US-BASED IMAGING

Contrast-enhanced ultrasound

CEUS is the imaging technique that uses intravenously injected microbubble contrast agents to observe the renal microvascular perfusion. It is used when there is need for detailed kidney perfusion assessment, such as in hypertensive patients or early CKD in order to detect microcirculatory deficits also in evaluating renal lesions and transplant perfusions. It has been used as valuable tool to characterize indeterminate renal masses and to distinguish cortical necrosis from infarction. In contrast to conventional Doppler US, CEUS is more sensitive to low-flow in small vessels, that allows to detect perfusion abnormalities in capillaries that Doppler cannot visualize. It can also reveal abnormalities well before changes in routine labs or creatinine occur. Thus, CEUS picks up renal microvascular and perfusion abnormalities well before overt kidney injury. For example, CEUS revealed ∼28% lower baseline cortical perfusion in patients with essential hypertension compared to normotensive controls (median 1476 vs. 2062 arbitrary units; P < 0.001), along with a blunted cortical flow reserve during stress—hypertensive kidneys increased perfusion index by only ∼34% vs. ∼56% in controls [18]. This CEUS-derived perfusion index thus represents an immediate bedside read-out of microvascular damage that cannot be captured by routine laboratory tests [12]. Instead of single cutoff values, CEUS provides semi-quantitative perfusion indices. In clinical practice, delayed cortical enhancement or reduced peak intensity suggest problem with microperfusion. For example, in dynamic CEUS, a prolonged time to peak or lower peak intensity in the cortex suggests fibrosis and hypoperfusion in patients with CKD. While there is no universal cut off value, low cortical perfusion intensity such as 1500 arbitrary units compared to more than 2000 in healthy tissue or a reduced perfusion response under stress are warning signs of microvascular damage. CEUS is a fast, reliable, and cost-effective imaging tool, which can remove the need for other more expensive imaging techniques such as computed tomography (CT) or MRI. It is a fast, reliable, and cost-effective imaging tool that avoids ionizing radiation and nephrotoxic contrast exposure, making it particularly suitable for patients with impaired kidney function. Across studies, CEUS consistently shows that patients with hypertension and early CKD have moderate to large reductions in kidney cortical blood flow, usually about 25%–30% lower than in healthy controls, along with a reduced ability to increase blood flow when needed [12, 18]. These findings are seen in both hypertensive and CKD populations, showing good biological consistency, although the exact numbers differ because CEUS provides semi-quantitative measurements. Delayed cortical enhancement, reduced peak intensity, and impaired stress responses repeatedly emerge as clinically meaningful indicators of microvascular dysfunction, despite the absence of universal cutoff values [12, 18].

Doppler resistive index

The intrarenal resistive index (RRI) is the Doppler US measurement that shows the blood flow through the kidney small arteries. It is calculated using waveforms from segmental or interlobar arteries during a standard renal US. As RRI doesn’t depend on probe angle, it reliably indicates the degree of vascular resistance and the health of small renal vessels. Conventional Doppler US findings align with these results. Once the RRI exceeds ∼0.70—especially as it approaches 0.80—it predicts a faster decline in eGFR and a higher rate of cardiovascular events, even in hypertensive patients with well-controlled blood pressure [19]. In DKD, similarly elevated RRI values (≈0.71–0.72) accompany more advanced nephropathy and higher albuminuria [20]. More broadly, in CKD patients an RRI ≥0.65 signifies extensive interstitial fibrosis and arteriosclerosis and portends a high risk of rapid renal function decline [21] . Moreover, each 0.01 increment in RRI has been associated with a 4% increase in mortality hazard and a 6% increase in dialysis progression hazard over ∼6 years, independent of blood pressure control [22]. Importantly, interventions that improve intrarenal hemodynamics can lower RRI—24 months of ACE inhibition (lisinopril) reduced RRI from ∼0.61 to 0.56 alongside a three-fold drop in microalbuminuria, whereas calcium channel blockade (nifedipine) had no effect [23]. Conversely, an extremely elevated RRI (≥0.80) identifies patients at particularly high risk, correlating with faster creatinine rise and nearly doubled long-term mortality in non-proteinuric CKD [24]. Because RRI is measured during a routine Doppler US, without contrast or radiation, and shows consistent results when standardized, it shows cost effective biomarker of renal blood flow (RBF). That makes it valuable for routine evaluation of both native and transplanted kidneys. Across the hypertensive, diabetic, and CKD populations, elevated intrarenal RRI has been linked to worsening renal function and higher cardiovascular risk. Values above 0.7 are commonly associated with faster declines in eGFR, while values near or above 0.8 has been linked to a particularly high-risk group [19–22, 24]. Although RRI can be affected by overall blood pressure and vascular conditions, its good reproducibility and strong links to clinical outcomes make it one of the most practical ultrasound markers for everyday clinical use.

Superb microvascular imaging

Superb microvascular imaging (SMI) is an advanced Doppler US technique that visualizes low velocity blood flow in very small blood vessels without using contrast. SMI is an emerging technology currently available in select US systems and its use is growing for difficult to diagnose cases. It is useful when fine-detail perfusion of the renal cortex is desired but there is no availability of contrast or MRI. In clinical practice, it can be used during standard US exam to assess cortical microvasculature in CKD, to evaluate the vascular patterns in tumor, enabling differentiation of malignant vs. benign lesions based on flow pattern, or to monitor the RBF changes after treatments. It is especially valuable detecting microvascular rarefaction in CKD patients noninvasively. SMI primarily provides qualitative and semi-qualitative data. Although there are no standardized numeric thresholds, SMI offers a visual threshold—if small vessels are barely detectable where they should be abundantly seen, then microcirculatory damage is likely present. In contrast to Doppler, SMI can directly visualize small-vessel blood flow that was previously below Doppler detection. Renal SMI resolves cortical vessels as small as ∼300–500 μm, revealing fine-scale perfusion heterogeneity that closely mirrors perfusion deficits seen on arterial spin labeling (ASL) MRI and can even show improvements with therapy [12]. This high-frame-rate technique adds granularity to noninvasive microvascular assessment, visualizing the small-vessel rarefaction that conventional Doppler could only infer [12]. In contrast to CEUS, SMI doesn’t require contrast injection, so it can be used in patients who can’t receive contrast. SMI is essentially a software feature on modern US machines, so once the equipment is available, the incremental cost of using SMI is negligible. By providing microvascular detail during a routine US, SMI can potentially reduce the need for more expensive tests. Across available studies, SMI provides clearer visualization of reduced microvascular blood flow in the kidney cortex by detecting low velocity flow which is below the sensitivity of conventional Doppler techniques. These findings are consistently seen across CKD populations, but interpretation is still mostly visual and semi-quantitative because there are no standardized numeric cutoffs. The differences mainly arise from technical factors, not real biological changes, so SMI works best as a supporting, not independent, biomarker [12].

US elastography

US elastography techniques measure tissue stiffness as a surrogate for fibrosis and can be performed during a routine renal US. A 2023 meta-analysis of 1394 participants demonstrated that shear-wave elastography (SWE) can noninvasively distinguish biopsy-proven renal fibrosis, with area under the receiver operating characteristic curve (AUROC) values ∼0.87 for mild, 0.78 for moderate, and 0.86 for severe fibrosis [25]. Consistently, in 162 biopsy-verified CKD cases, every 10 kPa reduction in cortical stiffness corresponded to a 4.5-fold higher odds of moderate-to-severe fibrosis on histology [26]. In DKD, cortical SWE values around 19 kPa identified late-stage DKD with ∼93% sensitivity and ∼86% specificity [20]. Moreover, a lower stiffness cutoff (∼9.2 kPa) could differentiate early-stage DKD (CKD stages 1–3) from healthy controls (67% sensitivity, 82% specificity) [27]. Notably, beyond renal outcomes, a radiomics nomogram combining six SWE-derived features with clinical factors predicted incident cardiovascular disease in DKD with an AUC ≈ 0.89 [28]. Hypertensive nephropathy shows a similar fibrotic imprint: acoustic radiation force impulse (ARFI) elastography found significantly lower cortical shear-wave velocity in chronic hypertension (∼2.37 m/s) compared to healthy kidneys (∼2.96 m/s), correlating with higher albuminuria (r = –0.76) and lower eGFR (r = 0.78) [29]. ARFI not only differentiates hypertensive kidney disease from normal tissue, but also correlates with hypertension grade and kidney damage severity, supporting its use as an objective, operator-independent endpoint in reno-protective trials [29]. Elastography is attractive because it is noninvasive, repeatable, and operator–independent when standardized that can potentially reduce need for renal biopsy. Elastography introduces minimal extra cost as it is a standard software module on modern US platforms, while providing wide clinical uses in many diseases such as DKD, hypertensive nephrosclerosis, CKD of unclear etiology, and renal transplant surveillance. Across CKD, DKD, and hypertensive nephropathy, renal elastography has shown strong ability to detect kidney fibrosis, with AUROC values generally in the 0.78–0.87 range. While in early CKD, the overlap with normal kidney tissue makes fibrosis harder to distinguish, its performance tends to be more reliable in advanced disease. Although reported stiffness thresholds appear promising in practice, they still depend on the imaging platform, with heterogeneity driven by technical factors and perfusion effects [25–27, 29]