Philip A. Kalra

Dispelling the myth: the use of renin–angiotensin blockade in atheromatous renovascular disease

BACKGROUNDnMany physicians retain reservations regarding the routine prescription of renin-angiotensin blockade (RAB) in patients with atheromatous renovascular disease (ARVD). Conversely, these patients are in most need of the cardio- and renal protection offered by RAB. This reservation is mostly because of fear of precipitating acute renal deterioration. We aimed to study whether RAB can be used safely in ARVD patients and whether it altered their outcome.nnnMETHODSnProspective observational study of all ARVD patients presenting to our tertiary referral centre from 1999-2009. Data capture included usage and tolerability of RAB, and correlation with endpoints of cardiovascular events, dialysis or death.nnnRESULTSnSix hundred and twenty-one subjects were available for analysis. Mean age (SD) of the cohort was 71.3 (8.8) years, median (interquartile range) follow-up 3.1 (2.1, 4.8), range 0.2-10.61 years. Seventy-four patients had an intolerance to RAB at study entry. When utilized prospectively, RAB was tolerated in 357 of 378 patients (92%), and this was even seen in 54/69 (78.3%) patients with bilateral>60% renal artery stenosis (RAS) or occlusion. Patients (4/21) who were intolerant of RAB during follow-up (and 12 retrospectively intolerant), underwent renal revascularization which facilitated safe use of these medications post-procedure. On multivariate time-adjusted analysis, patients receiving RAB were significantly less likely to die (P=0.02).nnnCONCLUSIONnRAB is well tolerated even in patients with bilateral severe RAS and reduced mortality in a large group of ARVD patients. We recommend all ARVD patients be considered for RAB therapy unless an absolute contra-indication exists. Intolerance of these agents due to renal dysfunction should be considered an emerging indication for renal revascularization to facilitate their re-introduction.

BOLD imaging: a potential predictive biomarker of renal functional outcome following revascularization in atheromatous renovascular disease

BACKGROUNDnStenting of the stenosed renal artery is commonly employed in atheromatous renovascular disease (ARVD) in order to revascularize the affected kidney. However, it is still far from clear which patient subgroups should be revascularized as stenting carries small but significant risks. We have previously demonstrated that the ratio of magnetic resonance-measured renal volume to isotopic single kidney glomerular filtration rate (isoSK-GFR) is higher in kidneys which show functional improvement after revascularization. Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) does not require contrast administration and is sensitive to changes in tissue concentration of deoxyhaemoglobin.nnnMETHODSnIn this study, we test the hypothesis that baseline BOLD R2* map signal and R2*:isoSK-GFR ratio will provide an additional independent predictive biomarker of response to revascularization.nnnRESULTSnStudies were performed in 28 subjects (16 ARVD and 12 controls). All subjects had R2* mapping and isoSK-GFR measured at baseline and at 4-month follow-up. MRI data were collected on a 3 T whole-body MRI scanner using a coronal dual-echo, 2D gradient-echo breath-hold acquisition. Parenchymal regions of interest (ROIs) were drawn on a representative slice through the middle of the kidney. Parametric maps of R2* were generated and mean values of R2* were calculated for every ROI. The ratio of R2*:isoSK-GFR at baseline was significantly greater in kidneys where renal function improved (5.91 ± 6.51) versus stable (1.78 ± 1.11), deteriorated (2.15 ± 1.79) or controls (1.5 ± 0.91), P = 0.003. R2*:isoSK-GFR ratio that was greater than 95% confidence interval of the control kidneys was 66.7% sensitive, but 85.7% specific in predicting a positive renal functional outcome.nnnCONCLUSIONSnThese pilot data show that BOLD R2* imaging, presumably by detecting intra-renal deoxyhaemoglobin in still viable hibernating parenchyma, coupled with isoSK-GFR may provide an effective predictive biomarker for positive renal functional response to revascularization. R2* imaging is non-invasive, quick to perform and could provide further insight into reversible parenchymal changes in ARVD kidneys.

Prediction and assessment of responses to renal artery revascularization with dynamic contrast-enhanced magnetic resonance imaging: a pilot study

The aim of this study was to assess the potential of dynamic contrast-enhanced (DCE) MRI to predict and evaluate functional outcomes after renal artery revascularization for renal artery stenosis (RAS). The single-kidney glomerular filtration rate (SK-GFR) was measured in 15 patients with atherosclerotic RAS with DCE-MRI and radioisotopes at baseline and 4 mo after revascularization. DCE-MRI also produced measurements of blood flow, blood volume, extraction fraction, tubular transit time, and functional volume. Stented kidneys (n = 22) were divided into three response groups on the basis of the changes in radioisotope SK-GFR: improved (n = 5), stable (n = 13), and deteriorated (n = 4). A good agreement was found between SK-GFR values from DCE-MRI and radioisotopes (correlation coefficient: 0.91). Before intervention, kidneys that improved had lower extraction fraction, higher blood volume, longer tubular transit time, and lower SK-GFR. After intervention, improved kidneys had increased functional volume, and deteriorated kidneys had reduced functional volume and extraction fraction. Revascularization improved blood flow and blood volume in all groups. This pilot study led to the hypothesis that well-vascularized kidneys with reduced extraction fractions are most likely to benefit from revascularization. More generally, DCE-MRI has the potential to replace radioisotope measurement of SK-GFR and may improve patient management by providing additional information on tissue perfusion.

Reverse cardiac remodelling and renal functional improvement following bilateral renal artery stenting for flash pulmonary oedema

Acute flash pulmonary oedema (AFPO) is a life-threatening syndrome almost unique to patients with atheromatous renovascular disease (ARVD). Although recurrent AFPO is a widely accepted indication to consider renal revascularization, this is based on a number of case reports/series describing a successful outcome post-procedure. There is limited literature on the pathophysiological mechanisms and treatment effects of revascularization to support this clinical decision making. We report the case of a 65-year-old lady who presented with three episodes of AFPO. Investigations revealed severe bilateral renal artery stenosis. Post-revascularization, she experienced substantial improvement in energy levels and New York Heart Association class, with improvement in her blood pressure and renal function. Post-procedure, there were dramatic improvements in her cardiac morphology and function that were sustained at 1 year (ejection fraction improved from 39 to 65%, left ventricular mass decreased from 161 to 116 g) as well as renal function (isotopic glomerular filtration rate increased from 22.4 to 34.2 mL/min). This report provides new insights into the pathophysiological relationships between renal and cardiac changes in AFPO; the extent of the cardiac morphological changes was striking and unexpected.

Association of Serum Ig Free Light Chains with Mortality and ESRD among Patients with Nondialysis-Dependent CKD

BACKGROUND AND OBJECTIVESnHigh levels of serum polyclonal combined Ig free light chains are associated with inflammation and decreased excretory kidney function, and they are an independent risk factor for mortality. Whether combined Ig free light chain predicted mortality and progression to ESRD in a stages 3-5 CKD cohort was assessed.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnThis was a prospective cohort study of 872 patients with stages 3-5 CKD (nondialysis) recruited into the Chronic Renal Insufficiency Standards Implementation Study. Patients were recruited to the Chronic Renal Insufficiency Standards Implementation Study in an unselected manner from secondary care nephrology clinics between 2004 and 2010. Combined Ig free light chain was measured at recruitment and analyzed by quartiles. The cohort was followed up for a median of 41.4 months (interquartile range =28.3-68.0 months). Cox regression analysis was undertaken to determine the variables associated with mortality and progression to ESRD.nnnRESULTSnCombined Ig free light chain quartiles were <49.4, 49.4-68.8, 68.9-100.7, and >100.7 mg/L. An independent association with death and progression to ESRD was associated with the third and fourth combined Ig free light chain quartiles (quartile 3: death: hazard ratio, 1.49; 95% confidence interval, 1.02 to 2.18; P=0.04; ESRD: hazard ratio, 1.72; 95% confidence interval, 1.0 to 2.97; P=0.05; quartile 4: death: hazard ratio, 1.99; 95% confidence interval, 1.34 to 2.93; P<0.001; ESRD: hazard ratio, 3.73; 95% confidence interval, 2.1 to 6.3; P<0.001). The other independent risk factors were (1) preexisting cardiovascular disease, age >65 years old, and eGFR=15-30 ml/min per 1.73 m(2) for death and (2) age ≤65 years old, eGFR<30 ml/min per 1.73 m(2), urinary protein-to-creatinine ratio >30 mg/mmol, and serum phosphate level >4.65 mg/dl for progression to ESRD.nnnCONCLUSIONSnAn elevated serum combined Ig free light chain level is an independent risk factor for mortality and progression to ESRD in patients with stages 3-5 CKD managed in secondary care.

Potential for Biomarkers of Chronic Kidney Disease-Mineral Bone Disorder to Improve Patient Care

Chronic kidney disease (CKD) is a growing public health problem. Cardiovascular disease is common in CKD, but standard risk assessment tools perform poorly in this population. Equally, despite CKD being associated with an increased risk for death and dialysis, standard biochemical measurements have limited prognostic value. Novel serum biomarkers may aid risk assessment; however, studies have shown varying clinical utility in relation to progression of CKD, incident cardiovascular disease and death. This inconsistency may relate to limitations in our understanding of the biological actions and interactions of these biomarkers. This review discusses a range of biomarkers in relation to these clinical endpoints in CKD-mineral bone disorder. We consider where biomarkers may enhance risk stratification and improve clinical management, but also highlight where they fall short of achieving this objective.

Variability in parathyroid hormone assays confounds clinical practice in chronic kidney disease patients

Background Intact parathyroid hormone (iPTH) measurements are used to guide therapy in renal patients, but variability in results can occur depending on the assay used. This study has investigated iPTH assay variation in North West England and paired data with regional audit data to determine clinical relevance of assay variability. Methods Thirty-seven haemodialysis patients had blood taken (EDTA plasma, and serum), and samples were processed at 17 laboratories that analyse iPTH for North West dialysis patients. Correction factors were calculated and applied to the iPTH assay results to enable direct comparisons. These correction factors were also applied to Regional Audit data to determine if iPTH assay variability explains the variation in unit performance in achieving PTH targets. Results The iPTH results from the 37 patients were significantly different when either analysed by different assays and/or different laboratories (Pu2009<u20090.001). The Abbott Architect method consistently produced the highest iPTH results. Of the 37 patients, between 49% and 65% would achieve the Kidney Disease: Improving Global Outcomes (KDIGO) iPTH target depending on the assay used. When results were adjusted using correction factors, 21% of the patients would require a change of management according to guidelines. Data from all haemodialysis units submitted for the regional audit were adjusted to the Roche assay and this led to a small change in achievement of KDIGO iPTH targets in individual units when compared to each other. Conclusions A combination of iPTH assay variability and diversity in clinical management leads to variation in achieving iPTH targets. Both need to be improved and/or standardized to improve patient care.

Current views on the management of atherosclerotic renovascular disease

Abstract Atherosclerotic renovascular disease (ARVD) is a common condition in both elderly patients and those with other vascular disease. No published randomized controlled trial has demonstrated an overall benefit of revascularization on any clinical or biochemical end-point, and optimal medical therapy in this condition is not clearly defined. In this review we consider the epidemiology of ARVD and discuss the evidence for current medical treatment. We also address the literature on revascularization, consider settings in which an interventional approach may still be considered, and touch upon on-going areas of research.

Arrhythmia in hemodialysis patients and its relation to sudden death

Sudden death in patients on hemodialysis is believed to be due to arrhythmia, but the evidence for this is surprisingly limited. Five studies involving implantable loop recorders in patients on hemodialysis have now been published, and 4 have shown that bradyarrhythmia rather than tachyarrhythmia are the pre-eminent arrhythmic associations of fatal events. The Monitoring in Dialysis study, reported in this issue, sheds new light on the relationships of arrhythmia to the conventional 3-session weekly hemodialysis cycle.

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.