New Progress in The Diagnosis And Treatment Of Ischemic Kidney Disease in 2022

Hemorrhagic kidney disease refers to chronic kidney disease (CKD) in which severe renal artery stenosis (70% to 75%) or obstruction causes a significant decrease in renal blood flow, severe renal ischemia, and progressive damage to renal function. The clinical manifestations of severe renal artery stenosis are mainly renovascular hypertension and ischemic kidney disease. The two often coexist, but they can also exist independently. In addition, it can also cause clinical manifestations such as acute pulmonary edema and acute coronary syndrome.

The etiology of ischemic kidney disease

The most common cause of renal artery stenosis is atherosclerotic lesions (about 90%), followed by fibromuscular dysplasia (about 10%), and about 1% is caused by Takayasu arteritis. Other less common causes include renal aneurysm, renal artery dissection, extravascular compression, and renal artery occlusion in allogeneic kidney transplantation. Atherosclerotic renal artery stenosis is common in the elderly, and patients often have traditional cardiovascular disease risks factors, such as male sex, obesity, hypercholesterolemia, diabetes, smoking, and high blood pressure. Fibromuscular dysplasia and Takayasu arteritis are more common in women. According to current reports, the prevalence of renal artery stenosis accounts for 1% to 3% in hypertensive populations, and as high as 20% in secondary hypertensive populations.

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Atherosclerotic renal artery stenosis is present in approximately 0.5% of patients and 5.5% of CKD patients in the US Medicare database. A foreign study using vascular ultrasound for diagnosis found that 6.8% of hypertensive patients aged >65 years had renal artery stenosis. However, since patients with renal artery stenosis are usually asymptomatic or without severe hypertension, it is easy to miss diagnosis and misdiagnose, resulting in the true prevalence may be underestimated. Therefore, it is very important to identify patients with renal artery stenosis early in the high-risk population and to give appropriate treatment.

Clinical diagnosis of ischemic kidney disease

The diagnosis of vascular stenosis in patients with ischemic kidney disease relies on imaging studies. Renal arteriography is the "golden indicator" for the traditional diagnosis of renal artery stenosis, but the examination is invasive and the application of a contrast medium may cause renal injury. Therefore, it is mainly used for patients who plan to undergo renal artery intervention at the same time. Duplex ultrasound, contrast agent-enhanced magnetic resonance angiography (MRA), and high-resolution computed tomography angiography are also widely used in the clinical diagnosis of renal artery stenosis, but the sensitivity and specificity of ordinary ultrasound diagnosis are limited, while the latter two This examination method needs to be applied to iodine contrast medium and gadolinium contrast medium, and there is a risk of kidney injury and nephrogenic systemic sclerosis, so it should be used with caution or even contraindicated in patients with renal insufficiency.

At present, new, safe, and non-invasive imaging examination methods have been continuously promoted and applied clinically. In 2017, the Chinese Expert Consensus on the Diagnosis and Treatment of Renal Artery Stenosis proposed that non-contrast-enhanced MRA can be used for the examination of renal artery stenosis, but this imaging technique is greatly disturbed by blood flow and intestinal tract and often exaggerates the degree of stenosis. With the continuous optimization of scanning sequences, a recent foreign study with the largest sample size so far compared the accuracy of non-contrast-enhanced MRA with contrast-enhanced MRA in the diagnosis of renal artery stenosis using 3D fat-suppressed inflow inversion recovery balanced SSFP sequence. The results showed that the two had excellent consistency, which further confirmed the effectiveness of this technique in the diagnosis of renal artery stenosis.

In addition, in 2021, China's "Expert Consensus on Ultrasound Diagnosis of Renal Artery Stenosis" recommended that contrast-enhanced ultrasound technology, which is more sensitive to blood flow detection, can be used for the detection of patients with renal artery stenosis who are not satisfied with routine ultrasound examination. In 2022, several studies on the application of contrast-enhanced ultrasound in the diagnosis of renal artery stenosis were published at home and abroad. The author reported that 85 patients with renal artery stenosis received contrast-enhanced ultrasound and renal arteriography. Compared with the diagnostic "golden index" renal angiography, the diagnostic sensitivity of contrast-enhanced ultrasonography was 95.7%, and the positive predictive value was 91.7%. The results were consistent with foreign studies. These latest findings demonstrate the safety and efficacy of a novel imaging modality for repeated follow-up of stenotic lesions.

In addition, a problem that requires special clinical attention in the diagnosis of ischemic kidney disease is that in addition to imaging the diagnosis of vascular stenosis, it is also necessary to judge whether renal artery stenosis has functional significance, that is, to evaluate whether vascular stenosis has caused renal artery stenosis. Impaired function and reduced renal blood flow are the very important clinical basis for the diagnosis and treatment of ischemic kidney disease. Serum creatinine, glomerular filtration rate (GFR) or estimated glomerular filtration rate (eGFR), radionuclide renal glomerular filtration rate, ultrasound renal artery resistance index, which can indirectly reflect renal function, ipsilateral renal Function, and presumed renal artery blood perfusion are the indicators recommended in the current guidelines for renal artery stenosis at home and abroad that require preoperative functional evaluation to evaluate renal ischemia to predict the curative effect after vascular reconstruction. However, these indicators are non-specific and cannot directly observe the insufficiency of intrarenal blood flow, so the accuracy of predicting the curative effect is limited. Therefore, there is a clinical need for a more accurate and intuitive method for assessing intrarenal blood perfusion, so that renal ischemia can be detected more sensitively and quickly, and the diagnosis of ischemic kidney disease can be confirmed.

3. Treatment of ischemic kidney disease

The treatment of ischemic kidney disease includes revascularization and drug therapy for renal artery stenosis. A percutaneous interventional stent implantation is the most commonly used and preferred revascularization treatment. Previous large-scale clinical studies of interventional therapy for renal artery stenoses, such as the ARSTRAL study and the CORAL study, did not observe that interventional therapy is superior to drug therapy in terms of renal benefits. Therefore, the current clinical focus and focus are how to detect renal ischemia early, accurately select the appropriate timing of revascularization, and preoperatively predict the renal function benefit after angioplasty. In the foregoing, serum creatinine, GFR or eGFR, and ultrasound renal artery resistance index are insensitive and non-specific for judging renal function. Radioactive technetium-99 is required for nuclide analysis of the glomerular filtration rate, which is costly and requires glomerular filtration. However, it has complex pharmacokinetics, which is not conducive to repeated clinical testing.

In recent years, some new renal blood flow assessment methods have been clinically verified. Blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) is a non-invasive imaging to assess renal oxygenation, which reflects renal ischemia. In 2022, the team of Peking University First Hospital reported that cortical R2* and medulla R2* scores in BOLD-MRI detection were positively correlated with postoperative GFR, and preoperative medullary R2* ≥ 23.7 S-1 had a positive effect on predicting renal failure after stenting. There is good sensitivity to functional improvement. Previous studies have known that contrast-enhanced ultrasonography can evaluate renal microvascular perfusion in CKD patients, but contrast-enhanced ultrasonography can provide multiple detection variables, and it is necessary to select sensitive and simple indicators for clinical application.

In 2022, the author performed contrast-enhanced ultrasonography before interventional surgery on patients with renal artery stenosis and used peak time > 5 s or the peak time of the affected kidney ≥ 25% compared with the contralateral kidney as the diagnostic criteria for renal blood flow hypoperfusion. The improvement of renal function of the patients 1 year after the operation, the results showed that preoperative intrarenal blood flow non-hypoperfusion was an independent predictor of postoperative renal function improvement. The results of these studies are used to clinically screen out patients who may benefit from interventional surgery, guide the formulation of patient treatment plans, and ultimately improve the efficacy of interventional stenting.

Drug therapy is also the first-line treatment for renal artery stenosis. For the high-risk factors of atherosclerosis, lipid-lowering, blood pressure-lowering, blood-sugar-lowering, and antiplatelet therapy should be used for a long time under the guidance of specialists. Among them, antihypertensive drugs are an important means to control renovascular hypertension, improve renal ischemia, and reduce the occurrence of cardiovascular events. European Society of Cardiology, American Heart Association, and "Chinese Expert Consensus on Diagnosis and Management of Renal Artery Stenosis" all recommend angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) or calcium channel blockade The drug is used for the treatment of hypertension in patients. During the application of ACEI/ARB, renal function and serum potassium should be monitored. For patients with bilateral renal artery stenosis and solitary renal artery stenosis, it should be used with caution and the changes in renal function should be monitored more closely.

The target value of antihypertensive treatment for patients with renal artery stenosis is not recommended in domestic and foreign guidelines and consensus. In 2021, the Improving Global Kidney Disease Outcomes Organization (KDIGO) released clinical practice guidelines for CKD blood pressure management, suggesting that the optimal antihypertensive target value is Systolic blood pressure <120 mmHg.

In the Chinese Hypertension Clinical Practice Guidelines published in 2022, it is recommended that CKD non-dialysis patients with high blood pressure and urinary protein > 300 mg/d have a blood pressure control target value of < 130/80 mmHg, and if the systolic blood pressure can be tolerated, it can be reduced to 120 mmHg. For CKD non-dialysis patients with hypertension and urinary protein ≤300 mg/d, the blood pressure control target value is <140/90 mmHg, which can be reduced to 130 mmHg if tolerated. At the same time, the guideline recommends blood pressure target values for hypertensive patients with different comorbidities and ages. Therefore, for patients with renal artery stenosis who are often accompanied by multiple underlying diseases, the target blood pressure should be set according to individual conditions.

Some previous animal experiments and small-scale clinical trials have shown that drugs that improve renal oxidative stress, inflammation, anti-fibrosis, and protect endothelial cells may have a renal protective effect on ischemic kidney disease. A study in the United States observed that infusion of mesenchymal stem cells can improve renal blood flow, and GFR and reduce inflammatory damage in the kidneys in patients with renal artery stenosis. A Mayo Clinic study observed that infusion of bone marrow mesenchymal cell-derived extracellular vesicles improved intrarenal microvascular remodeling, inflammation, and oxidative stress better than revascularization in a porcine model of renal artery stenosis. These drugs may hold good promise for the treatment of ischemic kidney disease in the future. However, the current research evidence is still limited, and it has not been recommended in domestic and foreign guidelines, and it needs to be confirmed in human and larger sample size studies in the future.

Ischemic kidney disease is a non-negligible cause of CKD and even end-stage renal disease. At present, early detection, accurate grasp of the timing of vascular reconstruction, and accurate prediction of whether patients will benefit from treatment are clinical hotspots and difficulties in current research. More clinical evidence-based medical data are needed to guide the progress of clinical diagnosis and treatment, and ultimately effectively lower blood pressure and protect patients' heart and kidney function.

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