| 1. |
- Abu Seman, N, et al.
(författare)
-
Genetic and biological effects of sodium-chloride cotransporter (SLC12A3) in diabetic nephropathy
- 2014
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 40:5, s. 408-416
-
Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background/Aims:</i></b> Solute carrier family 12 member 3 (<i>SLC12A3</i>) encodes a sodium/chloride transporter in kidneys. Previous reports suggest that Arg913Gln polymorphism in this gene is associated with diabetic nephropathy (DN), but the data appear to be inconsistent. Up to now, there is no biological evidence concerning the effects of <i>SLC12A3</i> in DN. In this study, we aim to evaluate the genetic effects of the <i>SLC12A3 </i>gene and its Arg913Gln polymorphism with genetic and functional analyses. <b><i>Methods:</i></b> We genotyped <i>SLC12A3</i> genetic polymorphisms including Arg913Gln in 784 non-diabetes controls and 633 type 2 diabetes (T2D) subjects with or without DN in a Malaysian population and performed a meta-analysis of the present and previous studies. We further analyzed the role of <i>slc12a3</i> in kidney development and progress of DN in zebrafish and db/db mice. <b><i>Results:</i></b> We found that <i>SLC12A3</i> Arg913Gln polymorphism was associated with T2D (p = 0.028, OR = 0.772, 95% CI = 0.612-0.973) and DN (p = 0.038, OR = 0.547, 95% CI = 0.308-0.973) in the Malaysian cohort. The meta-analysis confirmed the protective effects of <i>SLC12A3</i> 913Gln allele in DN (Z-value = -1.992, p = 0.046, OR = 0.792). Furthermore, with knockdown of zebrafish ortholog, <i>slc12a3 </i>led to structural abnormality of kidney pronephric distal duct at 1-cell stage. <i>Slc12a3</i> mRNA and protein expression levels were upregulated in kidneys of db/db mice from 6, 12, and 26 weeks at the age. <b><i>Conclusion:</i></b> The present study provided the first biological and further genetic evidence that <i>SLC12A3</i> has genetic susceptibility in the development of DN, while the minor 913Gln allele in this gene confers a protective effect in the disease. i 2014 S. Karger AG, Basel
|
|
| 2. |
- Axelsson, J, et al.
(författare)
-
Is fetuin-A/alpha2-Heremans-Schmid glycoprotein associated with the metabolic syndrome in patients with chronic kidney disease?
- 2008
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 28:4, s. 669-676
-
Tidskriftsartikel (refereegranskat)abstract
- <i>Introduction:</i> Components of the metabolic syndrome are highly prevalent in chronic kidney disease (CKD) patients – some of which paradoxically appear to predict an improved outcome in this population. We hypothesized that the circulating calcification inhibitor fetuin-A/AHSG, which is also a natural inhibitor of the tyrosine kinase insulin receptor, could be one factor explaining the association between increased fat mass and a survival advantage in CKD and thus conducted an explorational study to provide preliminary data to support further research into this hypothesis. <i>Patients and Methods:</i> In a cross-sectional study, we evaluated 198 CKD stage 5 patients (GFR 6.8 ± 0.2 ml/min; 62% males, mean age 52 ± 1 years) close to the start of renal replacement therapy. We studied circulating AHSG (ELISA) and two common functional <i>AHSG</i> gene polymorphisms (at amino acids Thr248Met (C-T) and Thr256Ser (C-G) using Pyrosequencing®) and related these to multiple components of the metabolic syndrome. <i>Results:</i> Median circulating AHSG was lower (p < 0.01) in type-2 (0.22 g/l) and type-1 (0.16 g/l) diabetics as compared to non-diabetic CKD-5 patients (0.24 g/l). AHSG correlated with both total and truncal fat mass in type-2 diabetics (rho 0.37 and 0.39; p < 0.001, respectively), but not in type-1 diabetics or non-diabetics. Both SNPs significantly influenced circulating levels of AHSG, and were also associated with significant differences in serum triglycerides and HDL cholesterol. Furthermore, there were significant differences in the prevalence of metabolic syndrome criteria between the <i>AHSG</i> Thr256Ser (C-G) genotype groups, with a more atherogenic lipid profile in AHSG high producers (Thr/Thr homozygotes). In multivariate analysis, the association between circulating AHSG and fat mass remained significant also after adjustment for age, gender, inflammation (CRP >10 mg/l), and <i>AHSG</i> genotype. <i>Conclusions:</i> The present, explorational, study supports further, mechanistic, studies into a physiological link between AHSG and body fat mass in patients with CKD. As we observed an association between higher fat mass and elevated AHSG levels, these preliminary results may form the basis of further study to establish if the observed associations may be one reason why obesity has been reported to constitute a survival advantage in CKD.
|
|
| 3. |
- Axelsson, J, et al.
(författare)
-
Serum retinol-binding protein concentration and its association with components of the uremic metabolic syndrome in nondiabetic patients with chronic kidney disease stage 5
- 2009
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 29:5, s. 447-53
-
Tidskriftsartikel (refereegranskat)abstract
- <i>Introduction:</i> Chronic kidney disease (CKD) is associated with insulin resistance also in the absence of overt diabetes mellitus. The liver-derived transport protein retinol-binding protein (RBP) has recently been proposed as a novel adipokine involved in the metabolism of glucose. Although RBP is elevated in type 2 diabetics with mild CKD, its role in advanced CKD is not well studied. We hypothesized that altered RBP levels in CKD could be one factor contributing to the uremic insulin resistance. <i>Patients and Methods:</i> In a cross-sectional study, we evaluated 141 nondiabetic stage 5 CKD patients (GFR 6.8 ± 2.0 ml/min; 62% males, mean age 52 ± 11 years) close to the start of renal replacement therapy. We studied circulating RBP (RIA), retinol and metabolic markers. Body composition was also assessed using DEXA and patients were divided according to truncal fat mass above (obese) or below (lean) the sex-specific median. A fasting plasma glucose ≥6.1 m<i>M</i> was defined as impaired glucose tolerance (IGT). <i>Results:</i> Serum RBP levels were significantly elevated in CKD as compared to previous reports in non-renal patients. Whereas levels of RBP did not differ between lean and obese patients without IGT, they were lower in lean CKD patients with IGT (5.9 ± 2.9 μ<i>M</i>) than in obese CKD patients with IGT (7.0 ± 2.9 μ<i>M</i>; p < 0.05). While RBP did not correlate with truncal or total fat mass or biomarkers of inflammation, in univariate analysis, we found weak correlations with HbA1c% (rho = 0.17; p < 0.05), fasting serum triglycerides (rho = 0.20; p < 0.001) and fasting apolipoprotein (Apo) A1 (rho = 0.29; p < 0.001). RBP also correlated negatively with ApoB (rho = –0.29; p < 0.001). In multivariate analysis, RBP was a significant and independent predictor of both HbA1c% and ApoA1 levels. Finally, RBP was strongly correlated with serum retinol, and calculating a retinol/RBP index further strengthened the observed correlations with HOMA-IR and HbA1c%. <i>Conclusions:</i> RBP is elevated in nondiabetic stage 5 CKD and correlates weakly with HbA1c and ApoA1. As RBP is thought to induce insulin resistance and directly affect lipoprotein metabolism in other disease states, these findings may support a role for RBP in contributing to the uremic metabolic syndrome, putatively by altering ApoA1 metabolism, but further studies are needed to test this hypothesis.
|
|
| 4. |
- Bakris, George L, et al.
(författare)
-
Design and Baseline Characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease Trial.
- 2019
-
Ingår i: American Journal of Nephrology. - : S. Karger AG. - 0250-8095 .- 1421-9670. ; 50:5, s. 333-344
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Among diabetics, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality, and progression of their underlying disease. Finerenone is a novel, non-steroidal, selective mineralocorticoid-receptor antagonist which has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD), while revealing only a low risk of hyperkalemia. However, the effect of finerenone on renal and CV outcomes has not been investigated in long-term trials yet.METHODS: The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease -(FIDELIO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important renal and CV outcomes in T2D patients with CKD. FIDELIO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 5.5 years. FIDELIO-DKD randomized 5,734 patients with an estimated glomerular filtration rate (eGFR) ≥25-<75 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30-≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death.CONCLUSION: FIDELIO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of renal and CV events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.
|
|
| 5. |
- Banerjee, T, et al.
(författare)
-
Dietary Factors and Prevention: Risk of End-Stage Kidney Disease by Fruit and Vegetable Consumption
- 2021
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 52:5, s. 356-367
-
Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> The association between fruit and vegetable (FV) intake and the risk of end-stage kidney disease (ESKD) has not been examined in the general population and fully explored in chronic kidney disease (CKD). We prospectively evaluated this relationship in US representative sample of adults and evaluated consistency by the presence or absence, and severity, of CKD. <b><i>Methods:</i></b> We used data from the Third National Health and Nutrition Examination Survey (1988–1994) linked with the US Renal Data System, including 14,725 adults aged ≥20 years and with follow-up for ESKD through 2008. Daily FV intake was ascertained using a food frequency questionnaire. We examined the association between selected categories of FV intake and ESKD using a Fine Gray competing risk model adjusting for sociodemographics, lifestyle, clinical and nutritional factors, estimated glomerular filtration rate, and albuminuria. We evaluated whether risk varied in individuals with severe versus any CKD. <b><i>Results:</i></b> 230 participants (1.5%) developed ESKD during follow-up. In the adjusted model, compared to highest intake, those in lowest categories of FV intake had a higher risk of ESKD, for <2 times/day (1.45 [1.24–1.68], 2 to <3 times/day (1.40 [1.18–1.61]), 3 to <4 times/day (1.25 [1.04–1.46]), and 4 to <6 times/day (1.14 [0.97–1.31]). There was suggestion of heterogeneity (<i>p</i> for interaction = 0.03) with possible stronger inverse association in patients with CKD than those without CKD. After stratification, we obtained similar strong inverse association when we examined ESKD incidence across intake of FVs in participants with CKD stages 1–4 (<i>n</i> = 5,346) and specifically in those with CKD stages 3–4 (<i>n</i> = 1,084). <b><i>Conclusions:</i></b> Low intake of FVs was associated with higher risk of ESKD in US adults with and without CKD, supporting an emerging body of literature on the potential benefits of plant-rich diets for prevention of ESKD.
|
|
| 6. |
- Chen, M, et al.
(författare)
-
Prenatal exposure to high level of glucocorticoids increases the susceptibility of renal proximal tubular cells to apoptosis induced by uropathogenic Escherichia coli toxins
- 2004
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 0250-8095 .- 1421-9670. ; 24:5, s. 497-502
-
Tidskriftsartikel (refereegranskat)abstract
- Prenatal exposure to excessive glucocorticoids may alter the developing fetus inducing metabolic and endocrine imbalance in various organs, including the kidney. This study aimed at evaluating whether prenatal exposure to high levels of glucocorticoids adversely affects renal cell survival and predisposes to renal cell death. Pregnant rats were injected with 0.1 mg/kg dexamethasone (DEX) i.p. from day 1 of gestation. Renal proximal tubular cells (PTCs) were prepared from 20-day-old offspring in the DEX (DEX cells) and control groups (CON cells). After 4 days’ culture, cells were exposed to uropathogenic <i>Escherichia coli</i> ARD6 toxins at concentrations known to induce apoptotic cell death. We found that cell death rate was significantly higher in DEX than in CON cells. Cells exhibited morphological and biochemical features of apoptosis. Conversely, the activity of the antioxidant enzyme catalase was significantly increased in renal cortex homogenate from 20-day-old DEX rats. The antioxidant vitamin E did not prevent apoptosis. These results indicate that prenatal exposure to high levels of glucocorticoids induces alterations in renal PTCs rendering them more sensitive to <i>E. coli</i> toxins via nonoxidative stress. With the increasing use of multiple doses of glucocorticoids in preterm infants, the possibility that antenatal glucocorticoids may lead to renal adverse consequences is of clinical relevance.
|
|
| 7. |
- Chen, M, et al.
(författare)
-
Uropathogenic Escherichia coli toxins induce caspase-independent apoptosis in renal proximal tubular cells via ERK signaling
- 2003
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 0250-8095 .- 1421-9670. ; 23:3, s. 140-151
-
Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Pyelonephritis is a risk factor for renal tubular epithelial cell damage. Recent studies have shown that <i>Escherichia coli</i> and/or its toxins may stimulate apoptotic cell death in renal tubular cells, but the underlying molecular mechanisms remain to be elucidated. <i>Methods:</i> Confluent LLC-PK<sub>1</sub> cells were exposed to <i>E. coli</i> toxins from overnight cultures of the uropathogenic O6K13H1 (O6) and the nonpathogenic W3110. The cell death was studied with morphological and biological assay. <i>Results:</i><i>E. coli</i> soluble toxins from uropathogenic O6:K13:H1(O6) strain were found to induce apoptosis in a dose- and time-dependent manner in LLC-PK1 cells. The expression of FasR and the phosphorylation of ERK1/2 were significantly upregulated by O6 soluble toxins in a time-dependent manner. Cell death was completely inhibited by two specific ERK1/2 inhibitors, but not by a broad caspase inhibitor, zVAD-fmk, implicating a caspase-independent pathway via ERK. Moreover, we found that lysophosphatidic acid could trigger a survival signal through G-proteins and PI3K. <i>Conclusion:</i> We demonstrate that apoptosis induced by uropathogenic <i>E. coli</i> toxins is dependent on ERK1/2. Caspases, although being activated, are not necessary for cell death, and they act after the ERK signaling at which point cells become committed to cell death or can be rescued.
|
|
| 8. |
- Cheng, LT, et al.
(författare)
-
Sex difference in the prevalence of left ventricular hypertrophy in dialysis patients
- 2009
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 29:5, s. 398-405
-
Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Left ventricular hypertrophy (LVH) is an important, independent negative predictor of cardiovascular morbidity and mortality in the general population and in dialysis patients. Previous studies suggest a sex dimorphism in the prevalence of LVH; however, this issue has never been approached in dialysis patients. <i>Methods:</i> This study enrolled 237 prevalent dialysis patients: 49 on hemodialysis (HD) and 188 on peritoneal dialysis (PD) from a single center. LVH was defined by echocardiography measurements, which were normalized to body surface area (BSA) and height<sup>2.7</sup>, respectively. <i>Results:</i> The mean ages in HD and PD patients were 60 ± 14 and 60 ± 13 years, with a median dialysis vintage of 43 and 20 months, respectively. Although there was no significant difference in age, diabetes, proportion of uncontrolled hypertension, antihypertensive medication and blood pressure between male and female patients within each dialysis modality, the prevalence of LVH (whether indexed to BSA or height<sup>2.7</sup>) was consistently higher in females than in males. When these patients were divided into LVH or non-LVH groups, a significant difference in sex distribution was observed between the two groups (62.0% vs. 41.0% when the BSA-indexed standard was used, p < 0.01; 62.8% vs. 37.1% when the height<sup>2.7</sup>-indexed standard was used, p < 0.001). In logistic regression analysis, female sex was identified as a risk factor of LVH (odds ratio, OR = 2.48, 95% confidence interval, CI = 1.33–4.59; when BSA-indexed LVH was treated as dependent variable, and OR = 4.05, 95% CI = 1.96–8.38, when height<sup>2.7</sup>-indexed LVH was treated as dependent variable) even after adjustment for age, diabetes, blood pressure and antihypertensive medication. <i>Conclusion:</i> This study showed that the prevalence of LVH determined by echocardiography was significantly higher in female dialysis patients than in male dialysis patients. Compared with males, female patients had a 2.5- to 4-fold higher risk to develop LVH even after adjustment for other potential confounding factors, which may indicate that elderly females in the uremic scenario are more prone to develop LVH than elderly males.
|
|
| 9. |
- Cherney, DZI, et al.
(författare)
-
Initial eGFR Changes with Ertugliflozin and Associations with Clinical Parameters: Analyses from the VERTIS CV Trial
- 2022
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 53:7, s. 516-525
-
Tidskriftsartikel (refereegranskat)abstract
- <b><i>Introduction:</i></b> Using data from the ertugliflozin cardiovascular outcomes trial in patients with type 2 diabetes mellitus (VERTIS CV; NCT01986881), associations between the initial estimated glomerular filtration rate (eGFR) “dip” with eGFR slope, glucosuria/natriuresis-related measures, and safety were investigated. <b><i>Methods:</i></b> Patients were categorized into tertiles based on change in eGFR at week 6: >+1.00 mL/min/1.73 m<sup>2</sup> (tertile 1), >−5.99 and ≤+1.00 (tertile 2), and ≤−6.00 (tertile 3). eGFR slope after week 6 and week 18 was assessed by tertile. Glucosuria/natriuresis-related measures were also determined. Adverse events (AEs) were analyzed in the acute (baseline–week 6) and chronic periods (week 6–30 days after last dose of trial medication). <b><i>Results:</i></b> In the ertugliflozin group, chronic eGFR slopes (95% CI, mL/min/1.73 m<sup>2</sup>/year; weeks 6–156) were −0.76 (−1.03, −0.50), −0.29 (−0.51, −0.07), and −0.05 (−0.26, 0.17) in tertiles 1, 2, and 3, respectively (<i>p</i> value <0.001), and approximately −1.5 mL/min/1.73 m<sup>2</sup>/year across tertiles in the placebo group (<i>p</i> value = 0.79). At week 18, least squares mean (LSM) changes from baseline in glycated hemoglobin (%) were −0.77, −0.71, and −0.67 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; a similar tertile-associated trend was observed for uric acid. At week 18, LSM changes from baseline in hematocrit (%) were 2.07, 2.33, and 2.55 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; similar tertile-associated trends were observed for blood pressure. All <i>p</i><sub>interaction</sub> values were <0.0001 for glucosuria- and natriuresis-related measures. Kidney-related AEs were reported more frequently in tertiles 3 and 2 in the chronic period for both placebo- and ertugliflozin-treated groups. In both periods and in all tertiles, incidences of AEs did not differ between placebo- and ertugliflozin-treated groups. <b><i>Conclusion:</i></b> With ertugliflozin, the tertile with the largest initial dip in eGFR had a slower rate of chronic eGFR decline. Initial eGFR changes were associated with changes in both glucosuria- and natriuresis-related measures.
|
|
| 10. |
- Chertow, GM, et al.
(författare)
-
Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome
- 2021
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 52:3, s. 180-189
-
Tidskriftsartikel (refereegranskat)abstract
- <b><i>Introduction:</i></b> Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. <b><i>Methods:</i></b> The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m<sup>2</sup>, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. <b><i>Results:</i></b> A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (<i>n</i> = 77) or placebo (<i>n</i> = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m<sup>2</sup>, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m<sup>2</sup> despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. <b><i>Discussion/Conclusion:</i></b> CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.
|
|
