International Journal of Molecular Sciences

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Advances in Chronic Kidney Disease

by Alan R. Parrish

Int. J. Mol. Sci. 2016, 17(8), 1314; https://doi.org/10.3390/ijms17081314 - 11 Aug 2016

Cited by 11 | Viewed by 4890

Abstract

Chronic kidney disease (CKD) is characterized by renal dysfunction that is present for more than 3 months; it is also associated with a number of comorbidities [1,2].[...] Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Endometriosis Might Be Inversely Associated with Developing Chronic Kidney Disease: A Population-Based Cohort Study in Taiwan

by Ben-Shian Huang, Wen-Hsun Chang, Kuan-Chin Wang, Nicole Huang, Chao-Yu Guo, Yiing-Jen Chou, Hsin-Yi Huang, Tzeng-Ji Chen, Wen-Ling Lee and Peng-Hui Wang

Int. J. Mol. Sci. 2016, 17(7), 1079; https://doi.org/10.3390/ijms17071079 - 7 Jul 2016

Cited by 14 | Viewed by 5128

Abstract

This study was conducted to determine the risk of chronic kidney disease (CKD) among women with endometriosis in Taiwan. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan. A total of 27,973 women with a diagnosis of [...] Read more.

This study was conducted to determine the risk of chronic kidney disease (CKD) among women with endometriosis in Taiwan. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan. A total of 27,973 women with a diagnosis of endometriosis and 27,973 multivariable-matched controls (1:1) from 2000 to 2010 were selected. Cox regression and computed hazard ratios (HR) with 95% confidence intervals (95% CI) were used to determine the risk of CKD among women with endometriosis. The incidence rates (IR, per 10,000 person-years) of CKD among women with and without endometriosis were 4.64 and 7.01, respectively, with a significantly decreased risk of CKD (crude HR 0.65, 95% CI 0.53–0.81; adjusted HR 0.69, 95% CI 0.56–0.86) among women with endometriosis. The IR of CKD progressively increased with age, but the trend of lower CKD risk among women with endometriosis was consistent. However, the lower risk of CKD in women with endometriosis was no longer statistically significant after adjusting for menopausal status (adjusted HR 0.85, 95% CI 0.65–1.10). The results suggest that endometriosis is inversely associated with CKD, but this effect was mediated by menopause. The possible mechanism of this association is worthy of further evaluation. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Association of Genetic Polymorphisms of Renin–Angiotensin–Aldosterone System-Related Genes with Arterio-Venous Fistula Malfunction in Hemodialysis Patients

by Yu-Wei Chen, Yu-Te Wu, Jhin-Shyaun Lin, Wu-Chang Yang, Yung-Ho Hsu, Kuo-Hua Lee, Shou-Ming Ou, Yung-Tai Chen, Chia-Jen Shih, Pui-Ching Lee, Chia-Hao Chan, Ming-Yi Chung and Chih-Ching Lin

Int. J. Mol. Sci. 2016, 17(6), 833; https://doi.org/10.3390/ijms17060833 - 27 May 2016

Cited by 24 | Viewed by 6468

Abstract

Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may [...] Read more.

Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may also contribute to malfunction of AVF. Previous studies have demonstrated the effect of genotype polymorphisms of angiotensin converting enzyme on vascular access malfunction. We conducted a multicenter, cross-sectional study to evaluate the association between genetic polymorphisms of renin-angiotensin-aldosterone system and AVF malfunction. Totally, 577 patients were enrolled. Their mean age was 60 years old and 53% were male. HD patients with AVF malfunction had longer duration of HD (92.5 ± 68.1 vs. 61.2 ± 51.9 months, p < 0.001), lower prevalence of hypertension (44.8% vs. 55.3%, p = 0.025), right-sided (31.8% vs. 18.4%, p = 0.002) and upper arm AVF (26.6% vs. 9.7%, p < 0.001), and higher mean dynamic venous pressure (DVP) (147.8 ± 28.3 vs. 139.8 ± 30.0, p = 0.021). In subgroup analysis of different genders, location of AVF and DVP remained significant clinical risk factors of AVF malfunction in univariate and multivariate binary logistic regression in female HD patients. Among male HD patients, univariate binary logistic regression analysis revealed that right-side AVF and upper arm location are two important clinical risk factors. In addition, two single nucleotide polymorphisms (SNPs), rs275653 (Odds ratio 1.90, p = 0.038) and rs1492099 (Odds ratio 2.29, p = 0.017) of angiotensin II receptor 1 (AGTR1), were associated with increased risk of AVF malfunction. After adjustment for age and other clinical factors, minor allele-containing genotype polymorphisms (AA and CA) of rs1492099 still remained to be a significant risk factor of AVF malfunction (Odds ratio 3.63, p = 0.005). In conclusion, we demonstrated that rs1492099, a SNP of AGTR1 gene, could be a potential genetic risk factor of AVF malfunction in male HD patients. Full article

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Kidney Injury Molecule-1 Is Specifically Expressed in Cystically-Transformed Proximal Tubules of the PKD/Mhm (cy/+) Rat Model of Polycystic Kidney Disease

by Stefan Gauer, Anja Urbschat, Norbert Gretz, Sigrid C. Hoffmann, Bettina Kränzlin, Helmut Geiger and Nicholas Obermüller

Int. J. Mol. Sci. 2016, 17(6), 802; https://doi.org/10.3390/ijms17060802 - 24 May 2016

Cited by 14 | Viewed by 8201

Abstract

Expression of kidney injury molecule-1 (Kim-1) is rapidly upregulated following tubular injury, constituting a biomarker for acute kidney damage. We examined the renal localization of Kim-1 expression in PKD/Mhm (polycystic kidney disease, Mannheim) (cy/+) rats (cy: mutated allel, +: wild type allel), an [...] Read more.

Expression of kidney injury molecule-1 (Kim-1) is rapidly upregulated following tubular injury, constituting a biomarker for acute kidney damage. We examined the renal localization of Kim-1 expression in PKD/Mhm (polycystic kidney disease, Mannheim) (cy/+) rats (cy: mutated allel, +: wild type allel), an established model for autosomal dominant polycystic kidney disease, with chronic, mainly proximal tubulointerstitial alterations. For immunohistochemistry or Western blot analysis, kidneys of male adult heterozygously-affected (cy/+) and unaffected (+/+) littermates were perfusion-fixed or directly removed. Kim-1 expression was determined using peroxidase- or fluorescence-linked immunohistochemistry (alone or in combination with markers for tubule segments or differentiation). Compared to (+/+), only in (cy/+) kidneys, a chronic expression of Kim-1 could be detected by Western blot analysis, which was histologically confined to an apical cellular localization in areas of cystically-transformed proximal tubules with varying size and morphology, but not in distal tubular segments. Kim-1 was expressed by cystic epithelia exhibiting varying extents of dedifferentiation, as shown by double labeling with aquaporin-1, vimentin or osteopontin, yielding partial cellular coexpression. In this model, in contrast to other known molecules indicating renal injury and/or repair mechanisms, the chronic renal expression of Kim-1 is strictly confined to proximal cysts. Its exact role in interfering with tubulo-interstitial alterations in polycystic kidney disease warrants future investigations. Full article

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Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules

by Annayya Aroor, Marcin Zuberek, Cornel Duta, Alex Meuth, James R. Sowers, Adam Whaley-Connell and Ravi Nistala

Int. J. Mol. Sci. 2016, 17(5), 780; https://doi.org/10.3390/ijms17050780 - 20 May 2016

Cited by 32 | Viewed by 6366

Abstract

Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is [...] Read more.

Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT₁R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10⁻⁸ M) treatment of T35OK-AT₁R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT₁R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis

by Amit Sharma, Md. Abdul Hye Khan, Scott P. Levick, Kin Sing Stephen Lee, Bruce D. Hammock and John D. Imig

Int. J. Mol. Sci. 2016, 17(5), 751; https://doi.org/10.3390/ijms17050751 - 18 May 2016

Cited by 28 | Viewed by 6006

Abstract

Cytochrome P450 (CYP) monooxygenases epoxidize the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid into novel epoxydocosapentaenoic acids (EDPs) that have multiple biological actions. The present study determined the ability of the most abundant EDP regioisomer, 19,20-EDP to reduce kidney injury in an experimental [...] Read more.

Cytochrome P450 (CYP) monooxygenases epoxidize the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid into novel epoxydocosapentaenoic acids (EDPs) that have multiple biological actions. The present study determined the ability of the most abundant EDP regioisomer, 19,20-EDP to reduce kidney injury in an experimental unilateral ureteral obstruction (UUO) renal fibrosis mouse model. Mice with UUO developed kidney tubular injury and interstitial fibrosis. UUO mice had elevated kidney hydroxyproline content and five-times greater collagen positive fibrotic area than sham control mice. 19,20-EDP treatment to UUO mice for 10 days reduced renal fibrosis with a 40%–50% reduction in collagen positive area and hydroxyproline content. There was a six-fold increase in kidney α-smooth muscle actin (α-SMA) positive area in UUO mice compared to sham control mice, and 19,20-EDP treatment to UUO mice decreased α-SMA immunopositive area by 60%. UUO mice demonstrated renal epithelial-to-mesenchymal transition (EMT) with reduced expression of the epithelial marker E-cadherin and elevated expression of multiple mesenchymal markers (FSP-1, α-SMA, and desmin). Interestingly, 19,20-EDP treatment reduced renal EMT in UUO by decreasing mesenchymal and increasing epithelial marker expression. Overall, we demonstrate that a novel omega-3 fatty acid metabolite 19,20-EDP, prevents UUO-induced renal fibrosis in mice by reducing renal EMT. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Label-Free Quantitative Proteomics Reveals Differences in Molecular Mechanism of Atherosclerosis Related and Non-Related to Chronic Kidney Disease

by Magdalena Luczak, Joanna Suszynska-Zajczyk, Lukasz Marczak, Dorota Formanowicz, Elzbieta Pawliczak, Maria Wanic-Kossowska and Maciej Stobiecki

Int. J. Mol. Sci. 2016, 17(5), 631; https://doi.org/10.3390/ijms17050631 - 2 May 2016

Cited by 23 | Viewed by 6658

Abstract

The major cause of mortality in patients with chronic kidney disease (CKD) is atherosclerosis related to traditional and non-traditional risk factors. However, the understanding of the molecular specificity that distinguishes the risk factors for classical cardiovascular disease (CVD) and CKD-related atherosclerosis (CKD-A) is [...] Read more.

The major cause of mortality in patients with chronic kidney disease (CKD) is atherosclerosis related to traditional and non-traditional risk factors. However, the understanding of the molecular specificity that distinguishes the risk factors for classical cardiovascular disease (CVD) and CKD-related atherosclerosis (CKD-A) is far from complete. In this study we investigated the disease-related differences in the proteomes of patients with atherosclerosis related and non-related to CKD. Plasma collected from patients in various stages of CKD, CVD patients without symptoms of kidney dysfunction, and healthy volunteers (HVs), were analyzed by a coupled label-free and mass spectrometry approach. Dysregulated proteins were confirmed by an enzyme-linked immunosorbent assay (ELISA). All proteomic data were correlated with kidney disease development and were subjected to bioinformatics analysis. One hundred sixty-two differentially expressed proteins were identified. By directly comparing the plasma proteomes from HVs, CKD, and CVD patients in one study, we demonstrated that proteins involved in inflammation, blood coagulation, oxidative stress, vascular damage, and calcification process exhibited greater alterations in patients with atherosclerosis related with CKD. These data indicate that the above nontraditional risk factors are strongly specific for CKD-A and appear to be less essential for the development of “classical” CVD. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury

by Pierre C. Dagher, Takashi Hato, Henry E. Mang, Zoya Plotkin, Quentin V. Richardson, Michael Massad, Erik Mai, Sarah E. Kuehl, Paige Graham, Rakesh Kumar and Timothy A. Sutton

Int. J. Mol. Sci. 2016, 17(5), 647; https://doi.org/10.3390/ijms17050647 - 29 Apr 2016

Cited by 13 | Viewed by 5344

Abstract

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in [...] Read more.

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Glycated Albumin versus Glycated Hemoglobin as a Glycemic Indicator in Diabetic Patients on Peritoneal Dialysis

by Hiroki Kobayashi, Masanori Abe, Yoshinori Yoshida, Hiroko Suzuki, Noriaki Maruyama and Kazuyoshi Okada

Int. J. Mol. Sci. 2016, 17(5), 619; https://doi.org/10.3390/ijms17050619 - 25 Apr 2016

Cited by 26 | Viewed by 6447

Abstract

Compared with glycated hemoglobin (HbA1c), glycated albumin (GA) is superior in estimating glycemic control in diabetic patients on hemodialysis (HD). However, the better index for assessment of glycemic control in diabetic patients on peritoneal dialysis (PD) and the impact of protein loss on [...] Read more.

Compared with glycated hemoglobin (HbA1c), glycated albumin (GA) is superior in estimating glycemic control in diabetic patients on hemodialysis (HD). However, the better index for assessment of glycemic control in diabetic patients on peritoneal dialysis (PD) and the impact of protein loss on GA are unknown. Twenty diabetic patients on HD were matched by age, sex, and baseline postprandial plasma glucose (PG) levels to 20 PD patients. PG, HbA1c, GA, and serum albumin levels were measured for six months. Protein loss in PD patients was estimated by measuring the protein concentration in the peritoneal dialysate and by 24 h urine collection. Although PG and HbA1c did not differ significantly between the groups, the PD group had significantly lower GA (17.8% versus 20.8%, p < 0.001) and GA/HbA1c ratio (2.95% versus 3.45%, p < 0.0001) than the HD group. Although the PG level correlated significantly with the GA levels in both groups, it was not correlated with the HbA1c levels in both groups. HbA1c level was negatively associated with erythropoiesis-stimulating agent (ESA) dose in both groups, whereas GA was not significantly associated with serum albumin, hemoglobin concentration, ESA dose, and protein loss. Multiple regression analysis identified GA as the only independent factor associated with PG in PD patients. Our results suggested that GA was not significantly associated with protein loss, hemoglobin, serum albumin, and ESA dose. Although GA might underestimate glycemic status, it provided a significantly better measure for estimating glycemic control than HbA1c, even in PD patients. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Effects of Atorvastatin Dose and Concomitant Use of Angiotensin-Converting Enzyme Inhibitors on Renal Function Changes over Time in Patients with Stable Coronary Artery Disease: A Prospective Observational Study

by Ewa Wieczorek-Surdacka, Jolanta Świerszcz and Andrzej Surdacki

Int. J. Mol. Sci. 2016, 17(2), 106; https://doi.org/10.3390/ijms17020106 - 2 Feb 2016

Cited by 5 | Viewed by 5165

Abstract

Angiotensin-converting enzyme inhibitors (ACEI) and statins are widely used in patients with coronary artery disease (CAD). Our aim was to compare changes in glomerular filtration rate (GFR) over time in subjects with stable CAD according to atorvastatin dose and concomitant use of ACEI. [...] Read more.

Angiotensin-converting enzyme inhibitors (ACEI) and statins are widely used in patients with coronary artery disease (CAD). Our aim was to compare changes in glomerular filtration rate (GFR) over time in subjects with stable CAD according to atorvastatin dose and concomitant use of ACEI. We studied 78 men with stable CAD referred for an elective coronary angiography who attained the then-current guideline-recommended target level of low-density lipoproteins (LDL) cholesterol below 2.5 mmol/L in a routine fasting lipid panel on admission and were receiving atorvastatin at a daily dose of 10–40 mg for ≥3 months preceding the index hospitalization. Due to an observational study design, atorvastatin dosage was not intentionally modified for other reasons. GFR was estimated during index hospitalization and at about one year after discharge from our center. Irrespective of ACEI use, a prevention of kidney function loss was observed only in those treated with the highest atorvastatin dose. In 38 subjects on ACEI, both of the higher atorvastatin doses were associated with increasing beneficial effects on GFR changes (mean ± SEM: −4.2 ± 2.4, 1.1 ± 1.6, 5.2 ± 2.4 mL/min per 1.73 m² for the 10-mg, 20-mg and 40-mg atorvastatin group, respectively, p = 0.02 by ANOVA; Spearman’s rho = 0.50, p = 0.001 for trend). In sharp contrast, in 40 patients without ACEI, no significant trend effect was observed across increasing atorvastatin dosage (respective GFR changes: −1.3 ± 1.0, −4.7 ± 2.1, 4.8 ± 3.6 mL/min per 1.73 m², p = 0.02 by ANOVA; rho = 0.08, p = 0.6 for trend). The results were substantially unchanged after adjustment for baseline GFR or time-dependent variations of LDL cholesterol. Thus, concomitant ACEI use appears to facilitate the ability of increasing atorvastatin doses to beneficially modulate time-dependent changes in GFR in men with stable CAD. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts

by Yang Shen, Naijun Miao, Jinlan Xu, Xinxin Gan, Dan Xu, Li Zhou, Hong Xue, Wei Zhang and Limin Lu

Int. J. Mol. Sci. 2016, 17(2), 146; https://doi.org/10.3390/ijms17020146 - 22 Jan 2016

Cited by 57 | Viewed by 7520

Abstract

Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other [...] Read more.

Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) in vivo and in angiotensin II (Ang II)–treated renal fibroblast NRK-49F cells in vitro. Our data showed that UUO induced renal fibrosis and combined with the activation of ERK signaling, the upregulation of fibronectin, collagen I, and transforming growth factor-β (TGF-β). The administration of metformin inhibited the activation of ERK signaling and attenuated the production of extracellular matrix (ECM) proteins and collagen deposition in the obstructed kidneys. In cultured renal fibroblasts, Ang II increased the expression of fibronectin and collagen I and also activated ERK signaling and TGF-β in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II–induced ERK signaling activation and ECM overproduction. Our results show that metformin prevents renal fibrosis, possibly through the inhibition of ERK signaling, and may be a novel strategy for the treatment of renal fibrosis. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia

by Patrícia Garrido, Sandra Ribeiro, João Fernandes, Helena Vala, Petronila Rocha-Pereira, Elsa Bronze-da-Rocha, Luís Belo, Elísio Costa, Alice Santos-Silva and Flávio Reis

Int. J. Mol. Sci. 2016, 17(1), 28; https://doi.org/10.3390/ijms17010028 - 25 Dec 2015

Cited by 13 | Viewed by 13819

Abstract

This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced [...] Read more.

This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum) protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Randomized Controlled Trial of Darbepoetin α Versus Continuous Erythropoietin Receptor Activator Injected Subcutaneously Once Every Four Weeks in Patients with Chronic Kidney Disease at the Pre-Dialysis Stage

by Tetsuya Furukawa, Kazuyoshi Okada, Masanori Abe, Ritsukou Tei, Osamu Oikawa, Noriaki Maruyama and Takashi Maruyama

Int. J. Mol. Sci. 2015, 16(12), 30181-30189; https://doi.org/10.3390/ijms161226229 - 18 Dec 2015

Cited by 9 | Viewed by 6784

Abstract

Continuous erythropoietin receptor activator (CERA) seems to maintain a stable hemoglobin (Hb) level because its half-life is longer than darbepoetin α (DA). Twenty chronic kidney disease (CKD) patients at the pre-dialysis stage who had been administered DA for over 24 weeks were randomly [...] Read more.

Continuous erythropoietin receptor activator (CERA) seems to maintain a stable hemoglobin (Hb) level because its half-life is longer than darbepoetin α (DA). Twenty chronic kidney disease (CKD) patients at the pre-dialysis stage who had been administered DA for over 24 weeks were randomly assigned to receive subcutaneous CERA or DA once every four weeks during 48 weeks. In both groups, the rate of achievement of target Hb level changed from 70% to 100% in weeks 0 to 48, with no significant difference between the groups. Compared with week 0, the Hb level was significantly increased from week 24 in the DA group and from week 8 in the CERA group. In addition, the reticulocyte count was significantly increased from week 4 in the CERA group compared with the DA group. There was no significant difference in the levels of estimated glomerular filtration rate and iron status between both groups. Because of the small number of patients in this study, only limited conclusions can be drawn. However, the results suggest that subcutaneous administration of DA or CERA once every four weeks to predialysis patients has similar effects on achievement of target Hb levels. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Review

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Role of mTOR Inhibitors in Kidney Disease

by Moto Kajiwara and Satohiro Masuda

Int. J. Mol. Sci. 2016, 17(6), 975; https://doi.org/10.3390/ijms17060975 - 21 Jun 2016

Cited by 48 | Viewed by 9582

Abstract

The first compound that inhibited the mammalian target of rapamycin (mTOR), sirolimus (rapamycin) was discovered in the 1970s as a soil bacterium metabolite collected on Easter Island (Rapa Nui). Because sirolimus showed antiproliferative activity, researchers investigated its molecular target and identified the TOR1 [...] Read more.

The first compound that inhibited the mammalian target of rapamycin (mTOR), sirolimus (rapamycin) was discovered in the 1970s as a soil bacterium metabolite collected on Easter Island (Rapa Nui). Because sirolimus showed antiproliferative activity, researchers investigated its molecular target and identified the TOR1 and TOR2. The mTOR consists of mTOR complex 1 (mTORC1) and mTORC2. Rapalogues including sirolimus, everolimus, and temsirolimus exert their effect mainly on mTORC1, whereas their inhibitory effect on mTORC2 is mild. To obtain compounds with more potent antiproliferative effects, ATP-competitive inhibitors of mTOR targeting both mTORC1 and mTORC2 have been developed and tested in clinical trials as anticancer drugs. Currently, mTOR inhibitors are used as anticancer drugs against several solid tumors, and immunosuppressive agents for transplantation of various organs. This review discusses the role of mTOR inhibitors in renal disease with a particular focus on renal cancer, diabetic nephropathy, and kidney transplantation. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis

by Feng Liu and Shougang Zhuang

Int. J. Mol. Sci. 2016, 17(6), 972; https://doi.org/10.3390/ijms17060972 - 20 Jun 2016

Cited by 46 | Viewed by 12399

Abstract

Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be [...] Read more.

Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be caused by the proliferation of renal inherent cells, including glomerular epithelial cells, mesangial cells, and endothelial cells, along with defective kidney repair, renal interstitial fibroblasts activation, and extracellular matrix deposition. Receptor tyrosine kinases (RTKs) regulate a variety of cell physiological processes, including metabolism, growth, differentiation, and survival. Many studies from in vitro and animal models have provided evidence that RTKs play important roles in the pathogenic process of renal fibrosis. It is also showed that tyrosine kinases inhibitors (TKIs) have anti-fibrotic effects in basic research and clinical trials. In this review, we summarize the evidence for involvement of specific RTKs in renal fibrosis process and the employment of TKIs as a therapeutic approach for renal fibrosis. Full article

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Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury

by Pu Duann, Elias A. Lianos, Jianjie Ma and Pei-Hui Lin

Int. J. Mol. Sci. 2016, 17(5), 662; https://doi.org/10.3390/ijms17050662 - 3 May 2016

Cited by 92 | Viewed by 10994

Abstract

Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with high mitochondria density for their function in active transport. Acute kidney injury (AKI) is [...] Read more.

Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with high mitochondria density for their function in active transport. Acute kidney injury (AKI) is an important clinical syndrome and a global public health issue with high mortality rate and socioeconomic burden due to lack of effective therapy. AKI results in acute cell death and necrosis of renal tubule epithelial cells accompanied with leakage of tubular fluid and inflammation. The inflammatory immune response triggered by the tubular cell death, mitochondrial damage, associative oxidative stress, and the release of many tissue damage factors have been identified as key elements driving the pathophysiology of AKI. Autophagy, the cellular mechanism that removes damaged organelles via lysosome-mediated degradation, had been proposed to be renoprotective. An in-depth understanding of the intricate interplay between autophagy and innate immune response, and their roles in AKI pathology could lead to novel therapies in AKI. This review addresses the current pathophysiology of AKI in aspects of mitochondrial dysfunction, innate immunity, and molecular mechanisms of autophagy. Recent advances in renal tissue regeneration and potential therapeutic interventions are also discussed. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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