Renal artery calcification

Renal artery calcifications are depositions of calcium salts on the wall of a renal artery, found incidentally on CT scans ¹. They are associated with extrarenal atherosclerosis and linked to hypertension ².

Terminology

The term “renal artery calcification” refers to mineral depositions detected on the walls of the renal arteries, considered when their density on CT scans is equal to, or greater than, 130 Hounsfield Units ³. It is believed that they are representative of atherosclerotic plaques ⁴, defined as regions with the referred density whose area is equal to, or exceeds, 1 mm^2,5.

Epidemiology

Renal artery calcifications are a common finding on CT scans ⁴.

Risk factors include

• 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 administrated ⁸
• diabetes mellitus ⁸
• osteoprotegerin (OPG) deficiency (in mice) or defects in OPG, its signalling pathway or ligand ⁹
• osteoporosis ⁹
• miR-125b expression ¹⁰

Associations

• 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
• BMI (body mass index) ¹²
• IMT (intima-media thickness of the carotids) ¹²

Diagnosis

Since renal artery calcification is not a particular disease, but a finding, there are no specific diagnostic criteria. Rather, its detection is based almost exclusively on radiological findings.

Pathology

Renal artery calcification can cause renal and systemic (extrarenal) impacts. Its presence can trigger mechanisms that result toin localized vasoconstriction and consequently cellular increase of the magnitude of the renin-angiotensin-aldosterone system response, thatwhich 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 afflict renal blood pressure regulation, and alongside water and salt retention ultimately lead to hypertension ². In a literary study, the presence of renal artery calcifications, as opposed to those of extrarenal origin, was 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 toin 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 disfunction is responsible for elevated morbidity and mortality ⁸.

Aetiology

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 causing factors ¹⁵.

Location

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

Classification

Since they do not supply the heart neitheror the brain, renal arteries are virtually 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.

Macroscopic appearance

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

Microscopic appearance

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.

Immunophenotype

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 aetiological 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 DM ²⁹.

The expression of S100A/calgranulin, and especially S100A9 is induced in patients with ectopic cardiac calcification as 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.

Serological markersMarkers

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.

Genetics

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.

Radiographic features

Virtually, the only way to confirm the presence of arterial calcification is through radiological imaging modalities. X-rays, ultrasonography and non-contrast CT scans can be used to detect macrocalcifications, while 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.

Plain radiograph

Vascular calcifications appear on x-rays as radiolucent (white) 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.

Ultrasound

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 (not exceeding 1 cm in maximum 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 proper distinguishing) 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

Computed tomography 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.

Angiography

Angiographic techniques are unable to depict macrocalcification, microcalcification or atherosclerotic plaques. Rather, they utilize the excellent vascular imaging potential of dyes to visualize arteries and all their branches, to assess any possible narrowing. It is known that calcifications are a causing factor of arterial stenosis, hence those detected raise suspicions of vascular calcium deposition ⁴⁴.

PET

Positron emission tomography 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 their low spatial resolution, PET scans are of excellent sensitivity.

Contrary to conventional CT, ¹⁸F-NaF PET scans 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.