Hematuria, whether gross or microscopic, is a common clinical presentation that prompts urological investigation due to its association with significant underlying pathology, most notably urinary tract malignancy [1]. Approximately 5% of patients with gross hematuria and 2-3% of those with microscopic hematuria are ultimately diagnosed with a urinary tract cancer [2]. Consequently, a thorough and accurate evaluation of the entire urinary tract—from the kidneys to the bladder—is imperative. Over the past two decades, computed tomography urography (CTU) has supplanted traditional intravenous pyelography as the gold-standard imaging modality for this purpose [3]. A comprehensive CTU protocol typically involves multiple acquisition phases: a pre-contrast scan to detect calculi, a nephrographic phase for optimal renal parenchymal assessment and characterization of renal masses, and a delayed excretory phase for opacification of the pelvicalyceal systems, ureters, and bladder to detect urothelial lesions [4]. This multi-phase approach provides unmatched anatomical detail and has demonstrated high sensitivity and specificity for detecting the varied causes of hematuria, including urolithiasis, renal cell carcinoma (RCC), and urothelial carcinoma (UC) [5]. Despite its diagnostic prowess, the principal drawback of standard multi-phase CTU is the substantial cumulative radiation dose. A typical triple- or quadruple-phase CTU can deliver an effective dose ranging from 15 to 35 millisieverts (mSv), which is a significant exposure considering the stochastic risk of radiation-induced malignancy [6]. This concern is amplified in younger patients, those with benign causes of hematuria, and individuals who may require repeated surveillance imaging. This has driven a concerted effort in the radiological community to develop and validate lower-dose CTU protocols that adhere to the As Low As Reasonably Achievable (ALARA) principle without compromising diagnostic quality [7]. One of the most promising low-dose strategies is the "hybrid" or "split-bolus" technique. In this approach, a single post-contrast acquisition is timed to capture both the nephrographic and excretory phases simultaneously. This is achieved by administering the intravenous contrast medium as two separate, timed injections (a split bolus), effectively eliminating one entire scanning phase and its associated radiation dose [8]. Early studies and retrospective analyses have suggested that split-bolus CTU can significantly reduce radiation exposure while maintaining good image quality and diagnostic yield [9, 10]. However, a research gap remains for large-scale, prospective, randomized trials that directly compare the diagnostic accuracy of a modern split-bolus protocol against the established standard triple-phase protocol in a real-world population of patients presenting with hematuria. Therefore, the aim of this study was to prospectively and randomly compare a hybrid split-bolus dual-phase CTU protocol with a standard triple-phase CTU protocol. We hypothesized that the hybrid protocol would offer a significant reduction in radiation dose while demonstrating non-inferior diagnostic accuracy for the detection of significant urinary tract pathology in patients undergoing evaluation for hematuria.

Study Design and Population This study was a prospective, single-center, randomized controlled trial conducted between March 2021 and August 2023 at a university-affiliated tertiary care hospital. We enrolled consecutive patients aged 18 years or older who were referred by urologists or primary care physicians for CTU for the evaluation of gross or microscopic hematuria (defined as ≥3 red blood cells per high-power field). Inclusion Criteria: 1. Age ≥ 18 years. 2. Clinical indication for CTU due to gross or microscopic hematuria. 3. Willingness and ability to provide informed consent. Exclusion Criteria: 1. Known allergy to iodinated contrast media. 2. Pregnancy. 3. Severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m²). 4. Patient refusal or inability to hold breath for the scan duration. 5. Prior definitive treatment for urinary tract malignancy. Randomization and Blinding A total of 180 eligible patients were randomized in a 1:1 ratio into two groups using a computer-generated random number sequence. Group A (n=90) was assigned to the standard triple-phase CTU protocol, and Group B (n=90) was assigned to the hybrid split-bolus CTU protocol. The radiologists interpreting the images were blinded to the protocol used. CTU Protocols All examinations were performed on a 128-slice CT scanner (Siemens Somatom Definition Edge). All patients were instructed to drink 1000 mL of water 60 minutes prior to the scan to ensure adequate bladder distention. Non-ionic, iodinated contrast medium (Iopromide, 370 mgI/mL) was used. Automated tube current modulation (CARE Dose 4D) and automated tube voltage selection (CARE kV) were enabled for all scans. • Group A: Standard Triple-Phase Protocol: 1. Non-Contrast Phase: A scan was performed from the top of the kidneys to the pubic symphysis. 2. Nephrographic Phase: A bolus of 100 mL of contrast medium was injected at 3.5 mL/s. A scan was performed with a 100-second delay from the start of injection. 3. Excretory Phase: An additional scan was performed 8 minutes after the contrast injection. • Group B: Hybrid Split-Bolus Protocol: 1. Non-Contrast Phase: Identical to Group A. 2. Combined Nephrographic-Excretory Phase: A split-bolus injection technique was used. An initial bolus of 50 mL of contrast was injected. After a 7-minute pause, a second bolus of 70 mL was injected at 4.0 mL/s. A single helical scan from the diaphragm to the pubic symphysis was acquired 100 seconds after the start of the second injection. Image Analysis and Reference Standard Two board-certified abdominal radiologists with 8 and 15 years of experience, respectively, independently reviewed all CTU examinations in a blinded fashion. Discrepancies were resolved by consensus. A standardized report form was used to document the presence, location, and characteristics of any abnormalities, including renal masses, urothelial lesions, stones, strictures, or inflammatory changes. Subjective image quality was assessed using a 5-point Likert scale (1=non-diagnostic, 2=poor, 3=adequate, 4=good, 5=excellent) for two parameters: (1) renal parenchymal enhancement in the corticomedullary/nephrographic phase, and (2) opacification and distension of the pelvicalyceal system and ureters. The final diagnosis, which served as the reference standard, was a composite determination based on: 1. Histopathological results from surgery or biopsy. 2. Cystoscopic findings. 3. Definitive findings on other imaging modalities (e.g., MRI). 4. Clinical and imaging follow-up for at least 12 months in cases of negative or benign findings. Statistical Analysis Statistical analysis was performed using SPSS version 27.0 (IBM Corp.). Patient characteristics were compared using the Student’s t-test for continuous variables and the chi-square or Fisher’s exact test for categorical variables. The primary outcome, diagnostic accuracy (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]), was calculated on a per-patient basis for the detection of any significant pathology and compared between groups using the chi-square test. The mean effective radiation doses, calculated from the dose-length product (DLP) using a conversion coefficient of 0.015 mSv/mGy•cm, were compared using an independent samples t-test. Subjective image quality scores were compared using the Mann-Whitney U test. A p-value < 0.05 was considered statistically significant.

Patient Demographics and Baseline Characteristics A total of 180 patients were successfully randomized and completed the study protocol (90 in Group A, 90 in Group B). The two groups were well-matched with no statistically significant differences in age, gender, BMI, or type of hematuria, as detailed in Table 1. Gross hematuria was the indication in 38.3% of patients, and microscopic hematuria in 61.7%. Table 1. Patient Demographics and Baseline Characteristics Characteristic Group A (Standard) (n=90) Group B (Hybrid) (n=90) p-value Age (years), mean ± SD 62.1 ± 13.4 63.5 ± 12.8 0.48 Gender, n (%) 0.81 Male 58 (64.4%) 56 (62.2%) Female 32 (35.6%) 34 (37.8%) BMI (kg/m²), mean ± SD 27.8 ± 4.1 28.1 ± 4.5 0.65 Type of Hematuria, n (%) 0.74 Gross 34 (37.8%) 35 (38.9%) Microscopic 56 (62.2%) 55 (61.1%) Diagnostic Yield and Accuracy The composite reference standard identified significant pathology in 61 of the 180 patients (33.9%). This included 22 cases of urothelial carcinoma (15 bladder, 7 upper tract), 11 cases of renal cell carcinoma, 25 cases of clinically significant urolithiasis (causing obstruction or >5 mm), and 3 cases of benign ureteral strictures. The diagnostic performance of each protocol is summarized in Table 2. In Group A (Standard CTU), there were 31 patients with significant findings; the protocol correctly identified 30 (sensitivity 96.7%). There was one false-negative case (a small, flat bladder carcinoma in situ) and one false-positive (a prominent fold mimicking a mass). In Group B (Hybrid CTU), there were 30 patients with significant findings; the protocol correctly identified 28 (sensitivity 93.5%). There were two false-negatives (one small upper tract UC and one flat bladder lesion) and two false-positives (blood clot and focal pyelonephritis mimicking a mass). There was no statistically significant difference in sensitivity (p=0.68), specificity (p=0.55), PPV (p=0.98), or NPV (p=0.45) between the two groups. Table 2. Per-Patient Diagnostic Accuracy for Significant Pathology Parameter Group A (Standard) (n=90) Group B (Hybrid) (n=90) p-value True Positives 30 28 True Negatives 58 58 False Positives 1 2 False Negatives 1 2 Sensitivity (%) [95% CI] 96.7 [83.3–99.9] 93.5 [78.6–99.2] 0.68 Specificity (%) [95% CI] 98.3 [90.9–99.9] 96.6 [88.5–99.6] 0.55 PPV (%) [95% CI] 96.8 [83.3–99.9] 93.3 [77.9–99.2] 0.98 NPV (%) [95% CI] 98.3 [91.1–99.9] 96.7 [88.5–99.6] 0.45 Radiation Dose and Image Quality The analysis of radiation dose revealed a highly significant difference between the two protocols, as shown in Table 3. The mean effective dose for the standard triple-phase protocol was 18.5 ± 4.1 mSv, whereas the dose for the hybrid split-bolus protocol was 10.2 ± 2.8 mSv. This represents a mean dose reduction of 8.3 mSv, or 44.9% (p<0.001). Subjective image quality scores were high for both groups. There was no significant difference in the scores for renal parenchymal enhancement. For urothelial opacification, the standard protocol scored slightly higher than the hybrid protocol (4.8 vs. 4.2), and this difference was statistically significant (p=0.02). However, in no case was urothelial opacification in the hybrid group rated as non-diagnostic (score < 3). Table 3. Comparison of Radiation Dose and Subjective Image Quality Parameter Group A (Standard) (n=90) Group B (Hybrid) (n=90) p-value DLP (mGy•cm), mean ± SD 1233.3 ± 273.1 680.0 ± 186.7 <0.001 Effective Dose (mSv), mean ± SD 18.5 ± 4.1 10.2 ± 2.8 <0.001 Parenchymal Quality Score, mean ± SD 4.7 ± 0.4 4.6 ± 0.5 0.21 Urothelial Quality Score, mean ± SD 4.8 ± 0.3 4.2 ± 0.7 0.02

The results of this prospective randomized trial provide strong evidence that a hybrid split-bolus CTU protocol can serve as a reliable and safer alternative to the standard triple-phase protocol for the evaluation of hematuria. Our primary finding is that the hybrid protocol achieved diagnostic accuracy that was statistically non-inferior to the standard protocol, while concurrently delivering a substantial, clinically meaningful reduction in radiation dose. The core purpose of CTU is the accurate detection of urinary tract pathology, particularly malignancy. In our study, the sensitivity and specificity of the hybrid protocol (93.5% and 96.6%, respectively) were comparable to those of the standard protocol (96.7% and 98.3%). These findings are consistent with previous, mostly retrospective, studies which have also shown high accuracy for split-bolus techniques [9, 11]. The few false-negative cases in our study, observed in both groups, involved small, flat urothelial lesions, which represent a known challenge for all imaging modalities, including CTU, and are often best detected via direct visualization at cystoscopy [12-15]. The ability of the hybrid protocol to maintain high diagnostic performance demonstrates that the simultaneous acquisition of nephrographic and excretory information in a single pass does not compromise the detection of clinically relevant lesions. The most significant advantage of the hybrid protocol is the dramatic reduction in radiation exposure. Our observed 44.9% reduction in mean effective dose, from 18.5 mSv to 10.2 mSv, is a direct consequence of eliminating one full scan phase. This dose reduction is not trivial; it aligns with the ALARA principle and is particularly important in the context of increasing public and medical awareness of the long-term risks of medical radiation [6, 7]. For a 60-year-old patient, an 8.3 mSv reduction may seem small, but for a 40-year-old patient with recurrent microscopic hematuria who may undergo multiple scans over their lifetime, the cumulative dose savings are substantial. A potential concern with split-bolus protocols is whether the image quality, particularly the opacification of the collecting systems, is sufficient for confident diagnosis. Our study addressed this by including subjective quality assessment. While we found a statistically significant decrease in the mean score for urothelial opacification in the hybrid group, the clinical importance of this finding appears minimal. The mean score of 4.2 corresponds to "good" quality, and no scan was deemed non-diagnostic. This suggests that while the ureters may be slightly less densely opacified compared to a dedicated excretory phase, the opacification is sufficient for detecting filling defects and wall thickening [10]. Furthermore, parenchymal enhancement, critical for detecting and characterizing renal masses, was equivalent between the two groups, confirming that the timing of the second bolus and scan in the hybrid protocol is effective. Our findings have direct implications for clinical practice. Given the equivalent diagnostic accuracy and superior safety profile, the hybrid split-bolus protocol should be considered the default CTU technique for the routine evaluation of hematuria. The standard triple-phase protocol, with its dedicated phases, might be reserved for specific clinical scenarios, such as complex cases requiring detailed renal mass characterization (e.g., suspected oncocytoma vs. RCC where washout characteristics are needed) or in post-operative assessments where a subtle leak is suspected. This study has several strengths, including its prospective, randomized design, which minimizes selection bias. Furthermore, the use of a robust composite reference standard and blinded interpretation by experienced radiologists enhances the validity of our accuracy assessments. Nevertheless, we acknowledge some limitations. First, this was a single-center study, and practice patterns or patient populations may differ elsewhere. Second, the reference standard, while pragmatic, was not based purely on histopathology for all patients, a common limitation in imaging trials. Finally, our cohort did not include a large number of morbidly obese patients, in whom the lower dose and potentially less dense opacification of the hybrid technique could theoretically be more challenging.

In conclusion, this study demonstrates that a hybrid split-bolus CT urography protocol is not inferior to the standard triple-phase protocol in terms of diagnostic accuracy for detecting significant pathology in patients with hematuria. Critically, it achieves this performance with a nearly 45% reduction in radiation dose. The slightly lower urothelial opacification was not found to be clinically limiting. These findings strongly support the adoption of the hybrid split-bolus protocol as the primary imaging technique for the routine evaluation of hematuria, offering a more favorable risk-benefit profile by balancing high diagnostic yield with a commitment to patient safety and radiation dose reduction.

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