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Preview: Nephrology Dialysis Transplantation - current issue

Nephrology Dialysis Transplantation Current Issue





Published: Fri, 28 Jul 2017 00:00:00 GMT

Last Build Date: Tue, 01 Aug 2017 04:49:04 GMT

 



Announcements

2017-07-28

News from ERA-EDTA






Does renal denervation lower sympathetic activity?

2017-07-28

The introduction of renal denervation (RDN) in the clinical arena has been a bumpy road. Initial expectations were sky high and at least some in the field expected that results of the Symplicity-HTNIII trial would allow widespread acceptance of the therapy. We now know that this has not happened. In fact, a small number of clinical trials initiated and financed by the medical device industries are presently under the way and first results are to be expected late 2017. Despite of the fact that many papers have been published (PubMed search on ‘renal denervation and human’ on 1 May 2017: 1560 articles), the mechanism(s) by which RDN would lower blood pressure is (are) still largely unknown.



NDT Digest: rapid revelations in renal disease

2017-07-28

NDT Digest, comprising a series of brief, one-page articles is an exciting new addition to NDT. It will be published monthly and will cover a diverse range of subjects. The articles are deliberately succinct and aim to provide pertinent updates, answer common clinical dilemmas and serve as an educational resource. The directed nature of the articles and the brevity will appeal both to those in training and the established physician. Figures will be redrawn by an art designer to allow a good quality download and easy use for teaching.






Sympathetic nerve traffic and blood pressure changes after bilateral renal denervation in resistant hypertension: a time-integrated analysis

2017-07-11

Abstract
Background
Renal denervation reduces blood pressure (BP) and sympathetic drive in experimental animal models, but the effect of this intervention on sympathetic activity in patients with treatment-resistant hypertension is still unclear.
Methods
In an incident series of 29 patients with treatment-resistant hypertension, we performed serial measurements (n = 123) of muscle sympathetic nerve activity (MSNA, microneurography) and standardized BP measurements. Data were analysed by mixed linear modelling (MLM) and by regression analysis of time-integrated changes of both MSNA and synchronous, standardized (in-lab) BP measurements.
Results
Bilateral renal denervation was accompanied by a marked reduction in MSNA (P = 0.01 by MLM), which was parallelled by a reduction in systolic (from 175 ± 14 to 156 ± 16 mmHg) and, to a lesser extent, in diastolic (from 96 ± 12 to 87 ± 6 mmHg) BP over time. Neither systolic nor diastolic BP associated to a significant extent with corrected MSNA (MSNAC) in the MLM analysis (systolic BP versus MSNAC: β = −0.08, P = 0.08; diastolic BP versus MSNAC: β = −0.007, P = 0.75). However, the study of time-integrated changes in MSNA and BP showed a robust association between proportional changes in MSNA over time and simultaneous changes in systolic and diastolic BP (β = 0.61, P < 0.001 and β = 0.37 P < 0.05).
Conclusions
Time-integrated changes in MSNAC and BP after bilateral renal denervation document a close link between the sympathetic activity and BP responses to this procedure. These findings further strengthen the relevance of the sympathetic nervous system both in the pathophysiology of resistant hypertension and in the BP-lowering effect of the procedure.



Graft survival of pediatric kidney transplant recipients selected for de novo steroid avoidance—a propensity score-matched study

2017-07-11

Abstract
Background
Steroid-avoidance protocols have gained popularity in pediatric kidney transplant recipients at low immunologic risk. The long-term safety of steroid avoidance in children with immunologic risk factors remains unknown.
Methods
Pediatric kidney transplant recipients from 2004 to 2014 in the Organ Procurement and Transplantation Network database who received tacrolimus and mycophenolate immunosuppression were investigated. Propensity score matching was used to compare graft survival in 1624 children who received steroid avoidance with 1624 children who received steroid-based immunosuppression. The effect of steroid avoidance on graft failure among immunologic risk strata was estimated using Cox proportional hazards regression in this propensity score-matched cohort.
Results
It was observed that 5-year graft survival was mildly improved in children receiving steroid avoidance (84.8% versus 81.2%, P = 0.03). This improvement in graft survival occurred in the first 2 years following transplant, when the hazard ratio (HR) for allograft failure in children receiving steroid avoidance was 0.62 [95% confidence interval (CI) 0.45–0.86]. In contrast, steroid avoidance was not associated with improved allograft survival during Years 2–10 following transplant (HR = 0.93; 95% CI 0.75–1.15). During this time period, HRs (95% CIs) for allograft failure within immunologic risk strata were not significantly different from the null value of 1: repeat kidney transplants, 1.84 (0.84–4.05); African-Americans, 1.02 (0.67–1.56); sensitized recipients, 1.24 (0.63–2.43); recipients of deceased donor kidneys, 1.02 (0.79–1.32); recipients of completely human leukocyte antigen-mismatched kidneys, 0.80 (0.47–1.37); and recipients with pretransplant glomerular disease, 0.94 (0.71–1.23).
Conclusions
In pediatric kidney transplant recipients receiving tacrolimus- and mycophenolate-based immunosuppression, steroid avoidance can be safely practiced in children with immunologic risk factors.



De novo low-dose sirolimus versus mycophenolate mofetil in combination with extended-release tacrolimus in kidney transplant recipients: a multicentre, open-label, randomized, controlled, non-inferiority trial

2017-06-26

Abstract
Background
Most of the previous studies reported that tacrolimus (TAC) with sirolimus (SRL) was associated with worse post-transplant outcomes in kidney transplantation, compared with TAC with mycophenolate mofetil (MMF). These might be attributable to high-dose SRL. However, outcomes using low-dose SRL with TAC for kidney transplantation are uncertain. The aim of this study was to assess the efficacy and safety of low-dose SRL with extended-release tacrolimus (ER-TAC) versus MMF with ER-TAC.
Methods
We randomly assigned 158 renal transplant patients to receive low-dose SRL or MMF in combination with ER-TAC and corticosteroid. The primary endpoint was the composite efficacy failure rate, including biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up, within 12 months post-transplantation. This trial is registered with ClinicalTrial.gov (number NCT01680952).
Results
The efficacy failure rate was 6.6% in the low-dose SRL group and 13.3% in the MMF group in the intention-to-treat population (absolute difference, 6.8%; 95% confidence interval, −2.8% to 16.3%). The incidence of BPAR within 12 months post-transplantation was 5.3% in the low-dose SRL group and 13.3% in the MMF group (P = 0.09). The mean estimated glomerular filtration rate at 12 months post-transplantation was 53.2 mL/min/1.73 m2 in the low-dose SRL group and 52.4 mL/min/1.73 m2 in the MMF group (P = 0.76). The incidences of adverse events and serious adverse events were similar between groups.
Conclusion
Low-dose SRL with ER-TAC was not inferior to MMF with ER-TAC with respect to efficacy and safety. When used for immunosuppression in kidney transplantation, low-dose SRL with ER-TAC can effectively prevent acute rejection and preserve renal function.



Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China

2017-03-27

Abstract
Background
FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD).
Methods
In the NDD study, 91 participants were randomized to low (1.1–1.75 mg/kg) or high (1.50–2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1–1.8 mg/kg), medium (1.5–2.3 mg/kg) and high (1.7–2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed.
Results
In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects.In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects.
Conclusions
FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.



Sphingosine-1-phosphate and its receptors in anti-neutrophil cytoplasmic antibody-associated vasculitis

2017-02-16

Abstract
Background
C5a plays a crucial role in anti-neutrophil cytoplasmic antibody (ANCA)–mediated neutrophil recruitment and activation. Our previous studies found that the interaction between sphingosine-1-phosphate (S1P) and C5a plays an important role in the ANCA-mediated activation of neutrophils. In the current study, the expression levels of S1P in plasma and its receptors (S1PR1–5) in kidneys were analysed in patients with ANCA-associated vasculitis (AAV).
Methods
Plasma samples from 32 AAV patients in active stage and 20 AAV patients in remission were collected. The plasma levels of S1P were determined by an enzyme-linked immunosorbent assay (ELISA). The expression of S1PR1–5 in the renal specimens from 24 AAV patients was detected by immunohistochemistry. The associations of the plasma levels of S1P and renal expression of S1PRs with clinical and pathological parameters were analysed.
Results
The level of plasma S1P was significantly higher in AAV patients in active stage than it was in both patients in remission and in normal controls. Correlation analysis showed that the plasma levels of S1P correlated with the initial serum creatinine levels (r = 0.502, P=0.003) and inversely correlated with the estimated glomerular filtration rate (eGFR; r = −0.358, P=0.044) in AAV patients. Double-labelling immunofluorescence assay suggested that S1PR1–5 were expressed on endothelial cells in the glomeruli and that S1PR1, 4 and 5 were expressed on neutrophils.
Conclusions
In AAV patients, the circulating S1P levels were elevated and the renal expression of S1PR2–5 was upregulated. The levels of circulating S1P and the renal expression of S1PR were associated with the renal involvement and disease activity of AAV.



Haemodialysis acutely deteriorates left and right diastolic function and myocardial performance: an effect related to high ultrafiltration volumes?

2016-10-13

Abstract
Background
The effect of acute preload reduction during haemodialysis on left ventricle (LV) and right ventricle (RV) function is not well understood. This study aimed to evaluate acute changes in novel echocardiographic and tissue Doppler-derived indices of LV and RV function during the first and a standard weekly dialysis session and to examine the possible effect of acute intradialytic volume changes in LV and RV diastolic function and pulmonary circulation loading.
Methods
Forty-one adult patients receiving standard thrice-weekly haemodialysis participated in this study. Two-dimensional echocardiographic and tissue Doppler imaging (TDI) studies were performed with a standard cardiac ultrasound device (Vivid 7 or Vivid e, GE, Horton, Norway) shortly before and after the first weekly and a standard dialysis session. Multiple linear regression analysis was applied to assess the effect of volume changes on peak early mitral (E) and tricuspid (E RV) velocities changes.
Results
Significant reductions from pre- to post-haemodialysis were noted in body weight and systolic blood pressure. Post-haemodialysis left and right atrial, LV and RV sizing echocardiographic parameters were lower. LV systolic function, represented by LV ejection fraction, cardiac output and mean peak systolic LV and RV velocities at the annulus level, was unchanged. Diastolic function indices such as E (first session: 0.96 ± 0.28 versus 0.75 ± 0.27 m/s, P < 0.001; standard session: 0.89 ± 0.24 versus 0.78 ± 0.29, P < 0.001) and E RV (first session: 0.89 ± 0.26 versus 0.67 ± 0.25 m/s, P < 0.001; standard session: 0.86 ± 0.24 versus 0.77 ± 0.31, P < 0.001), E/A LV ratio, TDI peak early mitral (E′) velocity and E′/A′ RV ratio were reduced after haemodialysis. Pulmonary circulation loading, represented by RV systolic pressure, was significantly improved. In multiple regression model analysis, intradialytic weight loss was independently associated with changes in E [β = 0.042 (95% CI 0.018–0.066)] and E RV [β = 0.084 (95% CI 0.057–0.110)].
Conclusions
This study shows that haemodialysis deteriorates cardiac diastolic function indices and improves pulmonary circulation loading, while systolic function remains unchanged. High intradialytic volume removal may affect cardiac diastolic function.



Echocardiographic associates of atrial fibrillation in end-stage renal disease

2016-09-29

Abstract
Background
The prevalence of atrial fibrillation (AF) in end-stage renal disease (ESRD) patients is relatively high. The present study evaluated the association between left atrial (LA) remodelling, including an increased size and myocardial fibrosis, and slow LA conduction and the occurrence of AF.
Methods
In 171 ESRD patients enrolled in the Implantable Cardioverter Defibrillators in Dialysis patients (ICD2) trial, the LA dimensions, LA conduction delay [as reflected by the time difference between P-wave onset on surface electrocardiogram and A′-wave on tissue Doppler imaging (PA-TDI)] and LA function were compared between patients who exhibited AF versus patients without AF. Based on ICD remote monitoring or clinical records, the occurrence of AF was detected.
Results
Of 171 patients, 47 (27%) patients experienced AF. Despite comparable left ventricular ejection fraction and prevalence of significant mitral regurgitation, patients with AF had significantly larger LA volume index (mean ± standard deviation) (29 ± 11 versus 23 ± 10 mL/m2, P = 0.001), longer PA-TDI duration (144 ± 30 versus 131 ± 27 ms, P = 0.010) and reduced late diastolic mitral annular velocity (A′) (7.1 ± 2.8 versus 8.2 ± 2.4 cm/s, P = 0.012) compared with patients without AF. On multivariable analysis, larger LA volume index [odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01–1.08, P = 0.017], longer PA-TDI duration (OR 1.02, 95% CI 1.00–1.03, P = 0.025) and reduced A′ (OR 0.84, 95% CI 0.72–0.98, P = 0.025) were independently associated with AF after adjusting for age and left ventricle diastolic relaxation.
Conclusion
ESRD patients with AF show more advanced changes in the LA substrate than ESRD patients without AF.



Engagement in decision-making and patient satisfaction: a qualitative study of older patients' perceptions of dialysis initiation and modality decisions

2016-08-30

Abstract
Background
Although shared decision-making (SDM) can better align patient preferences with treatment, barriers remain incompletely understood and the impact on patient satisfaction is unknown.
Methods
This is a qualitative study with semistructured interviews. A purposive sample of prevalent dialysis patients ≥65 years of age at two facilities in Greater Boston were selected for diversity in time from initiation, race, modality and vintage. A codebook was developed and interrater reliability was 89%. Codes were discussed and organized into themes.
Results
A total of 31 interviews with 23 in-center hemodialysis patients, 1 home hemodialysis patient and 7 peritoneal dialysis patients were completed. The mean age was 76 ± 9 years. Two dominant themes (with related subthemes) emerged: decision-making experiences and satisfaction, and barriers to SDM. Subthemes included negative versus positive decision-making experiences, struggling for autonomy, being a ‘good patient’ and lack of choice. In spite of believing that dialysis initiation should be the patient's choice, no patients perceived that they had made a choice. Patients explained that this is due to the perception of imminent death or that the decision to start dialysis belonged to physicians. Clinicians and family frequently overrode patient preferences, with patient autonomy honored mostly to select dialysis modality. Poor decision-making experiences were associated with low treatment satisfaction.
Conclusions
Despite recommendations for SDM, many older patients were unaware that dialysis initiation was voluntary, held mistaken beliefs about their prognosis and were not engaged in decision-making, resulting in poor satisfaction. Patients desired greater information, specifically focusing on the acuity of their choice, prognosis and goals of care.



Risk of pulmonary embolism in patients with end-stage renal disease receiving long-term dialysis

2016-07-22

Abstract
Background
This study compared the pulmonary embolism (PE) risks between Asian dialysis patients and a comparison cohort without clinical kidney disease.
Methods
From the National Health Insurance claims data of Taiwan, we identified 106 231 newly diagnosed end-stage renal disease patients undergoing dialysis in 1998–2010 and randomly selected 106 231 comparison subjects, frequency matched by age, sex and the index year. We further selected 7430 peritoneal dialysis (PD) patients and 7340 propensity score-matched hemodialysis (HD) patients. Incidence rates and hazard ratios (HRs) of PE and odds ratio (OR) of subsequent 30-day deaths from PE were evaluated among study cohorts by the end of 2011.
Results
The overall incident PE was nearly 3-fold greater in dialysis patients than in the comparison cohort (0.92 versus 0.33 per 1000 person-years), with an adjusted HR of 2.02 [95% confidence interval (CI) = 1.63–2.50]. The PE incidence was greater in the propensity score-matched HD patients, than in PD patients with an adjusted HR of 2.30 (95% CI = 1.23–4.29). There was a greater PE risk for central venous catheter users than non-users among HD patients (1.83 versus 0.75 per 1000 person-years). The 30-day mortality from PE was higher in dialysis patients than in the comparison cohort (16.5 versus 9.77%) with an adjusted OR of 2.56 (95% CI = 1.32–4.95).
Conclusions
Dialysis patients are at a nearly 2-fold increased hazard of developing PE and are at greater risk of fatality from PE compared with those without clinical kidney disease. This study also shows a higher PE risk in HD patients than in PD patients.



Macrophages in diabetic nephropathy in patients with type 2 diabetes

2016-07-14

Abstract
Background
Inflammation plays a role in the development of diabetic nephropathy (DN) in type 2 diabetes. Although macrophages have been found in experimental models of DN, little is known regarding the presence of macrophages in patients with DN. Therefore, we investigated the presence and phenotype of glomerular and interstitial macrophages in relation to clinical and histopathological parameters in patients with DN.
Methods
Renal autopsy samples were obtained from 88 type 2 diabetic patients with histologically proven DN and stained for CD68 and CD163 as general and M2/anti-inflammatory markers of macrophages. Renal damage was scored based on histopathological classification of DN. Control renal autopsy samples were obtained from patients without renal abnormalities and from diabetic patients without DN. Positive cells per glomerulus were counted. Interstitial macrophages were counted semi-quantitatively.
Results
Macrophages were present in all groups. In the DN group, the mean number of CD68+ cells per glomerulus and CD163+ cells per glomerulus was 4.2 (range 0–19) and 2.1 (range 0–14.47), respectively. The distribution was similar between all histopathological classes. Glomerular CD163+ macrophages were positively associated with DN class, interstitial fibrosis and tubular atrophy, and glomerulosclerosis. Interstitial CD68+ macrophages were correlated with glomerular filtration rate stage and albuminuria.
Conclusions
Our results demonstrate that macrophages are present in the glomeruli and interstitium of type 2 diabetic patients with DN and of controls. Although patients and controls had similar numbers of glomerular macrophages, glomerular anti-inflammatory CD163+ macrophages were associated with pathological lesions in DN. Taken together with the correlation between interstitial macrophages and interstitial fibrosis and tubular atrophy, DN class, and renal function, this finding suggests that macrophages may play a role in DN progression. Therefore, targeting macrophages may be a promising new therapy for inhibiting the progression of DN.



Iron-related parameters in dialysis patients treated with sucroferric oxyhydroxide

2016-06-24

Abstract
Background
Sucroferric oxyhydroxide is a non-calcium, iron-based phosphate binder indicated for the treatment of hyperphosphataemia in adult dialysis patients. This post hoc analysis of a randomized, 24-week Phase 3 study and its 28-week extension was performed to evaluate the long-term effect of sucroferric oxyhydroxide on iron parameters.
Methods
A total of 1059 patients were randomized to sucroferric oxyhydroxide 1.0–3.0 g/day (n = 710) or sevelamer carbonate (‘sevelamer’) 2.4–14.4 g/day (n = 349) for up to 52 weeks. The current analysis only included patients who completed 52 weeks of continuous treatment (n = 549). Changes in iron-related parameters and anti-anaemic product use during the study were measured.
Results
Some changes in iron-related parameters across both treatment groups were observed during the first 24 weeks of the study, and to a lesser extent with longer-term treatment. There were small, but significantly greater increases in mean transferrin saturation (TSAT) and haemoglobin levels with sucroferric oxyhydroxide versus sevelamer during the first 24 weeks (change in TSAT: +4.6% versus +0.6%, P = 0.003; change in haemoglobin: +1.6 g/L versus −1.1 g/L, P = 0.037). Mean serum ferritin concentrations also increased from Weeks 0 to 24 with sucroferric oxyhydroxide and sevelamer (+119 ng/mL and +56.2 ng/mL respectively; no statistically significant difference between groups). In both treatment groups, ferritin concentrations increased to a greater extent in the overall study population [>70% of whom received concomitant intravenous (IV) iron], compared with the subset of patients who did not receive IV iron therapy during the study. The pattern of anti-anaemic product use was similar in both treatment groups, with a trend towards higher use of IV iron and erythropoiesis-stimulating agents with sevelamer.
Conclusions
Initial increases in some iron-related parameters were observed in both treatment groups but were more pronounced with sucroferric oxyhydroxide. These differences between treatment groups with respect to changes in iron parameters are likely due to minimal iron absorption from sucroferric oxyhydroxide.



Prevalence of autosomal dominant polycystic kidney disease in the European Union

2016-06-20

Abstract
Background
Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease, but estimates of its prevalence vary by >10-fold. The objective of this study was to examine the public health impact of ADPKD in the European Union (EU) by estimating minimum prevalence (point prevalence of known cases) and screening prevalence (minimum prevalence plus cases expected after population-based screening).
Methods
A review of the epidemiology literature from January 1980 to February 2015 identified population-based studies that met criteria for methodological quality. These examined large German and British populations, providing direct estimates of minimum prevalence and screening prevalence. In a second approach, patients from the 2012 European Renal Association‒European Dialysis and Transplant Association (ERA–EDTA) Registry and literature-based inflation factors that adjust for disease severity and screening yield were used to estimate prevalence across 19 EU countries (N = 407 million).
Results
Population-based studies yielded minimum prevalences of 2.41 and 3.89/10 000, respectively, and corresponding estimates of screening prevalences of 3.3 and 4.6/10 000. A close correspondence existed between estimates in countries where both direct and registry-derived methods were compared, which supports the validity of the registry-based approach. Using the registry-derived method, the minimum prevalence was 3.29/10 000 (95% confidence interval 3.27–3.30), and if ADPKD screening was implemented in all countries, the expected prevalence was 3.96/10 000 (3.94–3.98).
Conclusions
ERA–EDTA-based prevalence estimates and application of a uniform definition of prevalence to population-based studies consistently indicate that the ADPKD point prevalence is <5/10 000, the threshold for rare disease in the EU.



Clinical associations of total kidney volume: the Framingham Heart Study

2016-06-18

Abstract
Background
Total kidney volume (TKV) is an imaging biomarker that may have diagnostic and prognostic utility. The relationships between kidney volume, renal function and cardiovascular disease (CVD) have not been characterized in a large community-dwelling population. This information is needed to advance the clinical application of TKV.
Methods
We measured TKV in 1852 Framingham Heart Study participants (mean age 64.1 ± 9.2 years, 53% women) using magnetic resonance imaging. A healthy sample was used to define reference values. The associations between TKV, renal function and CVD risk factors were determined using multivariable logistic regression analysis.
Results
Overall, mean TKV was 278 ± 54 cm3 for women and 365 ± 66 cm3 for men. Risk factors for high TKV (>90% healthy referent size) were body surface area (BSA), diabetes, smoking and albuminuria, while age, female and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 were protective. Participants with high TKV had higher odds of diabetes [odds ratio (OR) 2.15, P < 0.001] and lower odds of eGFR <60 mL/min/1.73 m2 (OR 0.32, P = 0.007). Risk factors for low TKV (<10% healthy referent size) were age, female and eGFR <60 mL/min/1.73 m2, while BSA and diabetes were protective. Participants with low TKV had higher odds of eGFR <60 mL/min/1.73 m2 (OR 6.12, P < 0.001) and albuminuria (OR 1.56, P = 0.03).
Conclusions
Low TKV is associated with markers of kidney damage including albuminuria and eGFR <60 mL/min/1.73 m2, while high TKV is associated with diabetes and decreased odds of eGFR <60 mL/min/1.73 m2. Prospective studies are needed to characterize the natural progression and clinical consequences of TKV.



Association between vascular access creation and deceleration of estimated glomerular filtration rate decline in late-stage chronic kidney disease patients transitioning to end-stage renal disease

2016-05-28

Abstract
Background
Prior studies have suggested that arteriovenous fistula (AVF) or graft (AVG) creation may be associated with slowing of estimated glomerular filtration rate (eGFR) decline. It is unclear if this is attributable to the physiological benefits of a mature access on systemic circulation versus confounding factors.
Methods
We examined a nationwide cohort of 3026 US veterans with advanced chronic kidney disease (CKD) transitioning to dialysis between 2007 and 2011 who had a pre-dialysis AVF/AVG and had at least three outpatient eGFR measurements both before and after AVF/AVG creation. Slopes of eGFR were estimated using mixed-effects models adjusted for fixed and time-dependent confounders, and compared separately for the pre- and post-AVF/AVG period overall and in patients stratified by AVF/AVG maturation. In all, 3514 patients without AVF/AVG who started dialysis with a catheter served as comparators, using an arbitrary 6-month index date before dialysis initiation to assess change in eGFR slopes.
Results
Of the 3026 patients with AVF/AVG (mean age 67 years, 98% male, 75% diabetic), 71% had a mature AVF/AVG at dialysis initiation. eGFR decline accelerated in the last 6 months prior to dialysis in patients with a catheter (median, from −6.0 to −16.3 mL/min/1.73 m2/year, P < 0.001), while a significant deceleration of eGFR decline was seen after vascular access creation in those with AVF/AVG (median, from −5.6 to −4.1 mL/min/1.73 m2/year, P < 0.001). Findings were independent of AVF/AVG maturation status and were robust in adjusted models.
Conclusions
The creation of pre-dialysis AVF/AVG appears to be associated with eGFR slope deceleration and, consequently, may delay the onset of dialysis initiation in advanced CKD patients.



Ursolic acid improves podocyte injury caused by high glucose

2015-11-13

Abstract
Background
Autophagy plays an important role in the maintenance of podocyte homeostasis. Reduced autophagy may result in limited renal cell function during exposure to high glucose conditions. In this study we investigated the effects of ursolic acid (UA) on autophagy and podocyte injury, which were induced by high glucose.
Methods
Conditionally immortalized murine podocytes were cultured in media supplemented with high glucose and the effects of the PI3K inhibitor LY294002 and UA on protein expression were determined. miR-21 expression was detected by real-time RT-PCR. Activation of the PTEN-PI3K/Akt/mTOR pathway, expression of autophagy-related proteins and expression of podocyte marker proteins were determined by western blot. Immunofluorescence was used to monitor the accumulation of LC3 puncta. Autophagosomes were also observed by transmission electron microscopy.
Results
During exposure to high glucose conditions, the normal level of autophagy was reduced in podocytes, and this defective autophagy induced podocyte injury. Increased miR-21 expression, decreased PTEN expression and abnormal activation of the PI3K/Akt/mTOR pathway were observed in cells that were cultured in high glucose conditions. UA and LY294002 reduced podocyte injury through the restoration of defective autophagy. Our data suggest that UA inhibits miR-21 expression and increases PTEN expression, which in turn inhibits Akt and mTOR and restores normal levels of autophagy.
Conclusions
Our data suggest that podocyte injury is associated with reduced levels of autophagy during exposure to high glucose conditions, UA attenuated podocyte injury via an increase in autophagy through miR-21 inhibition and PTEN expression, which inhibit the abnormal activation of the PI3K/Akt/mTOR pathway.



Why creating standardized core outcome sets for chronic kidney disease will improve clinical practice

2015-10-23

Abstract
Chronic kidney disease (CKD) is common and is associated with increased mortality, morbidity and cost. However, insufficient high-quality trial data are available to answer many relevant clinical questions in this field. In addition, a wide range of variable outcomes are used in studies, and often they are incompletely reported. Furthermore, there is a lack of patient-relevant outcomes, such as mortality, morbidity, quality of life, pain, need for dialysis or costs. Common problems with outcome reporting are as follows: choosing the wrong domains to measure; within domains, choosing the wrong measures (invalid surrogates, composite, non-patient relevant); within measures, choosing the wrong/variable metrics; and within metrics, choosing variable presentation methods. With this article, we aim to underline why standardized outcome reporting is key to achieving evidence-based guidance and improving clinical care for patients; highlight the frameworks available for achieving core outcome sets; and starting from these frameworks, we propose steps needed to develop a core outcome set in the field of CKD. We hope that standardized core outcome sets for nephrology will lead to the most important outcome of guideline production, improving outcomes for our patients.



Insulin resistance and vascular dysfunction in chronic kidney disease: mechanisms and therapeutic interventions

2015-09-15

Abstract
Insulin resistance (IR) is a novel cardiovascular risk factor that has been implicated in the pathogenesis of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Beyond its metabolic effects, insulin can potentially mediate the increased risk for CVD through its vasoactive properties. This review examines key clinical data and potential mechanisms linking IR and cardiovascular risk in CKD. While lifestyle interventions and pharmacotherapies with known insulin-sensitizing properties are promising therapeutic targets to reduce the CVD burden in this population, clinical trial data on the effect of insulin sensitization on vascular function in CKD are either lacking or conflicting and are limited by small sample size and short duration of intervention. Affirming the role of IR in lowering CVD risk in CKD will require prospective randomized controlled studies with sufficient sample size and hard clinical outcomes. Future research efforts should be directed at assessing the efficacy, safety and mechanisms by which novel insulin sensitizers such as bile acid sequestrant, selective and dual peroxisome proliferator-activated receptor modulators and modulators of gut microbiota and uraemic toxins alter vascular function in patients with CKD.



Sodium restriction potentiates the renoprotective effects of combined vitamin D receptor activation and angiotensin-converting enzyme inhibition in established proteinuric nephropathy

2015-08-25

Abstract
Background
Renin–angiotensin–aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator (VDRA) treatment reduces proteinuria, inflammation and fibrosis, but whether these effects depend on sodium intake has not been studied. We hypothesized that the renoprotective effects of VDRA treatment, with or without RAAS blockade, are modulated by sodium intake.
Methods
Six weeks after the induction of adriamycin nephrosis in Wistar rats, i.e. with established proteinuria, animals were treated with the VDRA paricalcitol, lisinopril, the combination, or vehicle; each treatment was given during either a high- (2% NaCl) or a low-sodium (0.05% NaCl) diet for 6 weeks. We assessed proteinuria, blood pressure, renal macrophage accumulation and renal expression of the pre-fibrotic marker alpha-smooth muscle actin (α-SMA) at the end of the treatment.
Results
Both paricalcitol and lisinopril individually, as well as in combination, reduced proteinuria and glomerular and interstitial inflammation during a low-sodium diet, but not during a high-sodium diet. All interventions also reduced focal glomerulosclerosis and interstitial expression of α-SMA during the low-sodium diet, while similar trends were observed during the high-sodium diet. The renoprotective effects of paricalcitol were not accompanied by blood pressure reduction. As proteinuria was already abolished by lisinopril during the low-sodium diet, the addition of paricalcitol had no further effect on proteinuria or downstream inflammatory or pre-fibrotic changes.
Conclusion
The renoprotective effects of the VDRA paricalcitol are blood pressure independent but do depend on dietary sodium status. The combination of RAAS blockade, dietary sodium restriction and VDRA may be a promising intervention to further retard renal function loss in CKD.



Complement in ANCA-associated glomerulonephritis

2015-08-14

Abstract
Background
Anti-neutrophil cytoplasmic antibodies (ANCA) are found in pauci-immune necrotizing crescentic glomerulonephritis. In the past, the role of complement in ANCA-associated vasculitis (AAV) was assumed to be minimal. More recently, however, it was found that blocking the complement cascade in a mouse model of AAV reduces glomerular damage. Immune complex deposits have been found in biopsies from AAV patients. In this study, we questioned whether immune complex formation or deposition may result in complement activation in ANCA-associated glomerulonephritis.
Methods
ANCA-positive patients from the Limburg Renal Registry were included between 1979 and 2011. Renal histology was documented together with immunoglobulin and complement immunofluorescence. In addition, C3d, properdin, C4d and mannose-binding lectin (MBL) were stained. Electron microscopy was performed. Circulating immune complexes were determined in a subset of patients, as well as C3 allotypes.
Results
C3c was found in 78 of 187 renal biopsies (41.7%) divided over 32.3% of proteinase-3 (PR3)-AAV patients and 52.3% of myeloperoxidase (MPO)-AAV patients (P = 0.006), whereas C3d was found positive in 51.1% of PR3-AAV patients and 70.4% of MPO-AAV patients (P = 0.105). C4d was found positive in 70.8%, properdin in 38.7% and MBL in 30.4% of patients. Whereas C4d and MBL positivity was similar between the AGN groups, properdin was more common in biopsies classified as crescentic compared with biopsies classified as focal or mixed. Renal biopsies positive for C3d and/or properdin showed more cellular crescents and less normal glomeruli compared with biopsies negative for C3d and/or properdin (P < 0.05). In 3 out of 43 renal biopsies analysed by electron microscopy, small electron dense deposits were found. In 14 of 46 patients analysed, circulating immune complexes were detectable. No association between histological findings and C3 allotypes was found.
Conclusions
In the majority of AAV patients, no immune complex deposits were found in their renal biopsies. C3d, C4d and C5b-9 staining, however, was found to be positive in a majority of analysed renal biopsies. Importantly, C3d and properdin staining was associated with cellular crescents. We hypothesize that local immune complexes are quickly degraded in AAV and therefore not visible by electron microscopy. Our findings are compatible with the hypothesis that complement activation in AAV occurs predominantly via alternative pathway activation.



Histologic versus clinical remission in proliferative lupus nephritis

2015-08-06

Abstract
Background
Treatment response in lupus nephritis (LN) is defined clinically, without consideration of renal histology. Few studies have systematically examined histologic responses to induction therapy. In LN patients who underwent protocol kidney biopsies after induction immunosuppression, we describe the renal histology of the second biopsy and correlate histologic activity and damage with short- and long-term kidney outcomes.
Methods
Patients with suspected LN were biopsied for diagnosis (Biopsy 1), and those with proliferative LN were rebiopsied after induction (Biopsy 2). Histologic activity and damage at each biopsy were calculated as the National Institutes of Health activity and chronicity indices. Complete and partial renal responses after induction and after long-term follow-up were determined clinically.
Results
One-third of patients who achieved a complete clinical response after induction had persistently high histologic activity, and 62% of patients who had complete histologic remission on rebiopsy were still clinically active. Chronic renal damage increased after induction even in complete clinical responders. Chronicity at Biopsy 2 associated with long-term kidney function and development of chronic kidney disease.
Conclusions
Early clinical and histologic outcomes are discordant in proliferative LN, and neither correlates with long-term renal outcome. The kidney accrues chronic damage rapidly and despite clinical response in LN. Preservation of kidney function may require therapeutic targeting of both chronic damage and inflammation during LN induction treatment.