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1.  The importance of early referral for the treatment of chronic kidney disease: a Danish nationwide cohort study 
BMC Nephrology  2012;13:108.
Background
Many patients with advanced chronic kidney disease are referred late to renal units. This is associated with negative aspects. The purpose of the present study was to characterize late versus early referrals for renal replacement therapy including their renal disease, health care contacts and medical treatment before renal replacement therapy (RRT) and the consequences for RRT modality and mortality.
Methods
Nationwide cohort study including 4495 RRT patients identified in the Danish Nephrology Registry 1999–2006. The cohort was followed to end 2007 by linkage to other national registries. Late referral: follow-up ≤16 weeks in renal unit before RRT start. Cox proportional hazards models were used to estimate the relative risk of mortality or waiting list status within 365 days in late referrals versus early referrals.
Results
A total of 1727 (38%) incident RRT patients were referred late. Among these, 72% were treated in non-nephrology hospital departments and 91% in general practice 2 years to 16 weeks before RRT start. Fewer late referrals received recommended pre-RRT treatment as judged by renin-angiotensin-system blockade: 32% versus 57% or the D-vitamin analogue alfacalcidol: 5% versus 30% (P < .001). Primary RRT modality was peritoneal dialysis: 18% in late versus 32% in early referrals (P < .001), 7% versus 30%, respectively, had an arteriovenous dialysis-fistula (P < .001) and 0.2% versus 6% were on the waiting-list for renal transplantation (P < .001) before RRT start. One-year-mortality was higher in late referrals: hazard ratio 1.55 (CI 95% 1.35–1.78). In a subgroup, 30% (CI 95% 25–35%) late and 9% (CI 95% 6–12%) early referrals had plasma creatinine ≤150% of upper reference limit within 1 to 2 years before RRT start (P < .001).
Conclusions
Late nephrology referrals were well-known to the healthcare system before referral for RRT start and more often had near normal plasma creatinine levels within 2 years before RRT start. They infrequently received available treatment or optimal first RRT modality. An increased effort to identify these patients in the healthcare system in time for proper pre-dialysis care including preparation for RRT is needed.
doi:10.1186/1471-2369-13-108
PMCID: PMC3469388  PMID: 22963236
Chronic kidney failure; Epidemiology; Late diagnosis; Treatment; Renal replacement therapy
2.  Anti-glomerular basement membrane glomerulonephritis and thrombotic microangiopathy in first degree relatives; a case report 
BMC Nephrology  2012;13:64.
Background
Anti-glomerular basement membrane glomerulonephritis and thrombotic microangiopathy are rare diseases with no known coherence.
Case Presentation
A daughter and her biological mother were diagnosed with pregnancy-induced thrombotic microangiopathy and anti-glomerular basement membrane glomerulonephritis, respectively. Both developed end-stage renal disease. Exploration of a common aetiology included analyses of HLA genotypes, functional and genetic aspects of the complement system, ADAMTS13 activity and screening for autoantibodies.
The daughter was heterozygous carrier of the complement factor I G261D mutation, previously described in patients with membranoproliferative glomerulonephritis and atypical haemolytic uremic syndrome. The mother was non-carrier of this mutation. They shared the disease associated complement factor H silent polymorphism Q672Q (79602A>G).
Conclusion
An unequivocal functional or molecular association between these two family cases was not found suggesting that the patients probably share another, so far undiagnosed and unknown, predisposing factor. It seems highly unlikely that two infrequent immunologic diseases would occur by unrelated pathophysiological mechanisms within first degree relatives.
doi:10.1186/1471-2369-13-64
PMCID: PMC3411442  PMID: 22834933
Aetiology; Anti-glomerular basement membrane glomerulonephritis; Atypical haemolytic-uremic syndrome; Thrombotic microangiopathy
3.  Benefit of Clopidogrel Therapy in Patients With Myocardial Infarction and Chronic Kidney Disease—A Danish Nation‐Wide Cohort Study 
Background
The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD).
Methods and Results
By linking nation‐wide registries, information about patients admitted with incident MI was found. Primary endpoints were all‐cause and cardiovascular (CV) mortality, a composite of all‐cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (PCI) treatment.
A total of 69 082 incident MI patients in the period 2002–2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all‐cause mortality and recurrent MI in PCI‐treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non‐end‐stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non‐end‐stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel‐treated patients not undergoing PCI and for non‐end‐stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI‐treated RRT patients and patients without kidney disease.
Conclusions
During a 1‐year follow‐up, after MI, clopidogrel was associated with improved outcomes in patients with non‐end‐stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear.
doi:10.1161/JAHA.114.001116
PMCID: PMC4310409  PMID: 25146707
kidney; myocardial infarction; revascularization
4.  Eplerenone Attenuates Pulse Wave Reflection in Chronic Kidney Disease Stage 3–4 - A Randomized Controlled Study 
PLoS ONE  2013;8(5):e64549.
Background
Patients with chronic kidney disease (CKD) have high cardiovascular mortality and morbidity associated with increased arterial stiffness. Plasma aldosterone levels are increased in CKD, and aldosterone has been found to increase vascular inflammation and fibrosis. It was hypothesized that aldosterone receptor inhibition with eplerenone could reduce arterial stiffness in CKD stage 3–4.
Study Design
The design was randomized, open, parallel group. Measurements of arterial stiffness markers were undertaken at weeks 1 and 24.
Intervention
24 weeks of add-on treatment with 25–50 mg eplerenone or standard medication.
Outcomes
Primary outcome parameter was carotid-femoral pulse wave velocity (cfPWV). Secondary outcomes were augmentation index (AIx), ambulatory arterial stiffness index (AASI) and urinary albumin excretion.
Results
Fifty-four CKD patients (mean eGFR 36 mL/min/1.73 m2, SD 11) were randomized. Forty-six patients completed the trial. The mean difference in cfPWV changes between groups was 0.1 m/s (95%CI: −1.0, 1.3), P = 0.8. The mean difference in AIx changes between groups was 4.4% (0.1, 8.6), P = 0.04. AASI was unchanged in both groups. The ratio of change in urinary albumin excretion in the eplerenone group compared to the control was 0.61 (0.37, 1.01), P = 0.05. Four patients were withdrawn from the eplerenone group including three because of possible side effects; one was withdrawn from the control group. Mild hyperkalemia was seen on three occasions and was easily managed.
Limitations
The full planned number of patients was not attained. The duration of the trial may have been too short to obtain full effect of eplerenone on the arteries.
Conclusions
Add-on treatment with eplerenone in CKD stage 3–4 did not significantly reduce cfPWV. There may be beneficial vascular effects leading to attenuated pulse wave reflection. Treatment was well-tolerated.
Trial Registration
ClinicalTrials.gov NCT01100203
doi:10.1371/journal.pone.0064549
PMCID: PMC3660355  PMID: 23704994
5.  Beneficial Effects on Arterial Stiffness and Pulse-Wave Reflection of Combined Enalapril and Candesartan in Chronic Kidney Disease - A Randomized Trial 
PLoS ONE  2012;7(7):e41757.
Background
Cardiovascular disease (CVD) is highly prevalent in patients with chronic kidney disease (CKD). Inhibition of the renin-angiotensinsystem (RAS) in hypertension causes differential effects on central and brachial blood pressure (BP), which has been translated into improved outcome. The objective was to examine if a more complete inhibition of RAS by combining an angiotensin converting enzyme inhibitor (ACEI) and an angiotensin receptor antagonist (ARB) compared to monotherapy has an additive effect on central BP and pulse-wave velocity (PWV), which are known markers of CVD.
Methods
Sixty-seven CKD patients (mean GFR 30, range 13–59 ml/min/1.73 m2) participated in an open randomized study of 16 weeks of monotherapy with either enalapril or candesartan followed by 8 weeks of dual blockade aiming at a total dose of 16 mg candesartan and 20 mg enalapril o.d. Pulse-wave measurements were performed at week 0, 8, 16 and 24 by the SphygmoCor device.
Results
Significant additive BP independent reductions were found after dual blockade in aortic PWV (−0.3 m/s, P<0.05) and in augmentation index (−2%, P<0.01) compared to monotherapy. Furthermore pulse pressure amplification was improved (P<0.05) and central systolic BP reduced (−6 mmHg, P<0.01).
Conclusions
Dual blockade of the RAS resulted in an additive BP independent reduction in pulse-wave reflection and arterial stiffness compared to monotherapy in CKD patients.
Trial Registration
Clinical trial.gov NCT00235287
doi:10.1371/journal.pone.0041757
PMCID: PMC3409235  PMID: 22860014
6.  Silencing of Renal DNaseI in Murine Lupus Nephritis Imposes Exposure of Large Chromatin Fragments and Activation of Toll Like Receptors and the Clec4e 
PLoS ONE  2012;7(3):e34080.
Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7–9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease.
doi:10.1371/journal.pone.0034080
PMCID: PMC3316608  PMID: 22479529
7.  Moderate Antiproteinuric Effect of Add-On Aldosterone Blockade with Eplerenone in Non-Diabetic Chronic Kidney Disease. A Randomized Cross-Over Study 
PLoS ONE  2011;6(11):e26904.
Background
Reduction of proteinuria and blood pressure (BP) with blockers of the renin-angiotensin system (RAS) impairs the progression of chronic kidney disease (CKD). The aldosterone antagonist spironolactone has an antiproteinuric effect, but its use is limited by side effects. The present study evaluated the short-term antiproteinuric effect and safety of the selective aldosterone antagonist eplerenone in non-diabetic CKD.
Study Design
Open randomized cross-over trial.
Setting and Participants
Forty patients with non-diabetic CKD and urinary albumin excretion greater than 300 mg/24 hours.
Intervention
Eight weeks of once-daily administration of add-on 25–50 mg eplerenone to stable standard antihypertensive treatment including RAS-blockade.
Outcomes & Measurements
24 hour urinary albumin excretion, BP, p-potassium, and creatinine clearance.
Results
The mean urinary albumin excretion was 22% [CI: 14,28], P<0.001, lower during treatment with eplerenone. Mean systolic BP was 4 mmHg [CI: 2,6], P = 0.002, diastolic BP was 2 mmHg [CI: 0,4], P = 0.02, creatinine clearance was 5% [CI: 2,8], P = 0.005, lower during eplerenone treatment. After correction for BP and creatinine clearance differences between the study periods, the mean urinary albumin excretion was 14% [CI: 4,24], P = 0.008 lower during treatment. Mean p-potassium was 0.1 mEq/L [CI: 0.1,0.2] higher during eplerenone treatment, P<0.001. Eplerenone was thus well tolerated and no patients were withdrawn due to hyperkalaemia.
Limitations
Open label, no wash-out period and a moderate sample size.
Conclusions
In non-diabetic CKD patients, the addition of eplerenone to standard antihypertensive treatment including RAS-blockade caused a moderate BP independent fall in albuminuria, a minor fall in creatinine clearance and a 0.1 mEq/L increase in p-potassium.
Trial Registration
Clinicaltrials.gov NCT00430924
doi:10.1371/journal.pone.0026904
PMCID: PMC3208556  PMID: 22073219

Results 1-7 (7)