Renal artery calcification

Last revised by Daniel J Bell on 23 Sep 2021

Renal artery calcifications, also known as renovascular calcifications, are deposits of calcium salts on the wall of a renal artery, found incidentally on imaging, usually CT 1. They are associated with extrarenal atherosclerosis and linked to hypertension 2.

The term “renal artery calcification” refers to mineral depositions detected on/in the walls of the renal arteries (or their branches), considered when their density ≥130 Hounsfield units on CT 3. It is believed that they are representative of atherosclerotic plaques 4, defined as regions with the relevant density whose area is ≥1 mm 2,5

Renovascular calcification is used synonymously with renal artery calcification. Although calcifications of the renal veins have been described they are very rare and usually represent the calcification of renal vein thrombus 51.

Renal artery calcifications are a common finding on CT 4.

  • white race 2
  • male gender 6
  • aortic calcifications (when absent, renal artery calcifications are virtually non-existent) 4
  • increased perirenal fat thickness 7
  • leptin deficiency (in ob/ob mice), especially when high doses of vitamin D3 are administered 8
  • diabetes mellitus 8
  • osteoprotegerin (OPG) deficiency (in mice) or defects in OPG, its signaling pathway or ligand 9
  • osteoporosis 9
  • miR-125b expression 10
  • hypertension (independent of cardiovascular disease risk factors, ascending aorta calcifications, kidney function, gender, and race) 2, 1.6 times more likely in patients with renal artery calcification 6
  • calcification of the coronaries, carotids, thoracoabdominal aorta, iliac arteries, aortic and mitral annuli 11
  • older age 12
  • diastolic blood pressure 12
  • body mass index (BMI) 12
  • intima-media thickness (IMT) of the carotids 12

Renal artery calcification can cause renal and systemic (extrarenal) impacts. Its presence can trigger mechanisms that result in localized vasoconstriction and consequently cellular increase of the magnitude of the renin-angiotensin-aldosterone system response, which further elevates blood pressure 25. Although arterial wall calcium may or may not obstruct blood flow, it potentially signals renal atherosclerotic and small vessel disease, which in turn can affect renal blood pressure regulation, and alongside water and salt retention ultimately lead to hypertension 2. In a study, the presence of renal artery calcifications, as opposed to those of extrarenal origin, were found to be the most accurate differentiator between hypertensive and non-hypertensive patients during CT scans 6.

It is known that arterial calcifications are strongly associated with atherosclerosis, which is responsible for 90% of renal artery narrowing 26. Diffuse calcifications correlate with higher grades of renal arterial stenosis on CT angiography, especially when located bilaterally, which is strongly linked to hypertension 4.

Clinically, high-grade renal artery calcifications are significantly associated with end-stage renal disease, either as the immediate causing factor or as an inducer of intrarenal calcification or downstream ischemia, that ultimately result in end-stage renal disease 4.

One of the risk factors for renal artery calcifications is perirenal fat of increased thickness. This can be effectively assessed using CT scans, which allow unreduced measurements and trustworthy predictions of volume, as opposed to the more convenient and conventionally deployed ultrasonography. Perirenal adipose tissue actively secretes adipokines and cytokines, that trigger inflammatory processes that predispose to atherosclerosis 7.

Renal artery calcifications are also a potent non-invasive marker of subclinical atherosclerosis in insulin-independent diabetic patients 12, in which subsequent renal dysfunction is responsible for elevated morbidity and mortality 8.

Conventional calcifications, of renal or extrarenal location, are generally a result of the conversion of vascular smooth muscle cells to osteoblasts, due to retention of phosphate, hypercalcemia, previous dialysis treatment, active vitamin D administration or calcification inhibitor deficiency among other causal factors 15.

Calcifications may be present at the intima, the media or both layers of the renal arteries 16-18. Clinically distinguishing between the two laminal locations can be significantly difficult (or even impossible), as this can only be achieved through histological investigation 18,19.

Since they do not supply the heart or the brain, renal arteries are considered a part of the peripheral vascular system 20. To assess the degree and/or the severity of the calcification, the peripheral arterial calcium scoring system (PACSS) can be used 21. This system scores arterial calcifications of the intima and media layers taking into consideration their unilateral or bilateral location and length in 5 grades, using HI-fluoroscopy and DSA in AP projection, as follows:

  • grade 0: no visible calcifications at the referred region
  • grade 1: unilateral calcification less than 5 cm in maximum diameter
  • grade 2: unilateral calcification equal to, or greater than, 5 cm in maximum diameter
  • grade 3: bilateral calcification less than 5 cm in maximum diameter
  • grade 4: bilateral calcification equal to, or greater than, 5 cm in maximum diameter

Alternatively, the Agatston system can be used for classification, whose score is calculated by multiplying the area of the calcification by its highest HU value 5,22-24.

Calcified renal arteries are firm, dense, and tubular, with solid white plaques 27.

Microscopically, as renal arteries are of muscular type, their internal elastic lamina and medial musculature are surrounded by a band of total calcification 27.

When atherosclerotic plaques become of type V, calcium becomes their main component, rendering them almost completely calcified 28.

On the other hand, when mixed type plaques are present, diffuse renal artery calcifications are more common, which are strongly associated with higher-grade stenosis 4.

It is crucial to highlight that there are no specific immunohistochemical/immunohistological markers for the detection of microscopic calcification. However, several markers can be helpful, especially when connected to the etiological factor.

In diabetic patients, calcification sites upregulate the expression of ALP, Runx2 and annexin II, while downregulating annexin V. Alizarin red stain was found to be able to reveal calcium deposition in resected aortic valves of patients with diabetes mellitus 29.

The expression of S100A/calgranulin, and especially S100A9 is induced in patients with ectopic cardiac calcification of pre-existing cardiovascular disease 30, but is more diffusely associated with atherosclerosis in general 32.

In cases of increased osteoblast activity and/or transformation of vascular smooth muscles cells to osteoblasts, markers such as osteoprotegerin, osteopontin, osteocalcin, MGP and bone matrix protein (BMP) are expected to be overexpressed 31. The more atherosclerotic plaques progress to type V and of fibrocalcific type, the more markers like BMP2 and transcription factors such as Cbfa1 and osterix are expressed 33.

As one of the main causes of renal artery calcification is a disequilibrium in mineral-bone metabolism, the levels of certain serological markers are expected to be disturbed in affected patients. More notably, serum osteoprotegerin, bone-specific alkaline phosphatase (BAP), intact PTH, phosphorus and osteocalcin levels are usually elevated, while 25[OH]D3, 1,25[OH]2D3 and fetuin A levels are usually reduced 34.

The presence of the Asp allele regarding the eNOS Glu298Asp polymorphism was found to predispose to calcified renal arterial atherosclerotic plaque formation 35, alongside the ACE1-D allele (deletion polymorphism) 36.

Virtually, the only way to confirm the presence of arterial calcification is through radiological imaging modalities. X-rays, ultrasonography and non-contrast CT may be used to detect macrocalcifications, whilst 18F-NaF PET scans are able to assess microcalcifications and angiography aids to visualize vascular stenosis 39. MRI is of limited value in the detection of calcifications, as they are proton-poor and diamagnetic, thus inconspicuous on conventional sequences 13,14.

Vascular calcifications appear on x-rays as radiopaque areas of bone-like attenuation, following the course of the affected vessels 40. When not extensive enough, they can be difficult to detect on x-rays, and appropriate magnification may be needed for their visualization.

Ultrasonography is one of the best modalities for the detection and characterization of calcifications on the walls of the renal arteries, mainly due to the convenience of their anatomical location in the abdomen.

The main ultrasonographic appearance of vascular calcification is that of hyperechoic foci accompanied by acoustic shadowing 41. Its pattern of sound reflection allows an echogenicity seven times greater than that of the normal vessel wall and three times greater than uncalcified (lipid-rich, hemorrhagic or fibrotic) atherosclerotic plaques 42.

It is important to note that small renal calculi (≤1 cm maximal diameter) can be almost impossible to differentiate from renal artery calcification (this does not apply to calculi larger than 2 cm, as their curvilinear shape allows confident distinction) when calcium is deposited proximally to the renal sinus. In these cases, an abdominal x-ray should be performed to avail in terms of differential diagnosis 41.

CT is the modality of choice for the detection of renal artery calcification 28,37, serving as a non-invasive, straightforward, fast, and reliable quantifying technique 43.

Calcium appears white on non-contrast CT images due to its high Hounsfield value 38, diagnostically accepted when equal to, or greater than, 130 HU. These hyperdense lesions are typically found on the arterial walls in any plane, and the combination of coronal, axial and sagittal views offers an excellent 3D anatomical topographic localization.

Quantification can be achieved by employing scoring techniques, like the Agatston or calcium volume score grading systems.

Angiographic techniques are unable to depict macrocalcification, microcalcification or atherosclerotic plaques. They employ the excellent vascular imaging potential of contrast media to visualize arteries and all their branches, to assess any possible narrowing. It is known that calcifications are a causal factor of arterial stenosis, hence acting as a surrogate marker for the presence of vascular calcium deposition 44.

PET using 18F-NaF, a detector of cellular mechanisms related to bone formation 45,46, is significantly helpful for the assessment of microcalcification, since the pathophysiological mechanism of vascular calcifications connects the procedure to osteoblast-related mechanisms. Despite its low spatial resolution, PET has excellent sensitivity for calcifications.

Contrary to conventional CT, 18F-NaF PET can detect early active calcium deposition on arterial walls in the form of microcalcifications, due to significantly higher resolution 47-49.

When in doubt, alizarin red stain can be used to verify 18F-NaF in sites suspicious for microscopic calcification 50.

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