The influence of multiple episodes of acute kidney injury on survival and progression to end stage kidney disease in patients with chronic kidney disease.

BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are common syndromes associated with significant morbidity, mortality and cost. The extent to which repeated AKI episodes may cumulatively affect the rate of progression of all-cause CKD has not previously been investigated. In this study, we explored the hypothesis that repeated episodes of AKI increase the rate of renal functional deterioration loss in patients recruited to a large, all-cause CKD cohort. METHODS: Patients from the Salford Kidney Study (SKS) were considered. Application of KDIGO criteria to all available laboratory measurements of renal function identified episodes of AKI. A competing risks model was specified for four survival events: Stage 1 AKI; stage 2 or 3 AKI; dialysis initiation or transplant before AKI event; death before AKI event. The model was adjusted for patient age, gender, smoking status, alcohol intake, diabetic status, cardiovascular co-morbidities, and primary renal disease. Analyses were performed for patients' first, second, and third or more AKI episodes. RESULTS: A total of 48,338 creatinine measurements were available for 2287 patients (median 13 measures per patient [IQR 6-26]). There was a median age of 66.8years, median eGFR of 28.4 and 31.6% had type 1 or 2 diabetes. Six hundred and forty three (28.1%) patients suffered one or more AKI events; 1000 AKI events (58% AKI 1) in total were observed over a median follow-up of 2.6 years [IQR 1.1-3.2]. In patients who suffered an AKI, a second AKI was more likely to be a stage 2 or 3 AKI than stage 1 [HR 2.04, p 0.01]. AKI events were associated with progression to RRT, with multiple episodes of AKI progressively increasing likelihood of progression to RRT [HR 14.4 after 1 episode of AKI, HR 28.4 after 2 episodes of AKI]. However, suffering one or more AKI events was not associated with an increased risk of mortality. CONCLUSIONS: AKI events are associated with more rapid CKD deterioration as hypothesised, and also with a greater severity of subsequent AKI. However, our study did not find an association of AKI with increased mortality risk in this CKD cohort.

Cardiac structure and function after revascularization versus medical therapy for renal artery stenosis: the ASTRAL heart echocardiographic sub-study.

BACKGROUND: The ASTRAL trial showed no difference in clinical outcomes between medical therapy and revascularization for atherosclerotic renal vascular disease (ARVD). Here we report a sub-study using echocardiography to assess differences in cardiac structure and function at 12 months. METHODS: ASTRAL patients from 7 participating centres underwent echocardiography at baseline and 12 months after randomisation. Changes in left ventricular ejection fraction (LVEF), left ventricular mass (LVM), left atrial diameter (LAD), aortic root diameter (AoRD), E:A, and E deceleration time (EDT) were compared between study arms. Analyses were performed using t-tests and multivariate linear regression. RESULTS: Ninety two patients were included (50 medical versus 42 revascularization). There was no difference between arms in any baseline echocardiographic parameter. Comparisons of longitudinal changes in echocardiographic measurements were: δLVEF medical 0.8 ± 8.7% versus revascularization - 2.8 ± 6.8% (p = 0.05), δLVM - 2.9 ± 33 versus - 1.7 ± 39 g (p = 0.9), δLAD 0.1 ± 0.4 versus 0.01 ± 0.5 cm (p = 0.3), δAoRD 0.002 ± 0.3 versus 0.06 ± 0.3 cm (p = 0.4), δE:A - 0.0005 ± 0.6 versus 0.03 ± 0.7 (p = 0.8), δEDT - 1.1 ± 55.5 versus - 9.0 ± 70.2 ms (p = 0.6). In multivariate models, there were no differences between treatment groups for any parameter at 12 months. Likewise, change in blood pressure did not differ between arms (mean δsystolic blood pressure medical 0 mmHg [range - 56 to + 54], revascularization - 3 mmHg [- 61 to + 59], p = 0.60). CONCLUSIONS: This sub-study did not show any significant differences in cardiac structure and function accompanying renal revascularization in ASTRAL. Limitations include the small sample size, the relative insensitivity of echocardiography, and the fact that a large proportion of ASTRAL patient population had only modest renal artery stenosis as described in the main study.

Design of a clinical risk calculator for major clinical outcomes in patients with atherosclerotic renovascular disease.

BACKGROUND: Risk stratification in atherosclerotic renovascular disease (ARVD) can influence treatment decisions and facilitate patient selection for revascularization. In this study, we aim to use variables with the best predictive value to design a risk calculator that can assist clinicians with risk stratification and outcome prediction. METHODS: Patients with a radiological diagnosis of ARVD referred to our tertiary renal centre were recruited into this prospective cohort study between 1986 and 2014. Primary clinical endpoints included: death, progression to end-stage kidney disease and cardiovascular events (CVE). A stepwise regression model was used to select variables with the most significant hazard ratio for each clinical endpoint. The risk calculator was designed using Hypertext Markup Language. Survival and CVE-free survival were estimated at 1, 5 and 10 years. RESULTS: In total, 872 patients were recruited into the Salford ARVD study with a median follow-up period of 54.9 months (interquartile range 20.2-96.0). Only models predicting death and CVE showed good performance (C-index >0.80). Survival probabilities obtained from the risk calculator show that most patients with ARVD have reduced long-term survival. Revascularization improved outcomes in patients with higher baseline estimated glomerular filtration rate and lower proteinuria but not in those with co-existing comorbidities and higher levels of baseline proteinuria. CONCLUSIONS: Although this risk calculator requires further independent validation in other ARVD cohorts, this study shows that a small number of easily obtained variables can help predict clinical outcomes and encourage a patient-specific therapeutic approach.

The effect of revascularization in patients with anatomically significant atherosclerotic renovascular disease presenting with high-risk clinical features.

Background: Patients with atherosclerotic renovascular disease (ARVD) and high-risk clinical presentations have largely been excluded from randomized controlled trials comparing renal revascularization and optimal medical therapy. Here, we explore the effect of revascularization on death, progression to end-stage kidney disease (ESKD) and cardiovascular events (CVE) in a highly selected cohort of patients with ARVD. Methods: All patients with a radiological diagnosis of ARVD referred to our tertiary centre have been recruited into a single-centre cohort study between 1986 and 2014. Patients with ≥70% unilateral or bilateral ARVD together with one or more of the following putative high-risk presentations were designated 'high-risk': flash pulmonary oedema (FPE), severe hypertension, rapidly deteriorating renal function. The effect of revascularization on clinical outcomes in high-risk patients, patients with bilateral severe ARVD and those with <1 g proteinuria at baseline was compared with 'control' patients who had the same degree of renal artery stenosis (RAS) but did not exhibit these features. Results: Median follow-up was 58.4 months [interquartile range (IQR) 25.4-97.3]. Revascularization was associated with a reduced risk of progression to ESKD, CVE and all combined events in patients with rapidly deteriorating renal function [ESKD: hazard ratio (HR) 0.47 (95% confidence interval, CI, 0.25-0.85), P = 0.01; CVE: HR 0.51 (95% CI 0.29-0.91), P = 0.02; Any: HR 0.51 (95% CI 0.29-0.90), P = 0.02]. High-risk patients with bilateral ≥70% RAS and those with <1 g/day baseline proteinuria also had significantly better renal and cardiovascular outcomes post-revascularization when compared with controls. Conclusion: Our results indicate that revascularization may be of benefit in patients with anatomically significant RAS who present with rapidly deteriorating renal function, especially in the presence of severe bilateral ARVD or <1 g/day proteinuria.

Respiratory manifestations of ANCA-associated vasculitis.

BACKGROUND: The prevalence of pulmonary manifestations of ANCA-associated vasculitis (AAV) is not well understood. This study describes the prevalence of respiratory complications of AAV detected via imaging in patients presenting to a secondary renal centre and describes the associations with mortality. METHODS: 105 patients with AAV were identified from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS). CRISIS is a prospective epidemiological study of patients with chronic kidney disease stages 3-5, both who did and did not require dialysis on presentation. Patients were recruited between 2000 and 2013. RESULTS: A chest X-ray was performed in 81.0% of patients with AAV on presentation, of which 56.5% were abnormal. A computed tomography (CT) thorax was performed in 27 patients during the course of their disease: 92.6% showed abnormalities, most commonly fibrosis (63.0%) and bronchiectasis (44.4%). Pulmonary vascultitis was confirmed in 22 of 105 patients (21.0%) after respiratory review or demonstrated by associated changes associated on CT scan. In a Cox regression model, there was no significant association between pulmonary vasculitis and mortality (P = 0.088), although there was a trend towards increased mortality with pulmonary vasculitis. CONCLUSIONS: Pulmonary manifestations of AAV were common, however only a small proportion of patients had had thorough respiratory investigations, suggesting that the pulmonary manifestations of AAV may be under-diagnosed.

Atherosclerotic renovascular disease - epidemiology, treatment and current challenges.

The neutral results of recent large randomized controlled trials comparing renal revascularization with optimal medical therapy in patients with atherosclerotic renovascular disease (ARVD) have cast doubt on the role of revascularization in the management of unselected patients with this condition. However, these studies have strengthened the evidence base for the role of contemporary intensive medical vascular protection therapy and aggressive risk factor control in improving clinical outcomes in ARVD. Patients presenting with 'high-risk' clinical features such as uncontrolled hypertension, rapidly declining renal function or flash pulmonary oedema are underrepresented in these studies; hence these results may not be applicable to all patients with ARVD. In this 'high-risk' subgroup, conservative management may not be sufficient in preventing adverse events, and indeed, observational evidence suggests that this specific patient subgroup may gain benefit from timely renal revascularization. Current challenges include the development of novel diagnostic techniques to establish haemodynamic significance of a stenosis, patient risk stratification and prediction of post-revascularization outcomes to ultimately facilitate patient selection for revascularization. In this paper we describe the epidemiology of this condition and discuss treatment recommendations for this condition in light of the results of recent randomized controlled trials while highlighting important clinical unmet needs and challenges faced by clinicians managing this condition.

Attenuation of Renal Functional Decline Following Angioplasty and Stenting in Atherosclerotic Renovascular Disease.

BACKGROUND: To date, renal revascularization has not been shown to be advantageous when compared to optimized medical treatment in patients with atheromatous renovascular disease (ARVD). This study aims to investigate the effect of revascularization in patients with pre-intervention worsening renal function and in those with stable renal function. PATIENTS AND METHODS: In this single-centre observational study, patients who were diagnosed with at least 60% angiographic stenosis unilaterally or bilaterally between January 1996 and October 2008 and who were followed-up until February 2011 were retrospectively analysed. Evolution of renal function was determined from the slope of reciprocal of serum creatinine (RCr-slope) before and after diagnostic angiography or revascularization; this required 5 or more creatinine measurements before and at least another 5 measurements post-procedure. Patients were divided into 2 groups: one comprising patients with negative RCr-slope before the procedure and a second group of patients with prior positive RCr-slope. A stepwise, adjusted logistic regression was used to determine the OR of revascularization on attenuation of RCr-slope. RESULTS: Data for 52 patients were analysed. Median age was 64 (58-72) and median follow-up was 15 (8-34) months. Only patients with a negative RCr-slope (-0.0078 (95% CI -0.0174, -0.0033) dl/mg/month) who underwent revascularization manifested an improved RCr-slope during follow-up (+0.0013 (95% CI -0.0002, 0.0039) dl/mg/month, p < 0.001). This finding remained statistically significant even after the adjustment for proteinuria and bilateral arterial disease. CONCLUSION: Revascularization may be indicated for patients with ARVD and progressively worsening renal function. This patient subgroup should ideally be evaluated in future randomized controlled trials.

The importance of proteinuria and prior cardiovascular disease in all major clinical outcomes of atherosclerotic renovascular disease - a single-center observational study.

BACKGROUND: Identification of patients at risk of developing adverse events would enable aggressive medical therapy and possibly targeted revascularization. The aim of this study is to characterize the determinants of long-term outcomes in atherosclerotic renovascular disease (ARVD). METHODS: Patients with a radiological diagnosis of ARVD were recruited into this single-center prospective cohort study between 1986 and 2014. Data collected included baseline co-morbid conditions, annualized prescribed medications and laboratory data (serum creatinine [υmol/L], proteinuria [g/24 h]). Multivariable Cox regression analysis was used to explore association with these end-points: death, end-stage kidney disease (ESKD), cardiovascular event (CVE) and the first of any of these events. RESULTS: A total of 872 patients were recruited into this study. However, 42 patients were excluded due to missing baseline data and hence case records for 830 patients were reviewed. Over median follow-up of 57.1 months (interquartile range: 21.7-96.9), incidence per 100 patient years of death, ESKD, CVE and any event was 13.5, 4.2, 8.9 and 21.0 respectively. Macrovascular disease (MVD), congestive heart failure (CHF), flash pulmonary oedema (FPE) and greater proteinuria at baseline were individually associated with increased risk for all end-points in multivariable analysis (Death: MVD -HR 1.24 [95% CI 1.02-1.50]; CHF -HR 1.33 [95% CI 1.08-1.64]; FPE - HR 2.10 [95% CI 1.50-2.92]; proteinuria - HR 1.14 [95% CI 1.08-1.20]). Higher estimated glomerular filtration rate at time of diagnosis was significantly associated with reduced risk of all end-points (Death: HR 0.92 [95% CI 0.89-0.94])., Administration of statins and renin angiotensin blockade (RAB) at baseline were also associated with reduced adverse events, especially death (RAB: HR 0.83 [95% CI 0.70-0.98]; statins: HR 0.79 [95% CI 0.66-.94]) and ESKD (RAB: HR 0.84 [95% CI 0.71-1.00]; statins: HR 0.79 [95% CI 0.66-0.93]). Revascularization was associated with reduced risk of death (HR 0.65 [95% CI 0.51-0.83]) and ESKD (HR 0.59 [95% CI 0.46-0.76]). CONCLUSION: All patients with ARVD require intensive vascular protection therapy to help mitigate systemic atherosclerosis, optimize cardiovascular risk and improve clinical outcomes. More effort is required to identify the minority of patients who may benefit from revascularization.

Three Decades of Atherosclerotic Reno-vascular Disease Management - Changing Outcomes in an Observational Study.

BACKGROUND/AIMS: Optimized medical therapy has improved cardiovascular outcomes in the general population. To investigate whether changes in the management of atherosclerotic renovascular disease (ARVD) have had an impact on clinical outcomes. METHODS: Recruitment into this single-center prospective cohort study started in 1986. Data was analyzed retrospectively. Patients were divided into four groups based on relationship of diagnosis year to landmark randomized controlled trials (RCT); group 1 - pre-large RCT data (1986-2000); group 2 - post-early RCT (2001-2004); group 3 - ASTRAL study recruitment era (2004-2009); group 4 - post-ASTRAL (2009-2014). RESULTS: In total, 872 patients were followed for a median 54.9 months (IQR 20.2-96.2). Over successive time-periods, there was an increase in baseline utilization of renin angiotensin blockade (RAB) (group 4: 69% vs. group 1: 31%, p<0.001), statins (74% vs 20%, p<0.001) and beta-blockers (43% vs 30%, p=0.024). Median time to death, end-stage kidney disease and cardiovascular events improved except in group 4, which displayed more baseline cardiovascular comorbidities. The number of investigative angiograms performed decreased from 139 per year between 2006 and 2008 to 74 per year in group 4. CONCLUSIONS: Although fewer patients are being investigated for ARVD in our center, these have more cardiovascular comorbidities. Nonetheless, optimized medical therapy may have contributed towards improved proteinuria, renal function and clinical outcomes in patients diagnosed with ARVD.

Associations of antiplatelet therapy and beta blockade with patient outcomes in atherosclerotic renovascular disease.

Randomized trials have shown a neutral effect of percutaneous revascularization compared with optimal medical therapy in patients with atherosclerotic renovascular disease (ARVD). However, there are few data to define what constitutes optimal medical therapy. We present a retrospective analysis of 529 ARVD patients. Separate analyses were performed comparing outcomes in patients prescribed/not prescribed beta blocker and antiplatelet agents. Analyses were adjusted for effects of baseline covariates on probability of treatment and on clinical outcome. Over a median follow-up period of 3.8 years, antiplatelet therapy was associated with a reduced risk for death (relative risk, 0.52 [95% confidence interval {CI}: 0.31-0.89]; P = .02). Beta blocker therapy was associated with a reduced for death (relative risk, 0.45 [95% CI: 0.21-0.97]; P = .04) and nonfatal cardiovascular events (relative risk, 0.74 [95% CI: 0.60-0.90]; P = .003). Although limited by small patient numbers, this study suggests that in ARVD, treatment with antiplatelet therapy and beta blockade may associate with a prognostic benefit.

Progress in the treatment of atherosclerotic renovascular disease: the conceptual journey and the unanswered questions.

Over the past decades, management of atherosclerotic renovascular disease (ARVD) has undergone significant progress, in parallel with increased knowledge about the complex pathophysiology of this condition. Modern multi-targeted medical management of atherosclerosis has driven a change in both the natural history and the clinical outcomes of ARVD. Progression to total renal artery occlusion is a much less common occurrence and while early studies have reported that up to 41% of patients reached renal end-points over a mean follow-up of 44 months, the latest randomized controlled trials have shown that progressive renal impairment occurs in 16-22% of patients, with <8% of patients reaching end-stage kidney disease (ESKD) over a similar time-frame. However, the results of the latest large ARVD trials investigating the effect of renal stenting upon clinical outcomes have been influenced by selection bias as high-risk patients with clinically significant renal artery stenosis (RAS) have largely been excluded from these studies. Although the neutral results of these trials have shown uncertainty about the role of revascularization in the management of patients with ARVD, there is evidence that revascularization can optimize outcomes in selected patients with a high-risk clinical phenotype. Future challenges lie in identifying important subgroups of patients with critical RAS and viable kidneys, while continuing to develop strategies to protect the renal parenchyma and hence improve clinical outcomes.

From anatomy to function: diagnosis of atherosclerotic renal artery stenosis.

Atherosclerotic renal artery stenosis (ARAS) affects 7% of the over 65 s and will be increasingly common with an ageing population. ARAS obstructs normal renal perfusion with adverse renal and cardiovascular consequences. Drug therapy is directed at reducing atherosclerotic risk. Two recent major trials of revascularization for ARAS showed that clinical outcomes were not improved beyond those offered by optimal drug therapy in most patients. This reflects experimental data showing that restoration of blood flow alone may not attenuate a cascade of tissue injury. A shift from anatomic to functional imaging of ARAS coupled to novel therapies might improve clinical outcomes in selected patients. This review outlines the case for separately assessing hemodynamic significance of arterial stenosis and functional reserve of renal parenchymal tissue. The authors consider current and emerging diagnostic techniques for ARAS and their potential to allow individualized and functionally directed treatments.

Hepatitis e infection in a renal transplant recipient.

An asymptomatic 35-year-old renal transplant recipient was noted to have deranged liver function tests. Liver biopsy revealed a portal inflammatory process with mild lobular activity and portal fibrous expansion, consistent with a virally mediated process. An extensive viral screen confirmed infection with Hepatitis E virus genotype 3 (HEV-3). There is increased awareness about locally acquired Hepatitis E virus (HEV) infection in the transplant population in the UK. The important implications of this infection are becoming more apparent as progression to liver cirrhosis can occur. However, the incidence, natural history, and treatment of HEV infection in the transplant population are not well established. This report illustrates a case of delayed spontaneous clearance of the HEV infection.

Myosin heavy chain-9-related disorders (MYH9-RD): a case report.

Myosin heavy chain-9-related disorders (MYH9-RDs) are a group of autosomal-dominant disorders caused by mutations in the MYH9 gene. The features include congenital macrothrombocytopaenia, inclusion bodies in neutrophils and a variable risk of developing sensorineural deafness, progressive renal impairment and presenile cataracts. A 44-year-old Caucasian man was initially thought to have Alport's syndrome and thrombocytopaenia secondary to idiopathic thrombocytopaenic purpura (ITP). A detailed family history and genetic analysis revealed a diagnosis of MYH9-RD. This case highlights the implications of a delayed diagnosis and the ongoing challenges encountered during management of individuals with this condition.

Successful management of severe hyponatraemia during continuous renal replacement therapy.

Rapid correction of chronic hyponatraemia can lead to osmotic demyelination syndrome. Ensuring a gradual correction can be difficult, especially in patients on renal replacement therapy (RRT). A 43-year-old renal transplant patient presented with severe chronic hyponatraemia. She required continuous RRT. The hyponatraemia was corrected successfully by manually adjusting sodium concentration in the dialysate. Our case describes an effective method to ensure severe hyponatraemia is corrected safely during continuous RRT.