Yair Lotan, MD

 is a professor of urology; chief of urologic oncology; the Jane and John Justin Distinguished Chair in Urology, in Honor of Claus G. Roehrborn, MD; and vice chair of clinical affairs at the University of Texas Southwestern Medical Center in Dallas. 

 is a professor of urology and executive vice chair of the Department of Urology at Vanderbilt University Medical Center in Nashville, Tennessee. 

Chair of the Department of Urology and the Director of the Urologic Oncology Fellowship at Mayo Clinic in Rochester, Minnesota. 

 is the owner and lead methodologist of Nomadic EBM Methodology.

 is a professor and interim chair of the Department of Urology at Penn State Health Milton S. Hershey Medical Center in Pennsylvania.

The lockdown of more than 26 million people in Shanghai, China, on March 31, 2022, following a spike in COVID-19 cases impacted GE Healthcare’s primary pharmaceutical manufacturing facility for iohexol (Omnipaque) iodinated contrast media (ICM). As of mid-May 2022, the FDA continues to report shortages of GE Healthcare’s iohexol and iodixanol intravenous (IV) contrast media products.1 GE Healthcare anticipates product supply availability to improve the week of May 23, but a 20% allocation level has been established until then.

The acute shortages impacting hospitals and imaging centers globally have emphasized the importance of judicious resource allocation. The evaluation of microscopic hematuria (MH) is particularly relevant to examine in this setting, based on both its prevalence (variously estimated to occur in 6.5% of the population) and the fact that the diagnostic evaluation for hematuria has historically been heavily weighted to the use of computer tomography (CT) imaging with iodixanol IV contrast.

 Indeed, prior guideline recommendations have essentially suggested CT urogram (CTU) with cystoscopy as the evaluation for all patients with microhematuria who are older than 35 years.

Notably, the updated 2020 American Urological Association (AUA)/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU) guidelines for MH help to address the issue of contrast utilization by both providing a risk-stratified approach based on likelihood for harboring malignancy—whereby IV contrast–based CTU is recommended only for high-risk patients—and by outlining alternative modalities to the imaging evaluation.

 Specifically, risk strata were created based on clinical features, including patient age, gender, smoking history, extent of hematuria on urinalysis (UA), and history of risk factors for urothelial cancer (eg, exposures). In patients with MH classified as low-risk, the guidelines recommend clinicians should engage patients in shared decision-making to decide between either repeating a UA within 6 months or proceeding with cystoscopy and renal ultrasound.

Meanwhile, for patients classified as intermediate risk of malignancy, the guidelines offer cystoscopy with renal ultrasound for evaluation.

 As such, the use of multiphasic CTU, which utilizes ICM and includes imaging of the urothelium, to evaluate MH is recommended by the new guidelines only for high-risk patients.

This risk-based approach for MH evaluation represents 1 important step the medical/urologic community can adopt to restrict IV contrast utilization. These recommendations were based on the balance of risks and benefits, as CTU has additional cost and toxicity relative to renal ultrasound and a relatively small yield of identifying malignancy, especially in low- and intermediate-risk patients, where the incidence of upper tract malignancy is very low. Further, the guidelines offer that for patients in the high-risk category, magnetic resonance urography (MRU) may be utilized to image the upper urinary tract, which would provide an alternative to utilizing CT IV contrast.

Data on the performance of imaging with noncontrast CT, MRU, and renal ultrasound were collated as part of the analysis for the AUA/SUFU guidelines. Because all modalities are quite sensitive for detection of renal cortical tumors—most of which are renal cell carcinoma (RCC)—the comparisons among modalities focused on performance characteristics for detection of upper tract urothelial carcinoma (UTUC), which is a relatively rare finding in patients with microhematuria.

The current gold standard for upper tract imaging is CTU. Four studies identified by the systematic review underpinning the guidelines reported on the diagnostic test characteristics of CTU for the detection of UTUC and RCC in a hematuria population.

Based on pooling of the 6 sensitivities and specificities in the 4 studies, the pooled sensitivity for CTU detection of UTUC or RCC was 94.16% (95%CI, 83.77%-98.05%) and the specificity was 99.09% (95%CI, 96.59%-99.76%).

 Only 1 study reported on the diagnostic ability of nonenhanced CT for UTUC detection in solely MH patients.

 The study defined pathologic confirmation of malignancy as the reference standard. In patients who underwent CTU for initial evaluation of asymptomatic MH, the noncontrast images of a randomized portion of the cases was categorized as normal, and all cases categorized as suspicious and benign were submitted to 2 blinded radiologists who independently classified each study into 1 of the aforementioned categories. When compared with the CTU reports, the negative predictive values of noncontrast images were 97.25% and 94.92% for radiologist 1 and radiologist 2, respectively, with an associated specificity of 88.6% and 97.95%. Of the 5 true upper tract malignancies, both blinded radiologists correctly identified 4 of the 5.

Two studies reported on the diagnostic test characteristics of ultrasound for the detection of UTUC and RCC.

 reported on detection of both UTUC and RCC, whereas Unsal et al

 reported on detection of only UTUC.5 Both studies defined pathologic confirmation of malignancy as the reference standard. In the Tan et al study, the sensitivity for RCC was 85.7% (95% CI, 62.1%-97.5%) with a specificity of 99.2% (95% CI, 98.8%-99.5%), but the sensitivity for UTUC was low at 14.3% (95% CI, 0.9%-49.4%).

 The Unsal et al study had a much higher sensitivity for UTUC of 96%, with specificity of 100%.

One study reported on the diagnostic test characteristics of MRU for the detection of neoplastic lesions in patients with MH or gross hematuria.

 Martingano et al defined pathologic confirmation of malignancy as the reference standard. In this study, the sensitivity for RCC or UTUC was 83% and specificity was 86% based on review by 2 radiologists.

Although there is not a considerable amount of data, there are other options for use of oral ICM, such as sorbitol-mannitol-xanthan gum (Breeza; Beekley Medical) and diatrizoate meglumine and diatrizoate sodium solution USP (Gastrografin; Bracco Diagnostics Inc).

 Similarly, sorbitol-mannitol-xanthan gum and iothalamate meglumine (Cysto-Conray; Guerbet LLC) can be used for cystography, retrograde ureterography, as well as for percutaneous renal access and nephrostomy procedures.

The global shortage of ICM has necessitated rapid adaptation of workflows and clinical pathways, which are particularly important for practicing urologists who are evaluating patients for hematuria. Based on the meta-analyses for the AUA/SUFU guidelines

 for evaluation of microhematuria, CTU has the highest sensitivity for detection of UTUC compared with unenhanced CT, MRU, and renal ultrasound. However, given the rarity of UTUC

—particularly in the setting of the current shortage of ICM—we believe the risk-stratified approach to evaluation, as recommended in the 2020 guidelines, offers appropriate resource conservation. Indeed, to review:

• For patients with low-risk microhematuria undergoing evaluation, consider shared decision-making for a period of observation with repeat UA, or evaluate with a cystoscopy and renal ultrasound. For patients with intermediate-risk microhematuria, cystoscopy with renal ultrasound is recommended.

• For patients with high-risk microhematuria, the guidelines do recommend CTU. However, the authors believe that in the setting of ICM shortage, a tiered approach may be considered, with initial renal ultrasound or noncontrasted CT with subsequent CTU for those with abnormal findings. Importantly, MRU represents an alternative modality to evaluate high-risk patients, albeit with potential cost and access implications.

• Patients with gross (macroscopic) hematuria are at highest risk for receiving a diagnosis of a urologic malignancy among patients with hematuria. These patients should be prioritized for CTU, again, with the option of using MRU as the initial imaging study, pending local ICM availability.

Other mitigation strategies for urology patients include the following:

• Consult with local radiology colleagues to discuss use of alternative contrast agents for cystography, retrograde ureterography, and for percutaneous renal access and nephrostomy procedures.

• Delaying routine cancer surveillance imaging or utilizing MR-based imaging for cancer follow-up as available/appropriate

• Using MRI with and without contrast to delineate and stage renal cortical tumors

The authors recognize that ICM is also relevant in multiple other clinical settings urologists manage, including new cancer diagnosis staging, and evaluation of suspected perioperative complications. Thus, in addition to monitoring supplies of ICM, the leadership team must also monitor availability of the alternative imaging strategies, as large-scale diversion of contrasted CT into MRI and ultrasound could lead to resource shortages in those areas. Such alternatives include delaying the timing of CTs requiring IV contrast and employing lower-dose regimens when ICM is necessary. It is critical for urologists to communicate with their radiology colleagues, pharmacy colleagues, and administrative leaders to form a local strategy for conserving supplies while still delivering the highest-quality care available.

A comprehensive plan would include designating a leadership team with all relevant disciplines represented; gathering information, such as local supply of ICM and local availability of alternative imaging options; establishing clinical protocols to prioritize use of ICM in crucial scenarios while conserving its use in others; and establishing a communication plan to disseminate the information. A recent study highlights some short-, mid-, and long-term strategies to manage the shortage of iohexol.

1. Shortage of contrast media for CT imaging affecting hospitals and health systems. American Hospital Association. May 12, 2022. Accessed June 7, 2022. 

2. Davis R, Jones JS, Barocas DA, et al. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. 

.2012;188(suppl 6):2473-2481. doi:10.1016/j.juro.2012.09.078

3. Barocas DA, Boorjian SA, Alvarez RD, et al. Microhematuria: AUA/SUFU guideline. 

.2020;204(4):778-786. doi:10.1097/JU.0000000000001297

4. Janssen KM, Nieves-Robbins NM, Echelmeier TB, Nguyen DK, Baker KC. Could nonenhanced computer tomography suffice as the imaging study of choice for the screening of asymptomatic microscopic hematuria? 

.2018;120:36-41. doi:10.1016/j.urology.2018.07.013

5. Tan WS, Sarpong R, Khetrapal P, et al. Can renal and bladder ultrasound replace computerized tomography urogram in patients investigated for microscopic hematuria? 

.2018;200(5):973-980. doi:10.1016/j.juro.2018.04.065

6. Chen CY, Tsai TH, Jaw TS, et al. Diagnostic performance of split-bolus portal venous phase dual-energy CT urography in patients with hematuria. 

.2016;206(5):1013-1022. doi:10.2214/AJR.15.15112

7. Ascenti G, Mileto A, Gaeta M, Blandino A, Mazziotti S, Scribano E. Single-phase dual-energy CT urography in the evaluation of haematuria. 

.2013;68(2):e87-e94. doi:10.1016/j.crad.2012.11.001

8. Unsal A, Calişkan EK, Erol H, Karaman CZ. The diagnostic efficiency of ultrasound guided imaging algorithm in evaluation of patients with hematuria. 

.2011;79(1):7-11. doi:10.1016/j.ejrad.2009.10.027

9. Martingano P, Cavallaro MF, Bertolotto M, Stacul F, Ukmar M, Cova MA. Magnetic resonance urography vs computed tomography urography in the evaluation of patients with haematuria. 

.2013;118(7):1184-1198. doi:10.1007/s11547-013-0955-6

10. Grist TM, Canon CL, Fishman EK, Kohi MP, Mossa-Basha M. Short-, mid-, and long-term strategies to manage the shortage of iohexol. 

.Published online May 19, 2022. doi:10.1148/radiol.221183

11. Commander CW, Johnson DC, Raynor MC, et al. Detection of upper tract urothelial malignancies by computed tomography urography in patients referred for hematuria at a large tertiary referral center. 

.2017;102:31-37. doi:10.1016/j.urology.2016.10.055

Articles

"The global shortage of ICM has necessitated rapid adaptation of workflows and clinical pathways, which are particularly important for practicing urologists who are evaluating patients for hematuria," write Yair Lotan, MD, and colleagues.

Strategies to mitigate impact of intravenous ICM shortage

 section in which residents from the nation’s leading urology programs present their toughest cases and how they ultimately managed them. Cases inform readers of the problem-solving process and provide a lesson from the authors’ experience.  

 is professor of urology and chief of urologic oncology at the University of Texas Southwestern, Dallas.

	A 48-year-old male is referred from an outside provider for evaluation of gross hematuria for several weeks. He denies any dysuria or subjective difficulty with voiding. His medical history is remarkable for prune belly syndrome, atrial fibrillation, hypertension, and type II diabetes mellitus. Records regarding his childhood surgical history are unfortunately scant, though notable for a remote vesicostomy that was subsequently closed, an enterocystoplasty, and abdominoplasty.

	More recently, he had undergone a right simple nephrectomy 5 years prior for a non-functional kidney in the setting of recurrent urinary tract infections. The patient reports a long history of intermittent management with a urethral catheter, although he notes that he currently evacuates his bladder via spontaneous voiding without difficulty. He denies any family history of malignancies and notes that he did smoke approximately a half-pack per day of cigarettes for 2 years, from 1984 to 1986.

	On physical examination, the patient’s body mass index is 32 kg/m

, and he is noted to have a well-healed, large, left-sided paramedian scar from the pubic bone to above the umbilicus; a midline scar at his prior vesicostomy site; and laxity of his abdominal wall with redundancy of his overlying skin. Testes are palpable bilaterally. Laboratory evaluation reveals creatinine of 1.5 mg/dL (calculated GFR of 50 mL/min/1.73 m

); hemoglobin and hematocrit are 9.9 g/dL and 30.1%, respectively. Electrolytes, platelets, coagulation profile, liver function tests, and remainder of lab results are within normal range.

Persistent ureteral stone in a 76-year-old male

	To his initial appointment, the patient brings MR images of his abdomen and pelvis, displayed in the figure. The imaging reveals a 5.6 x 4.3 x 4.5-cm mass at the anterior bladder dome with inflammation extending to the perivesical fat. No pelvic lymphadenopathy or sites of metastatic disease are found. Severe left-sided hydoureteronephrosis extends to the level of an abnormally conformed bladder, consistent with a patulous collecting system, with ureteral insertion into the dome. His abdominal wall musculature appears thin, and his prostate appears diminutive with an apparent atrophic left seminal vesicle.

	Figure. MRI of the abdomen and pelvis reveal a solitary left kidney with severe hydroureteronephrosis seen in axial (A) and coronal T2-weighted (B) views. A 5.6 x 4.3 x 4.5-cm mass is seen at the anterior bladder dome (C) with inflammation extending to the perivesical fat on T1-weighted imaging in axial view (yellow circle). No pelvic lymphadenopathy or sites of metastatic disease are found. (Figure courtesy of Nirmish Singla, MD, and Yair Lotan, MD)

	He undergoes a transurethral resection of the tumor that reveals muscle-invasive urothelial carcinoma with >90% squamous differentiation and no lymphovascular invasion. The bladder appears to have been augmented with small bowel, and the tumor is located within the native portion of the bladder.

A case of hydronephrosis, sepsis, and pain

	The concern for a potentially increased risk of intravesical malignancy following augmentation enterocystoplasty has generated considerable interest. At present, however, we lack definitive evidence supporting this association. In 2010, Higuchi et al reported that bladder augmentation was not an independent risk factor in the development of bladder cancer in a relatively sizable cohort of patients with congenital bladder abnormalities 

), though their study is limited by its single-institution, retrospective nature.

	Given the controversy surrounding this topic, there are currently no guidelines to routinely screen asymptomatic patients with prior bladder augmentation for intravesical malignancy. Nonetheless, many urologists would still elect to pursue some means of monitoring, whether through urine studies, imaging, cystoscopic evaluation, or some combination thereof.

	The present case further highlights the issue of transitional care, commonly faced by pediatric urologists. Indeed, there are several challenges inherent in transitioning pediatric urology patients to adult providers-a process that must be carefully orchestrated. Some obstacles to this transition include locating adult urologists with special expertise, maintaining comprehensive documentation regarding childhood medical and surgical care, coordinating care with other adult specialties such as nephrology, and navigating the adult health care environment (

	In our patient’s case, unfortunately much was unknown regarding his prior history, such as the original indications for bladder augmentation, whether ureteral reimplantation was pursued, and the type and length of bowel segment used, which are all important to know prior to offering surgical intervention.

Metallic stents efficacious for malignant ureteral obstruction

	There are additional challenges worth consideration in the subsequent management of our patient’s malignancy. First, the role of neoadjuvant chemotherapy remains unclear in the setting of variant histology, as endorsed by the 2017 AUA guideline on muscle-invasive bladder cancer 

). Several operative challenges during radical cystectomy can be anticipated in his case as well. Given his multiple prior abdominal surgeries including bowel resection, extensive scarring can be anticipated, and preoperative consultation with a general surgeon may be worthwhile for intraoperative assistance with adhesiolysis and dissection.

Next: "Deciding on a type of diversion poses another challenge"

	Deciding on a type of diversion poses another challenge. Given his patulous ureter and unclear degree of bowel resection for prior reconstructions, the possibility of utilizing a cutaneous ureterostomy is worth consideration. Although long-term outcomes of ureterostomies in adults are not well known, the likelihood of stenosis is conceivably low in his case, while obviating the need to resect further bowel. Finally, given his history of prune belly syndrome, fascial closure must be meticulous, and the increased risk of parastomal hernia warrants discussion as well.

	Given his predominantly squamous histology and baseline renal dysfunction in the setting of a solitary kidney, the decision was ultimately made to proceed with upfront radical cystectomy. A midline incision was initially made. Several dense adhesions were encountered and lysed with the assistance of our general surgery colleagues, including adhesions between the small bowel and augmented bladder. The patulous left ureter was located coursing into the augmented bladder segment, and following its ligation, appeared to have a diameter larger than that of the small bowel lumen.

Multivitamin use may reduce prostate Ca recurrence

	A large bladder mass was palpable at the anterior portion of the bladder. Once the bladder was successfully removed en bloc with the prostate, the left ureter was noted to have been tunneled under the sigmoid mesentery proximally. There were significant adhesions proximally with the bowel and mesentery that made the dissection of the left ureter challenging, and it was felt that an attempt to free it to allow for a cutaneous ureterostomy would be precarious and possibly injure its blood supply. As such, a decision was made to bridge the gap between the ureter and skin using an ileal conduit, which was anastomosed to the solitary left ureter in an end-to-end fashion.

	Postoperatively, the patient had a relatively uncomplicated course, and his final pathology revealed pT3bN0 high-grade urothelial carcinoma with squamous and sarcomatoid differentiation arising in the dome, anterior, and posterior walls of the bladder with invasion into the perivesical soft tissues. Lymphovascular invasion was present, and all margins were negative. He is currently under consideration for adjuvant systemic immune therapy trials with our medical oncology colleagues.

	In summary, we present the unique case of a 48-year-old male with prune belly syndrome, solitary left kidney, and prior enterocystoplasty, who was found to have muscle-invasive bladder cancer with extensive squamous differentiation. Our case highlights multiple complexities in his management, including the role for multimodal care, operative challenges necessitating consultation with other surgical colleagues, and the importance of having multiple strategies in the operating room should the initial plans prove less desirable.

	Our case also highlights the controversy surrounding the development of and screening for intravesical malignancy in patients with prior enterocystoplasty, for which a stronger level of clinical evidence is necessary. Finally, our case more broadly underscores the challenges inherent in transitional care within urology.

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Imaging reveals a mass at the anterior bladder dome with inflammation extending to the perivesical fat. No pelvic lymphadenopathy or sites of metastatic disease are found.

Yair Lotan, MD

Articles

Strategies to mitigate impact of intravenous ICM shortage

Challenging cases in urology: Hematuria in a man with prune belly syndrome