Significant Renovascular Disease Research Articles

Cardiovascular Disease Prevention in Patients With Atherosclerotic Renovascular Disease-Induced Resistant Hypertension: Further Considerations for 24-Hour BloodPressure Profiles.

Cardiovascular Disease Prevention in Patients With Atherosclerotic Renovascular Disease-Induced Resistant Hypertension: Further Considerations for 24-Hour BloodPressure Profiles.

Spleno-renal artery transposition in a solitary functioning kidney for treatment-resistant hypertension and acute kidney injury

Renal Artery Stenosis (RAS) is an important cause of treatment-resistant hypertension. Uncontrolled hypertension with RAS can cause progressive chronic kidney disease (CKD) leading to end-stage kidney disease. Therapeutic revascularisation can...

Long-Term Outcomes and Causes of Death in Patients With Renovascular Disease Undergoing Renal Artery Stenting.

Renovascular disease (RVD) can lead to hypertension and chronic kidney disease (CKD). Patients with advanced peripheral arterial disease (PAD) have a 5-year mortality of ∼30%. Rate and causes of death in patients with significant RVD, who share similar risk factors with patients having PAD, are not well defined. We assessed consecutive patients with RVD who underwent renal artery stenting at our institution over 6 years. Specific causes of death were ascertained, and the probability of survival was estimated. Cox models were fit to identify predictors of outcomes. We identified 281 patients with RVD who underwent renal stenting. Follow-up was available for all patients (median 5.1 years). All-cause mortality was 24.2% at 5 years and 33.7% at 7 years (compounded annualized death rate: 5.5%). Of the 68 deaths, 36 (52.9%) were cardiovascular (13.2% acute myocardial infarction, 13.2% stroke, 11.8% sudden death, and 10.3% congestive heart failure) and 32 (47.1%) deaths had noncardiovascular causes. In patients with RVD undergoing stenting, cardiovascular events are the most common causes of death. Compared to patients with advanced PAD, RVD may have a lower 5-year mortality.

Cardiac Function In Renovascular Hypertensive Patients With and Without Renal Dysfunction

Hypertension impairs left ventricular (LV) diastolic and systolic function, which might be aggravated by inflammation or neurohumoral activation. We hypothesized that LV diastolic dysfunction is more common in patients with renovascular hypertension (RVHT) compared with essential hypertension (EHT). Hypertensive patients who underwent both renal imaging to exclude RVHT and cardiac echocardiography within a 3-year period were identified retrospectively. Patients with significant renovascular disease were included in the RVHT group (n = 75); those without significant renovascular disease were included in the EHT group (n = 69). Cardiac function and structure were compared. Baseline renal function was preserved (serum creatinine ≤ 2mg/dl) in EHT patients and impaired (serum creatinine > 2mg/dl) in only 9 RVHT patients. RVHT patients had higher systolic blood pressure, E/e' ratio, and greater prevalence of concentric hypertrophy but lower estimated glomerular-filtration-rate (eGFR) compared with EHT patients. Increased prevalence of LV diastolic dysfunction remained statistically significant in patients with RVHT after multivariable adjustment for age, sex, blood pressure, eGFR, diabetes, smoking, and statin use, with a relative risk (95% CI) for abnormal E/e' of 1.70 (95% confidence interval = 1.05-2.90; P = 0.03) compared with EHT. RVHT patients with severe renal dysfunction showed greater impairments in cardiac systolic and diastolic function compared with those in EHT patients or preserved renal function RVHT patients. Among hypertensive patients undergoing echocardiography, cardiac structure and diastolic function are impaired in RVHT patients compared with EHT patients and remain different after adjustment for multiple significant covariables. When associated with significant renal dysfunction, RVHT aggravates LV hypertrophy and both systolic and diastolic dysfunction. Hence, identification of RVHT and renal dysfunction warrants development of targeted management strategies.

The Role of Sonography in Renal Artery Stenosis Evaluation and Stent Placement

A literature review has been conducted to demonstrate the role of duplex sonography in evaluating renal artery stenosis (RAS) as a screening method for patients prior to percutaneous transluminal renal artery stent (PTRAS) placement. The review also evaluates the role of ultrasound surveillance following PTRAS and establishes the overall influence of ultrasound on defining stent efficacy for managing hemodynamically significant renovascular disease. Recent studies have narrowed criteria for intervention through duplex sonographic assessment of RAS to better predict patient benefit and response to stent placement. Studies using sonographic parameters evaluating patients for renal artery stenosis, criteria-dependent stent placement, and postintervention follow-up have shown improved patient response, helping ensure effective and appropriate care in RAS management.

Captopril-enhanced renal scintigraphy in the diagnosis of pediatric hypertension

Hypertension in childhood is no longer a rare condition mainly secondary to renal, or renovascular diseases, as a growing proportion of children are obese and hypertensive, with the phenotype of metabolic syndrome. Thus, we need to reconsider our practice in the examination of the hypertensive child and redefine the place of non-invasive methods for screening of renovascular hypertension, and specifically, to evaluate the value of captopril-enhanced renal scintigraphy at the two ends of the palette: the obese child with hypertension and the severely hypertensive prepubertal child. Renal artery stenosis in children is mainly due to fibromuscular dysplasia and stenoses associated with syndromes involving single or multiple smaller branch vessels. This explains the low specificity and sensitivity of the color-Doppler ultrasound method and captopril renal scintigraphy. Even the more sophisticated computed tomography (CT) and magnetic resonance imaging (MRI) angiographic techniques are, at present, not sensitive enough to exclude stenoses of the small branches definitely. Thus, children in whom there is a strong suggestion of renovascular hypertension should undergo angiography with a view to endovascular treatment, as non-invasive imaging has no significant benefit and might lead to a delay in treatment. In the cases when the probability of renovascular disease is moderate a basic assessment of renal function and structure is sufficient. In the neonate, catheter-associated thromboembolic disease is among the most common causes hypertension. It should be controlled medically until the patient is old enough to undergo angiography and angioplasty successfully. Thus, in this age group, there is a place for functional imaging with renal sonography and angiotensin-converting enzyme inhibitor (ACEI) renography to detect hemodynamically significant renovascular disease, with the limitations mentioned above. However, the rapid technical evolution of non-invasive methods requires periodic re-consideration of the actual standpoints.

Heart and renal failure in renovascular hypertension caused by giant cell arteritis - case report

We report a case of a male teenager with severe heart and acute renal failure as the dominant clinical manifestations of renovascular hypertension (RVH) caused by atypical giant cell arteritis (GCA). Unrecognized RVH and treatment of the consequent heart failure by angiotensin-converting enzyme inhibitors (ACEI) probably contributed to progression of renovascular disease to bilateral renal artery occlusion. Recurrent "flash" pulmonary edemas could not be prevented until surgical revascularization of the only functioning right kidney was achieved by an aortorenal bypass. Prompt post-operative normalization of heart function and arterial hypertension occurred despite the histopathological finding of the resected renal artery compatible with GCA and 4-year duration of significant renovascular disease. At the last check-up, the patient was asymptomatic, with normal arterial pressure on the prescribed treatment: carvedilol, hydrochlorothiazide, prednisolone 20 mg daily and aspirin. Subsequent follow-up is necessary to observe the evolution of GCA as an exceptionally rare cause of RVH.

Progression of atherosclerotic renovascular disease: a prospective population-based study

Previous reports from select hypertensive patients suggest that atherosclerotic renovascular disease (RVD) is rapidly progressive and associated with a decline in kidney size and kidney function. This prospective, population-based study estimates the incidence of new RVD and progression of established RVD among elderly, free-living participants in the Cardiovascular Health Study (CHS). The CHS is a multicenter, longitudinal cohort study of cardiovascular risk factors, morbidity, and mortality among men and women aged >65 years old. From 1995 through 1996, 834 participants underwent renal duplex sonography (RDS) to define the presence or absence of significant RVD. Between 2002 and 2005, a second RDS study was performed in 119 participants (mean study interval, 8.0 +/- 0.8 years). Significant RVD was defined as hemodynamically significant stenosis (renal artery peak systolic velocity [RA-PSV] exceeding 1.8 m/s) or renal artery occlusion. Prevalent RVD was significant RVD at the first RDS, and incident disease was defined as new significant RVD at the second RDS. Significant change of RVD was defined as a change in RA-PSV of greater than two times the standard deviation of expected change over time, regardless of hemodynamic significance or progression to renal artery occlusion. The second RDS study cohort included 119 CHS participants with 235 kidneys (35% men; mean age, 82.8 +/- 3.4). On follow-up, no prevalent RVD (n = 13 kidneys; 6.0%) progressed to occlusion. Twenty-nine kidneys without RVD at the first RDS demonstrated significant change in PSV at the second RDS; including nine kidneys with new significant RVD (8 new stenoses; 1 new occlusion). Controlling for within-subject correlation, the overall estimated change in RVD among all 235 kidneys was 14.0% (95% confidence interval [CI], 9.2% to 21.4%), with progression to significant RVD in 4.0% (95% CI, 1.9% to 8.2%). Longitudinal increase in diastolic blood pressure and decrease in renal length were significantly associated with progression to new (ie, incident) significant RVD but not prevalent RVD. This is the first prospective, population-based estimate of incident RVD and progression of prevalent RVD among free-living elderly Americans. In contrast to previous reports among select hypertensive patients, CHS participants with a low rate of clinical hypertension demonstrated a significant change of RVD in only 14.0% of kidneys on follow-up of 8 years (annualized rate, 1.3% per year). Progression to significant RVD was observed in only 4.0% (annualized rate, 0.5% per year), and no prevalent RVD progressed to occlusion.

Renovascular disease in children and adolescents

This retrospective review describes the surgical management of renovascular disease in 25 consecutive children and adolescents with severe hypertension. Patients </=21 years of age (mean age, 11.6 +/- 5.4 years; 12 females, 13 males) underwent repair of 34 renal arteries (RAs), and their management forms the basis of this report. Early and late blood pressure responses were adjusted for gender, age, and height. RA repair was evaluated by angiography, renal duplex sonography (RDS) scanning, or both. Primary patency and survival were estimated by product-limit methods. Thirty-four RAs among 32 kidneys were repaired. Bilateral renal RA disease to a solitary kidney was present in nine patients. RA lesions included dysplasia (44%), RA hypoplasia (20%), midaortic syndrome (12%), RA aneurysm (12%), dissection (8%), and arteritis (4%). All patients had severe hypertension (>95 th percentile systolic or diastolic pressure adjusted for gender, age, and height). RA repair comprised 25 bypasses (73%) consisting of 28% saphenous vein, 60% hypogastric artery, and 12% polytetrafluoroethylene; 2 patch angioplasties (6%), and 7 reimplantations (21%). Branch RA exposure was required in 28 kidneys (88%), and branch reconstruction was required in 61%. Warm in situ repair was used in 53%, in situ cold perfusion in 24%, and ex vivo cold perfusion in 23%. Of six bilateral RA repairs, one was staged and two patients are awaiting a staged repair. Combined aortic reconstruction was required in three patients. No unplanned nephrectomy was performed. There were no perioperative deaths. Hypertension was cured in 36%, improved in 56%, and failed in 8% at mean follow-up of 46.4 +/- 7.8 months. The mean calculated glomerular filtration rate increased from 82.0 mL/min/1.73 m 2 preoperatively to 98.2 mL/min/1.73 m 2 postoperatively. The postoperative patency of 30 RA reconstructions was evaluated by angiography, RDS scanning, or both. At mean follow-up of 32.8 months (median, 21.2 months), primary RA patency was 91%. No failures were observed after 2 months follow-up. Estimated survival was 100% at 60 months, with one death 9 years after surgery. Renovascular hypertension in children and adolescents was caused by a heterogeneous group of lesions. All patients had RA repair, with arterial autografts in most of the RA bypasses. Cold perfusion preservation was used in half of the complex branch RA repairs. These strategies provided 91% primary patency at mean follow-up of 32.8 months, with beneficial blood pressure response in 92%. Surgical repair of clinically significant renovascular disease in children and adolescents is supported by these results.

Atherosclerotic renovascular disease in chronic heart failure: should we intervene?

Renal artery stenosis (RAS) is most commonly caused by atherosclerosis, which is also the most common cause of chronic heart failure (CHF). One-third of patients with CHF are reported to have significant renovascular disease. The presence of RAS confers a worse outcome in studies of hypertension and coronary disease, though data are lacking for patients with CHF. As the kidney is intricately involved in the fluid retention that occurs in CHF, an adverse effect of RAS on outcome would be expected. Presentations of RAS in CHF include flash pulmonary oedema, hypertension, worsening of CHF, and worsening renal function. RAS commonly progresses and may cause worsening of renal function in patients with CHF and previously stable renal function. A variety of investigations that can safely and accurately identify RAS in CHF are available, although none is recommended in current guidelines for the management of CHF. Treatment for RAS, whether for hypertension, for renal dysfunction, or for pulmonary oedema, is at the discretion of the physician due to the lack of adequate randomized controlled trials demonstrating the efficacy and safety of intervention. As it is not clear how RAS should be managed in CHF, screening cannot be advocated. Currently, a multicentre randomized outcome trial, which includes a cohort of patients with RAS and CHF, is in progress to provide answers in this area of uncertainty.

Renovascular disease in patients with hypertension: detection with duplex ultrasound.

The aim of this study was to evaluate the accuracy of duplex ultrasound for the diagnosis of renovascular disease in a cohort of hypertensive patients. In 78 patients suspected of renovascular hypertension on clinical grounds duplex ultrasound examination of the renal arteries was performed. Renal angiography was used as the standard of reference. Duplex ultrasound was inconclusive in 11 kidneys (7%). None of the supernumerary renal arteries was detected with duplex ultrasound. The overall prevalence of significant renovascular disease (> or =50% stenosis) was 20%. Based on the combination of parameters at thresholds commonly applied in current literature: ie PSV(max) >180 cm/sec and RAR >3.5 the overall sensitivity of duplex ultrasound for detection of haemodynamically significant renovascular disease was 50.0% with a specificity of 91.3% (PPV: 87.9%; NPV: 59.1). Lowering the thresholds for both parameters improved the test results at the cost of a significant increase of false positive examinations. In a population of hypertensive patients clinically suspected of renovascular hypertension, only limited results for duplex ultrasound could be acquired in the detection of renovascular disease. This result, in combination with the wide range of sensitivities and specificities published in international literature and the relatively large number of incomplete examinations does not support the general application of duplex ultrasound as a screening procedure for detection and assessment of renovascular disease.

Surgical renal artery reconstruction without contrast arteriography: the role of clinical profiling and magnetic resonance angiography

Purpose: Contrast arteriography is the accepted gold standard for diagnosis and treatment planning in patients with atherosclerotic renovascular disease (RVD). In this study, the results of a selective policy of surgical renal artery reconstruction (RAR) with magnetic resonance angiography (MRA) as the sole preoperative imaging modality are reviewed. Methods: From May 1993 to May 1998, 25 patients underwent RAR after clinical evaluation, and aortic/renal MRA performed with a gadolinium-enhanced and 3-dimensional phase contrast technique. Clinical presentations suggested severe RVD in all patients and included poorly controlled hypertension (16 patients), hospitalization for hypertensive crises and/or acute pulmonary edema (13), and deterioration of renal function within one year of operation (15). Thirteen patients had associated aortic pathologic conditions (12 aneurysms, 1 aortoiliac occlusive disease), and eight of these patients also underwent noncontrast computed tomography scans. Significant renal dysfunction (serum creatinine level, ≥2.0 mg/dL) was present in all but 4 patients with 14 of 25 patients having extreme (creatinine level, ≥3.0 mg/dL) dysfunction. Results: Hemodynamically significant RVD in the main renal artery was verified at operation in 37 of 38 reconstructed main renal arteries (24/25 patients). A single accessory renal artery was missed by MRA. RAR was comprehensive (bilateral or unilateral to a single-functioning kidney) in 21 of 25 patients and consisted of hepatorenal bypass graft (3 patients), combined aortic and RAR (13 patients), isolated transaortic endarterectomy (8 patients), and aortorenal bypass graft (1 patient). Early improvement in both hypertension control and/or renal function was noted in 21 of 25 patients without operative deaths or postoperative renal failure. Sustained favorable functional results at follow-up, ranging from 5 months to 4 years, were noted in 19 of 25 patients. Conclusion: MRA is an adequate preoperative imaging modality in selected patients before RAR. This strategy is best applied in circumstances where the clinical presentation suggests hemodynamically significant bilateral RVD and/or in patients at substantial risk of complications from contrast angiography. (J Vasc Surg 1999;29:1012-21.)

M009 Post-captopril intra-renal Doppler waveform analysis as a screening tool for functionally significant renovascular disease

M009 Post-captopril intra-renal Doppler waveform analysis as a screening tool for functionally significant renovascular disease

Radiographic evaluation of the renal vasculature.

Renal artery stenosis is an important cause of hypertension and progressive renal insufficiency. Additionally, there is increasing concern that renovascular disease is a significant, but previously-unrecognized, cause of end-stage renal disease in certain subsets of patients. Advances in revascularization techniques offer a greater opportunity for blood pressure control and for the restoration or preservation of renal function. Accurate imaging of the renal vasculature, however, is essential for the proper selection of those individuals who might best benefit from such intervention. Although conventional or digital subtraction arteriography remains the gold standard diagnostic test, significant advances in non-invasive imaging techniques now offer the clinician several options for the accurate diagnosis of hemodynamically significant renovascular disease. These techniques include captopril renography, duplex ultrasonography, magnetic resonance angiography, and spiral/fast computed tomography. In this review, the advantages and limitations of these imaging techniques are compared and contrasted with an emphasis on their usefulness in screening for renovascular disease. Also reviewed are recent applications of these techniques for measurement of renal function, predicting outcome of revascularization, and the clinical monitoring of patients with renovascular disease managed either medically or by revascularization.

Captopril Renography in the Diagnosis of Renovascular Disease

Several investigators have reported methods for the use of renal scintigraphy in the diagnosis of renal artery stenosis. We report the experience of Duke University Medical Center, and offer some suggestions for standardizing and optimizing the use of this potential screening tool. We evaluated 140 clinically selected hypertensive adults with postcaptopril renal scintigraphy (renography), pre- and postcaptopril peripheral renin activity, and conventional renal arteriography. Postcaptopril renography (using 99mTc-diethylenetriaminepentaacetic acid (DTPA) to measure glomerular filtration and [131I]iodohippurate to measure renal plasma flow) was considered abnormal if one kidney contributed 47% or less of total activity. Postcaptopril renin was considered elevated if it was at least 4 ng/mL/h. Renovascular disease was defined as 50% or greater main renal artery stenosis. Of 140 subjects, 31 (22%) had significant renovascular disease. Captopril-stimulated DTPA renography suggested asymmetric function in 24 (74%) of these, but was also abnormal in 61 of 109 (56%) with normal renal arteries. Captopril-stimulated hippuran renography performed in a similar manner. Captopril-stimulated renin activity was elevated in only 58% of subjects with renal artery stenosis, and had a false positive rate of 24%. These data differ from reports from other centers, perhaps due to differences in renography methods, criteria for interpretation of renography, and/or patient selection criteria.

Renovascular Disease and Renal Complications of Angiotensin-Converting Enzyme Inhibitor Therapy

Renal complications of angiotensin-converting enzyme (ACE) inhibitor therapy are widely recognized, but few authors have documented the incidence or spectrum of these conditions. In a retrospective study of 530 consecutive patients presenting to our unit as acute uraemic emergencies over a six-year period, 85 (16 per cent) had renovascular disease that was considered to be responsible for their loss of renal function. Twenty-one (4 per cent) patients had uraemia which could be clearly attributable to ACE inhibitor treatment; 18 of these cases were shown to have significant renovascular pathology. Following withdrawal of the ACE inhibitor the renal failure reversed in the majority of patients. We also examined 400 consecutive hypertensive patients referred over a similar period and, although vascular imaging was performed only when it was considered to be clinically indicated, 58 (14.5 per cent) of these patients were shown to have renovascular pathology. A further five patients with stable chronic renal disease were seen to have a deterioration in their glomerular filtration rate coincident with commencement of ACE inhibitor therapy; this reversed when the agents were withdrawn. These observations indicate that significant renovascular disease may be more common than has been hitherto recognized and that injudicious use of ACE inhibitors may result in serious complications. Methods which may minimize such iatrogenic disease are suggested.

Renal duplex sonography: Evaluation of clinical utility

With the exception of conventional angiography, no previously proposed screening test has the necessary sensitivity/specificity to guide further evaluation for correctable renovascular disease. Recently, renal duplex sonography has been suggested as a useful substitute in such screening for renovascular disease. This report analyzes our data collected over the past 10 months in evaluation of renal duplex sonography to examine its diagnostic value. The study population for renal duplex sonography validity analysis consisted of 74 consecutive patients who had 77 comparative renal duplex sonography and standard angiographic studies of the arterial anatomy to 148 kidneys. Renal duplex sonography results from six kidneys (4%) were considered inadequate for interpretation. This study population contained 26 patients (35%) with severe renal insufficiency (mean 3.6 mg/dl) and 67 hypertension (91%). Fourteen patients (19%) had 20 kidneys with multiple renal arteries. Bilateral disease was present in 22 of the 44 patients with significant renovascular disease. Renal duplex sonography correctly identified the presence of renovascular disease in 41 of 44 patients with angiographically proven lesions, and renovascular disease was not identified in any patient free of disease. When single renal arteries were present (122 kidneys), renal duplex sonography provided 93% sensitivity, 98% specificity, 98% positive predictive value, 94% negative predictive value, and an overall accuracy of 96%. These results were adversely affected when kidneys with multiple (polar) renal arteries were examined. Although the end diastolic ratio was inversely correlated with serum creatinine (r = −0.3073, p = 0.009), low end diastolic ratio in 35 patients submitted to renovascular reconstruction did not preclude beneficial blood pressure or renal function response. We conclude from this analysis that renal duplex sonography can be a valuable screening test in the search for correctable renovascular disease causing global renal ischemia and secondary renal insufficiency (ischemic nephropathy). Renal duplex sonography does not, however, exclude polar vessel renovascular disease causing hypertension alone nor does it predict hypertension or renal function response after correction of renovascular disease.

Renal duplex sonography: Evaluation of clinical utility

With the exception of conventional angiography, no previously proposed screening test has the necessary sensitivity/specificity to guide further evaluation for correctable renovascular disease. Recently, renal duplex sonography has been suggested as a useful substitute in such screening for renovascular disease. This report analyzes our data collected over the past 10 months in evaluation of renal duplex sonography to examine its diagnostic value. The study population for renal duplex sonography validity analysis consisted of 74 consecutive patients who had 77 comparative renal duplex sonography and standard angiographic studies of the arterial anatomy to 148 kidneys. Renal duplex sonography results from six kidneys (4%) were considered inadequate for interpretation. This study population contained 26 patients (35%) with severe renal insufficiency (mean 3.6 mg/dl) and 67 hypertension (91%). Fourteen patients (19%) had 20 kidneys with multiple renal arteries. Bilateral disease was present in 22 of the 44 patients with significant renovascular disease. Renal duplex sonography correctly identified the presence of renovascular disease in 41 of 44 patients with angiographically proven lesions, and renovascular disease was not identified in any patient free of disease. When single renal arteries were present (122 kidneys), renal duplex sonography provided 93% sensitivity, 98% specificity, 98% positive predictive value, 94% negative predictive value, and an overall accuracy of 96%. These results were adversely affected when kidneys with multiple (polar) renal arteries were examined. Although the end diastolic ratio was inversely correlated with serum creatinine (r = -0.3073, p = 0.009), low end diastolic ratio in 35 patients submitted to renovascular reconstruction did not preclude beneficial blood pressure or renal function response. We conclude from this analysis that renal duplex sonography can be a valuable screening test in the search for correctable renovascular disease causing global renal ischemia and secondary renal insufficiency (ischemic nephropathy). Renal duplex sonography does not, however, exclude polar vessel renovascular disease causing hypertension alone nor does it predict hypertension or renal function response after correction of renovascular disease.

Results of Surgical Treatment of Renovascular Hypertension

We have used a comprehensive protocol to identify secondary forms of hypertension and operated upon 77 patients with functionally significant renovascular disease. The population included 52 patients with atherosclerotic renal arterial lesions (31 unilateral and 21 bilateral) and 25 patients with fibrodysplasia (19 unilateral and 6 bilateral). In the entire population there was a 90 per cent cured-improved rate, a 5 per cent failure rate and a 5 per cent postoperative mortality. The cure rate was highest in the unilateral fibrodysplasia group and lowest in those with bilateral atherosclerotic disease. The choice of initial operative approach was based on an attempt to preserve renal mass; in 11 patients vascular reconstruction was attempted and these required secondary nephrectomy because of early or late failure. All 11 patients had a good result after nephrectomy. Our observations indicate that a vigorous operative approach to renovascular hypertension is beneficial once accurate demonstration of a functionally significant lesion is made.