Study on Ageing, a nationally representative cohort of community-dwelling adults aged ≥50 years. We defined childhood and adulthood SEP according to father's and respondent's occupation respectively. SEP was categorised as high (reference), intermediate, low and never worked. CKD was defined as a glomerular filtration rate < 60 mL/min/1.73 m2 estimated from the combination of creatinine and cystatin C. We used logistic regression to estimate the age-adjusted association between SEP and CKD separately in men and women.
RESULTS: Low childhood SEP was strongly associated with CKD in women, after adjusting for adulthood SEP (OR 1.90 [95% CI 1.24-2.92]), supporting the critical period hypothesis. This association was not explained by traditional CKD risk factors. Women who experienced low childhood SEP and whose circumstances improved in adulthood also had increased odds of CKD, further supporting a critical period effect in childhood. There was comparatively less evidence in support of the pathway or accumulation models. We did not observe a statistically significant association between SEP and CKD in men.
CONCLUSIONS: Our findings suggest that women exposed to disadvantaged SEP in childhood represent an at-risk group in whom there may be opportunities for identification of CKD and facilitation of health-promoting behaviours from an early age.

Keywords:  Chronic kidney disease; Critical period; Life course; Socioeconomic position

DOI:  https://doi.org/10.1159/000488362
Drug Discov Today. 2018 May 17. pii: S1359-6446(18)30070-9. [Epub ahead of print]

Renal Pre-Competitive Consortium (RPC2): discovering therapeutic targets together.

Mark Tomilo, Heather Ascani, Barbara Mirel, Maria Chiara Magnone, Carol Moreno Quinn, Anil Karihaloo, Kevin Duffin, Uptal D Patel, Matthias Kretzler.

  Despite significant effort, patients with kidney disease have not seen their outcomes improved significantly over the past two decades. This has motivated clinicians and researchers to consider alternative methods to identifying risk factors, disease progression markers, and effective therapies. Genome-scale data sets from patients with renal disease can be used to establish a platform to improve understanding of the molecular basis of disease; however, such studies require expertise and resources. To overcome these challenges, we formed an academic-industry consortium to share molecular target identification efforts and expertise across academia and the pharmaceutical industry. The Renal Pre-Competitive Consortium (RPC2) aims to accelerate novel drug development for kidney diseases through a systems biology approach. Here, we describe the rationale, philosophy, establishment, and initial results of this strategy.

Keywords:  consortium; genomics; kidney; precompetitive; renal; therapeutics

DOI:  https://doi.org/10.1016/j.drudis.2018.05.021
Am J Nephrol. 2018 May 18. 47(5): 304-316

Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study.

Japan Multi-Institutional Collaborative Cohort (J-MICC) Study Group

   BACKGROUND: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide.
METHODS: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects.
RESULTS: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations.
CONCLUSION: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

Keywords:  Chronic kidney disease; Genome-wide association study; Population-based cohort

DOI:  https://doi.org/10.1159/000488946
Int Urol Nephrol. 2018 May 19.

Change in kidney function after unilateral adrenalectomy in patients with primary aldosteronism: identification of risk factors for decreased kidney function.

Il Young Kim, In Seong Park, Min Jeong Kim, Miyeun Han, Harin Rhee, Eun Young Seong, Dong Won Lee, Soo Bong Lee, Ihm Soo Kwak, Sang Heon Song, Hyun Chul Chung.

   PURPOSE: Glomerular filtration rate (GFR) has been reported to decrease after unilateral adrenalectomy in patients with primary aldosteronism (PA). The aim of this study was to identify clinical predictors for decreased GFR after adrenalectomy in patients with PA.
METHODS: The records of 187 patients (98 patients with PA and 89 with non-PA adrenal disease) who were followed up for at least 6 months after unilateral adrenalectomy were retrospectively analyzed. Estimated GFR (eGFR) was investigated at 1, 3, and 6 months postoperatively. Preoperative risk factors for eGFR% decline at 1 month ([preoperative eGFR-eGFR at 1 month]/preoperative eGFR × 100) and postoperative CKD development were investigated.
RESULTS: The eGFR decreased significantly at 1 month and remained stable in the PA group. However, there were no significant changes in eGFR in the non-PA group over the 6-month period. In the PA group, a high preoperative eGFR and high aldosterone to renin ratio (ARR) were independently associated with eGFR% decline at 1 month. In patients with PA but without preoperative CKD (n = 68), a low preoperative eGFR and high ARR were independent risk factors for developing postoperative CKD. The best preoperative cut-off values of eGFR and ARR for predicting the development of postoperative CKD were ≤ 102 ml/min/1.73 m2 and ≥ 448 ng/dl:ng/ml/h, respectively.
CONCLUSIONS: Renal function deteriorated significantly after unilateral adrenalectomy in patients with PA. Clinicians must pay attention to postoperative renal function in PA patients at elevated risk of developing decreased kidney function.

Keywords:  Adrenalectomy; Chronic kidney disease; Glomerular filtration rate; Primary aldosteronism

DOI:  https://doi.org/10.1007/s11255-018-1887-9
Am J Nephrol. 2018 May 18. 47(5): 361-371

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction.

Qing Kuang, Ning Xue, Jing Chen, Ziyan Shen, Xiaomeng Cui, Yi Fang, Xiaoqiang Ding.

   BACKGROUND: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H2S) level. Nevertheless, the role of H2S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H2S in patients with different stages of CKD, and to identify the role of H2S in the progression of CKD and its relationship with cardiovascular diseases.
METHODS: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H2S was measured with spectrophotometry. Sulfhemoglobin, the integration of H2S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction.
RESULTS: The plasma H2S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H2S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = -0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H2S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H2S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H2S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3-5 patients was significantly higher than that in CKD stages 1-2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative -correlation between plasma H2S level and LVEF (ρ = -0.204, p < 0.05) in CKD patients. The H2S level also correlated negatively with cTnT concentration (ρ = -0.249, p < 0.01).
CONCLUSIONS: Plasma H2S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD -patients.

Keywords:  Cardiac dysfunction; Chronic kidney disease; Hydrogen sulfide

DOI:  https://doi.org/10.1159/000489606
J Chin Med Assoc. 2018 May 16. pii: S1726-4901(18)30098-4. [Epub ahead of print]

Risk factors of the peptic ulcer bleeding in aging uremia patients under regular hemodialysis.

Xi-Hsuan Lin, Chung-Chi Lin, Yuan-Jen Wang, Jiing-Chyuan Luo, Shih-Hao Young, Ping-Hsien Chen, Ming-Chih Hou, Fa-Yauh Lee.

   BACKGROUND: Previous studies have shown that uremia patients under hemodialysis (HD) have a significantly higher occurrence of peptic ulcer bleeding (PUB) than healthy controls and that elderly patients remain at high risk of peptic ulcer disease (PUD) and PUB. Here we aimed to identify the risk factors for PUB in aging (≥65-years-old) uremic patients under regular HD.
METHODS: Using data from the National Health Insurance Research Database of Taiwan, we compared 18,252 aging regular HD patients and 17,883 age-, gender-, and medication-matched patients without kidney disease (control group). The log-rank test was performed to analyze the differences in accumulated hazard of PUB between the two groups. Cox proportional hazard regressions were performed to evaluate independent risk factors for PUB between the two groups and identify risk factors of PUB in aging HD patients.
RESULTS: In a 7-year follow-up, aging HD patients had significantly higher incidences of PUB than the matched controls (p < 0.001 by the log-rank test). By Cox proportional hazard regression analysis, HD (hazard ratio [HR] = 4.61; 95% confidence intervals [CI] 4.03-5.27) was independently associated with increased risk of PUB. Age, diabetes mellitus (DM), history of uncomplicated PUD, cirrhosis, and use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids were risk factors for PUB in aging HD patients.
CONCLUSION: Aging HD patients are associated with higher risk of PUB. The use of NSAIDs and corticosteroids and co-morbidities including DM, history of uncomplicated PUD, and cirrhosis were identified as risk factors for PUB in these patients.

Keywords:  Aging; Co-morbidity; Hemodialysis; Peptic ulcer bleeding; Uremia

DOI:  https://doi.org/10.1016/j.jcma.2018.03.007