Spina bifida (SB) is the most common, permanently disabling, congenital birth defect in the United States (US),^{1, 2} with downstream effects on multiple organ systems. Among SB phenotypes, myelomeningocele (MMC) is the most severe survivable form. At birth, most infants with SB are thought to have normal kidney health.³ However, individuals with SB reach end-stage kidney disease (ESKD) by nearly two decades younger age than individuals without SB.^{4, 5} Kidney dysfunction is therefore an acquired condition in SB that some believe occur in up to 50% of individuals by their 3^rd decade of life.^{6, 7}

Measurement of kidney dysfunction varies depending on the modality used,⁸ such as imaging or laboratory testing. Renal bladder ultrasound (RUS) is often used to screen for hydronephrosis. Given how kidney function may be altered in neurogenic bladder from backpressure or vesicoureteral reflux leading to febrile urinary tract infections, hydronephrosis in the literature has often been used as a measure of kidney health as shown in a recent systematic scoping review.⁸ Laboratory-based testing for estimated glomerular filtration rate (eGFR) is commonly used to define chronic kidney disease (CKD). In the National Spina Bifida Patient Registry (NSBPR), most participating SB centers routinely used RUS, but not serum creatinine measurements,⁹ which is commonly used to calculate eGFR. RUS screening may be favored over venipuncture in children to avoid the pain and distress known to be associated with needle-related procedures.¹⁰ However, the correlation of these two modalities of kidney dysfunction have not been well-studied, which, given the bias in practice patterns towards ultrasound over serum creatinine, raises concerns of underdiagnosing CKD in the SB population when using RUS alone. In addition, differences in recommendations on serum creatinine testing by age group in the Spina Bifida Association’s Guidelines for the Care of People with Spina Bifida¹¹ or on laboratory testing in general across different guidelines^{11, 12} may further cloud practice patterns of kidney surveillance with limited evidence supporting these recommendations.

Given that RUS is often considered a screening tool that triggers checking serum creatinine in both clinical practice and in the Guidelines,¹¹ we sought to determine the diagnostic test characteristics of ultrasound-based hydronephrosis for low kidney function defined by creatinine-based eGFR. Based on data suggesting that hydronephrosis is a transient finding dependent on bladder filling,¹³ we hypothesized that hydronephrosis diagnosed by screening RUS would have low sensitivity to serve as a high-yield screening tool for low eGFR.

In UMPIRE, a total of 221 participants were included (Figure 1). The median age of the cohort was age 2.4 years (interquartile range [IQR] 1.9–3.8), 53% were male, 63% were Non-Hispanic white, and 9% had thoracic level lesions (Table 1). The median time between RUS and serum creatinine was 0 months (IQR 0–6). A quarter (25%) of participants were determined to have any hydronephrosis, and nearly a quarter (24%) had eGFR <90 mL/min/1.73m². In NSBPR, a total of 2,269 participants with MMC were included (Figure 2). The median age of the cohort was age 13 years (IQR 9.6–16.3), 50% were male, 54% were Non-Hispanic white, and 15% had thoracic level lesions. The median time between RUS and serum creatinine was 0 months (IQR 0–3). Fewer participants (15%) had any hydronephrosis and 17% had eGFR <90 mL/min/1.73m².

In SB, kidney health is an essential, life-long health concern. In the current study, we compared a commonly used imaging test for kidney health, hydronephrosis on RUS, against a commonly used laboratory test for kidney health, creatinine-based eGFR. These tests reflect common practice patterns across many urologists and centers who care for patients with SB, with RUS used more often than serum creatinine testing in childhood but not necessarily in adults.^{9, 19} We found that ultrasound-based hydronephrosis had poor sensitivity for CKD based on creatinine-based eGFR. Our results indicate that RUS alone is a poor screening marker of kidney health and should be combined with routine serum testing.

Aside from our findings, RUS offers many advantages over routine serum testing that otherwise would strengthen its case as an ideal screening test. RUS is non-invasive and safe with minimal morbidity to the patient, is nearly ubiquitous across most pediatric centers, and is relatively easy to perform with trained technicians. In contrast, venipuncture can be quite distressing for both the child and caregiver.²⁰ Although attention in more recent years has been placed on effective pain management strategies during needle-related procedures,²¹ significant needle fear can persist into adulthood and negatively affect medical adherence.¹⁰

As per the Spina Bifida Association Guidelines, serial RUS are recommended in SB to monitor for bladder or kidney dysfunction.¹¹ An example of the former is that detection of hydronephrosis could prompt a urodynamics study to assess for elevated bladder storage pressures or vesicoureteral reflux. For kidney health, however, the Guidelines recommend obtaining serum creatinine testing only if there is a change in the upper urinary tract for certain age groups (i.e., 1–5 years old).¹¹ Our study results, and those from prior literature, do not support this latter recommendation. Indeed, our study results support recommendations from other guidelines, such as the European Association of Urology Paediatric Urology Guidelines, that recommend annual laboratory testing.¹²

The major, critical limitation of using hydronephrosis alone is its poor sensitivity for CKD. An ideal screening test would achieve close to 100% sensitivity, meaning there are zero to very few false negatives or false reassurances that there is no CKD. In our current study, we found a sensitivity of 25% in the UMPIRE cohort (who are 1–5 years old) and 24% in the NSBPR cohort for a creatinine-based eGFR <90 mL/min/1.73m². Another interpretation is that patients who have CKD will have ~75% chance of having no hydronephrosis on RUS. Prior retrospective work from a single institution using more conservative, Cystatin-C-based eGFR calculations found similarly poor sensitivity of ultrasound-based hydronephrosis for CKD.²² We suspect that a combination of the transient nature of hydronephrosis (i.e., dependency on bladder fullness at time of RUS¹³) and the greater physiologic renal reserve found in younger children may drive our findings, as supported by our sensitivity analysis using high-grade hydronephrosis that found similar results. It is important to note that while creatinine values may be abnormal in settings of dehydration or infection, most values in UMPIRE are collected during ambulatory clinic visits and not from inpatient hospitalizations.

Although ultrasound-based hydronephrosis alone is a poor screening marker, we are not advocating that hydronephrosis should not be checked routinely. Our results found specificities of 75–87% in the UMPIRE and NSBPR cohorts, meaning that 75–87% of patients without CKD will test negative for concurrent hydronephrosis. Another interpretation is that patients who do not have CKD will have 13–25% chance of having hydronephrosis on RUS. Given that hydronephrosis could also trigger bladder function evaluation with urodynamics, RUS maintains a vital role in urologic screening in SB. We are suggesting that, for kidney health, routine serum testing be combined with routine imaging testing, as parallel testing (versus serial testing) increases overall sensitivity.

One other study finding warrants further discussion. We noted a significant difference in prevalence of eGFR <90 mL/min/1.73m² between the UMPIRE and NSBPR cohorts, with a higher prevalence in the former (24% versus 17%). This finding may be due in part to detection bias from the more regimented and standardized follow-up protocol of the UMPIRE cohort when compared to the non-standardized follow-up protocol within the NSBPR cohort. There are also likely more NSBPR participants, being older, who underwent bladder reconstructive surgery, which may help mitigate kidney dysfunction. Further, as shown in the study flowcharts of the Figures, many more NSBPR participants were excluded than UMPIRE participants. This selection bias may also have contributed to the difference in CKD prevalence between cohorts. However, separation of the UMPIRE and NSBPR groups by age was necessary to ensure separation of a strict surveillance protocol for kidney health from a non-protocolized surveillance strategy.

Our study results should be interpreted in context of its strengths and limitations. Given the wide clinical spectrum and heterogeneity of SB, we restricted our study population to individuals with MMC, which is the most severe survivable form of SB. We examined the two largest SB registries in North America, both of which are multi-centered, reflect the clinical spectrum of MMC, and likely reflect different management paradigms of individuals with MMC. Lastly, we analyzed our results with two different sensitivity analyses with similar, robust results about the poor sensitivity of hydronephrosis.

Our study has limitations. As the reference in the current study for determining diagnostic test characteristics, creatinine-based eGFR was used, which has well-known unreliability and variability and is not the gold standard used for measuring true GFR (which is urinary inulin clearance or iohexol plasma clearance).^{23, 24} However, increasing the uptake of gold standard testing faces barriers including prolonged duration of the test and the requirement of intravenous catheters. Use of recumbent length or arm-span as a proxy for standing height may provide bias for eGFR calculations, though multiple studies in healthy volunteers show very high correlations between arm-span and height with small differences.²⁵ Similarly, though the Schwartz eGFR equation was developed in a cohort of children as young as 1-year-old, GFR in children does not approach typical adult levels until age 1.5-to-2-years-old, which may bias results.²⁶ However, ~75% of the UMPIRE cohort was >2 years old, so results are unlikely to change substantially. Cystatin-C may be a more reliable marker for CKD than serum creatinine,²⁷ but since serum creatinine is used more commonly in practice than serum cystatin-C,¹⁹ and since the Guidelines mention serum creatinine specifically,¹¹ our study design reflects contemporaneous clinical practice patterns and guideline recommendations. Additionally, since low muscle mass in youth with MMC may cause creatinine-based eGFR to be overestimated, a low creatinine-based eGFR likely signifies an even lower actual GFR. We did not adjust for bladder fullness at time of RUS, which may impact degree of hydronephrosis,¹³ though we suspect a single cross-sectional timepoint to hold minimal value and more chronic bladder fullness to be more meaningful. Our study evaluated only hydronephrosis as an RUS outcome, when other outcomes such as thinned cortex, dysplasia, or hyperechogenicity may also be concerning findings for CKD, but were not captured in UMPIRE and NSBPR. We did not evaluate nuclear medicine scans nor urine studies such as microalbuminuria, but these were not the focus of our current study and may be a part of future directions, along with prospective studies to validate our findings. Our study results may have limited generalizability, given that we assessed only patients with MMC and at NSBPR and UMPIRE clinic sites, which may not be representative of the larger pediatric SB population in the US. Lastly, our study identified relatively few outcome events for eGFR <60 mL/min/1.73m², which limits the power of our analyses for more severe CKD.

In conclusion, in our study of two large SB cohorts in the US, ultrasound-based hydronephrosis has poor diagnostic sensitivity for low eGFR based on serum creatinine. Our findings indicate that RUS alone is a poor screening marker of kidney health and should be combined with routine serum testing of at least serum creatinine. Current CKD screening protocols in people with spina bifida should include at least annual serum laboratory testing in addition to annual RUS.