Inflammation and Oxidative Damage in Ischaemic Renal Disease

Ischaemic renal disease as result of atherosclerotic renovascular disease activates a complex biological response that ultimately leads to fibrosis and chronic kidney disease. Large randomised control trials have shown that renal revascularisation in patients with atherosclerotic renal artery disease does not confer any additional benefit to medical therapy alone. This is likely related to the activation of complex pathways of oxidative stress, inflammatory cytokines and fibrosis due to atherosclerotic disease and hypoxic injury due to reduced renal blood flow. New evidence from pre-clinical trials now indicates a role for specific targeted therapeutic interventions to counteract this complex pathogenesis. This evidence now suggests that the focus for those with atherosclerotic renovascular disease should be a combination of revascularisation and renoprotective therapies that target the renal tissue response to ischaemia, reduce the inflammatory infiltrate and prevent or reduce the fibrosis.

Peristenotic Collateral Circulation in Atherosclerotic Renovascular Disease

The significance of peristenotic collateral circulation (PCC) development around a stenotic renal artery is unknown. We tested the hypothesis that PCC is linked to loss of kidney function and recovery potential in patients with atherosclerotic renovascular disease (ARVD). Thirty-four patients with ARVD were assigned to medical-therapy with or without revascularization based on clinical indications. The PCC was visualized using multidetector computed tomography and defined relative to segmental arteries in patients with essential hypertension. PCC number before and 3 months after treatment was correlated with various renal parameters. Thirty-four stenotic kidneys from 30 patients were analyzed. PCC number correlated inversely with kidney volume. ARVD–stenotic kidneys with baseline PCC (collateral ARVD [C-ARVD], n=13) associated with elevated 24-hour urine protein and stenotic kidney vein level of tumor necrosis factor-α, lower single-kidney volume and blood flow, and greater hypoxia than in stenotic kidneys with no PCC (no collateral ARVD [NC-ARVD], n=17). Revascularization (but not medical-therapy alone) improved stenotic kidney function and reduced inflammation in both NC-ARVD and C-ARVD. In C-ARVD, revascularization also increased stenotic kidney volume, blood flow, and oxygenation to levels comparable to NC-ARVD, and induced PCC regression. However, revascularization improved systolic blood pressure, plasma renin activity, and filtration fraction only in NC-ARVD. Therefore, patients with C-ARVD have greater kidney dysfunction, atrophy, hypoxia, and inflammation compared with patients with NC-ARVD, suggesting that PCC does not effectively protect the stenotic kidney in ARVD. Renal artery revascularization improved in C-ARVD stenotic kidney function, but not hypertension or renin-angiotensin system activation. These observations may help direct management of patients with ARVD.

Atherosclerotic renovascular disease

Atherosclerotic renovascular disease (ARVD) refers to atheromatous narrowing of one or both renal arteries and frequently coexists with atherosclerotic disease in other vascular beds. Patients with this condition are at high risk of adverse cardiovascular events, with mortality around 8% per year. Many patients with ARVD have chronic kidney disease, but only a minority progress to endstage kidney disease, suggesting that pre-existing hypertensive and/or ischaemic renal parenchymal injury is the usual cause of renal dysfunction. Many patients with ARVD are asymptomatic, but there can be important complications such as uncontrolled hypertension, rapid decline in kidney function, and recurrent acute heart failure (flash pulmonary oedema). Management—patients with ARVD should receive medical vascular protective therapy just like other patients with atheromatous disease. This involves antiplatelet agents such as aspirin, statins, antihypertensive agents (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the drugs of choice), optimization of glycaemic control in diabetic patients, and advice/help to stop smoking. On the basis of randomized controlled trial data, they should not be offered revascularization by angioplasty/stenting for the purpose of improving blood pressure control or stabilizing/improving renal function. However, there is evidence that a subgroup of patients with specific complications of ARVD (as previously mentioned) may benefit from revascularization.

Spleno-renal anastomotic bypass revascularization for worsening renal failure and uncontrolled hypertension in bilateral calcific atherosclerotic renal artery stenosis

Following the recent publications of the STAR-study, the ASTRAL trial, the HERCULES trial and the CORAL trial on renal revascularization versus medical therapy in the management of atherosclerotic renovascular disease, there has been a near paradigm shift implying the nonutility of revascularization as a useful and necessary therapeutic option. Our recent experience with a patient who underwent an anastomotic bypass revascularization for worsening renal failure and uncontrolled hypertension in bilateral calcific atherosclerotic renal artery stenosis in Burlington, VT rekindled this debate. We posit that in appropriately selected patients, patients with acutely worsening renal failure, uncontrolled hypertension and/or symptomatic pulmonary edema, there is indeed a place for revascularization therapy, especially in the light of improved and safer surgical and anesthesiology techniques. It must be correctly acknowledged that the above well popularized randomized trials recruited mostly patients with otherwise stable chronic kidney disease at the time of enrollment. Similarly, only 12% of the patients in both arms of the ASTRAL trial demonstrated rapidly worsening renal failure prior to enrollment

Association of novel biomarkers with major clinical outcomes in a cohort of patients with atherosclerotic renovascular disease

Introduction In this study, we investigate whether the addition of biomarkers to a model based on traditional risk factors improves risk prediction and patient selection for revascularization in atherosclerotic renovascular disease. Methods Patients in the Salford Renovascular Study who had the following biomarkers analysed on a baseline sample were included in this study: FGF-23, Cystatin C, kidney injury molecule-1, myeloperoxidase, neutrophil gelatinase-associated lipocalin, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), high-sensitivity Troponin T and anti-apolipoprotein A1 IgG. Cox proportional hazards models and net reclassification index were used to study the effects of either individual or a panel of biomarkers on predicting death, end-stage kidney disease and cardiovascular events. Results A total of 112 patients were followed up for a median 59.9 months (IQR 33.6–86.9). In total, 75 patients died, 21 reached end-stage kidney disease and 36 suffered a cardiovascular event. Only NT-proBNP maintained a statistically significant association with all end-points (death: HR 1.62 [95% CI 1.26–2.10], P < 0.0005; end-stage kidney disease: HR 1.51 [95% 1.19–1.91], P = 0.001; cardiovascular event: HR 1.56 [95% CI 1.23–1.97], P < 0.0005). Risk reclassification improved with addition of all biomarkers as a panel to the base model. Only patients with NT-proBNP concentrations above 300 ng/L gained benefit from revascularization with regard to all adverse end-points compared with medically managed patients. Conclusions NT-proBNP is independently associated with increased risk for all adverse events in atherosclerotic renovascular disease. Novel biomarkers may have an incremental risk predictive value when used in combination with traditional risk factors, and NT-proBNP may have value in patient selection for revascularization. Given the small size of this study, larger multicentre studies are required to validate these findings.

Understanding and managing atherosclerotic renovascular disease: still a work in progress

Atherosclerotic renovascular disease (ARVD) is an unresolved therapeutic dilemma despite extensive pre-clinical and clinical studies. The pathophysiology of the disease has been widely studied, and many factors that may be involved in progressive renal injury and cardiovascular risk associated with ARVD have been identified. However, therapies and clinical trials have focused largely on attempts to resolve renal artery stenosis without considering the potential need to treat the renal parenchyma beyond the obstruction. The results of these trials show a staggering consistence: although nearly 100% of the patients undergoing renal angioplasty show a resolution of the vascular obstruction, they do not achieve significant improvements in renal function or blood pressure control compared with those patients receiving medical treatment alone. It seems that we may need to take a step back and reconsider the pathophysiology of the disease in order to develop more effective therapeutic strategies. This mini-review discusses potential therapeutic alternatives that focus on the renal parenchyma distal to the vascular obstruction and may provide additional tools to enhance current treatment of ARVD.

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.