Asymptomatic, microscopic hematuria in epidermolysis bullosa: A single center retrospective case series.

To the Editor: Epidermolysis bullosa (EB) is a group of genodermatoses defined by skin fragility. Recessive dystrophic EB (RDEB) and junctional EB are known to cause extracutaneous manifestations which include urinary tract and renal involvement.1Fine J.D. Johnson L.B. Weiner M. et al.Genitourinary complications of inherited epidermolysis bullosa: experience of the national epidermolysis bullosa registry and review of the literature.J Urol. 2004; 172: 2040-2044Crossref PubMed Scopus (63) Google Scholar,2Chan S.M.H. Dillon M.J. Duffy P.G. Atherton D.J. Nephro-urological complications of epidermolysis bullosa in paediatric patients.Br J Dermatol. 2007; 156: 143-147Crossref PubMed Scopus (29) Google Scholar There are no reports regarding the frequency of hematuria in EB without accompanying urologic disease. During baseline assessments for determination of eligibility for clinical trials, urinalyses (UAs) were performed for patients of all EB subtypes. Here, we present a retrospective analysis of these cases. Participants were screened for urinary tract infection (UTI) and menstrual status. The history of hormonal therapies, genitourinary disease, and presence of groin wounds were gathered via chart review. Mann-Whitney U and Fisher’s exact tests were used to compare age, sex, groin wounds, and EB subtypes across those with and without hematuria. Twenty-seven participants with dipstick UAs were identified (Supplementary Tables I and II, available via Mendeley at https://doi.org/10.17632/cr8h9z8vjg.2). None had known urologic disease or recent UTIs. With one exception, creatinine levels were below the reference upper limit. All premenopausal patients denied menses at testing aside from one where these data were missing. The majority (14/27, 52%) demonstrated dipstick UA positive for blood (“dipstick hematuria”) including 20% of men and 71% of women (P = .018, Table I). Of 17 women, 7 were postmenopausal and none were on hormone replacement therapy. The mean age with hematuria was significantly greater than without (44.9 vs 28.1 years, P = .019). Seventy-five percent (3/4) with groin wounds and 48% (11/23) without had dipstick hematuria. Microscopic UA was available for 8 subjects. Two of 4 patients with dipstick hematuria met the criterion for microscopic hematuria. As of May 2022, of 14 patients, none with dipstick hematuria developed the urologic disease.Table IGroup characteristics of epidermolysis bullosa patients with and without dipstick hematuriaCharacteristicParticipants without hematuriaParticipants with any hematuriaP valueAge (mean ± SD, y)28.1 ± 18.344.9 ± 16.0.019∗P < .05 (Mann-Whitney U Test, U = 42)Sex.018∗P < .05 (Fisher’s exact test) Male (%) n = 108 (80)2 (20) Female (%) n = 175 (29)12 (71)EB subtype.033∗P < .05 (Fisher’s exact test) JEB intermediate (%) n = 21 (50)1 (50) RDEB intermediate (%) n = 61 (17)5 (83) RDEB inversa (%) n = 41 (25)3 (75) RDEB severe (%) n = 119 (82)2 (18) DDEB severe (%) n = 21 (50)1 (50) EBS (%) n = 20 (0)2 (100)Groin wound presence.596 (Fisher’s exact test) Yes (%) n = 41 (25)3 (75) No (%) n = 2312 (52)11 (48)Total (%) N = 2713 (48)14 (52)DDEB, Dominant dystrophic epidermolysis bullosa; EBS, epidermolysis bullosa simplex; JEB, junctional epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis bullosa; SD, standard deviation.∗ P < .05 Open table in a new tab DDEB, Dominant dystrophic epidermolysis bullosa; EBS, epidermolysis bullosa simplex; JEB, junctional epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis bullosa; SD, standard deviation. Historically, genitourinary complications were considered ominous and reported in a minority of patients with EB.1Fine J.D. Johnson L.B. Weiner M. et al.Genitourinary complications of inherited epidermolysis bullosa: experience of the national epidermolysis bullosa registry and review of the literature.J Urol. 2004; 172: 2040-2044Crossref PubMed Scopus (63) Google Scholar, 2Chan S.M.H. Dillon M.J. Duffy P.G. Atherton D.J. Nephro-urological complications of epidermolysis bullosa in paediatric patients.Br J Dermatol. 2007; 156: 143-147Crossref PubMed Scopus (29) Google Scholar, 3Fine J.D. Johnson L.B. Weiner M. et al.Inherited epidermolysis bullosa and the risk of death from renal disease: experience of the National Epidermolysis Bullosa Registry.Am J Kidney Dis. 2004; 44: 651-660Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Our findings indicate that microscopic hematuria in EB may be more common than initially thought. The presence of groin wounds cannot solely explain our observation, because many patients without groin wounds had dipstick hematuria. Interestingly, we found that patients with RDEB-inversa and RDEB-intermediate appeared more susceptible than RDEB severe. Given the cohort had largely low-to-normal creatinine levels, low frequency of proteinuria, and negative UTI symptomology, we suspect EB predisposes individuals to increased sensitivity to urinary tract microtrauma, which manifests as occult hematuria. As our cohort with hematuria was older and female predominant, it is possible chronic trauma and inflammation over time are contributory, and anatomic sex differences influence susceptibility. Although 6 of 7 postmenopausal patients demonstrated dipstick hematuria, prior literature suggests that vaginal atrophy, menopausal status, and hormonal therapy alone are not risk factors for microhematuria.4Richter L.A. Lippmann Q.K. Jallad K. et al.Risk factors for microscopic hematuria in women.Female Pelvic Med Reconstr Surg. 2016; 22: 486-490Crossref PubMed Scopus (9) Google Scholar Our study is limited by the lack of additional workup including cystoscopy or other imaging. Further, we primarily had access to dipstick UAs, which are less reliable than microscopic analysis. Nevertheless, we did confirm that 50% of a subset of dipstick hematuria cases had true microscopic hematuria, which exceeds the reported dipstick false positivity of 1% to 35%.5Simerville J.A. Maxted W.C. Pahira J.J. Urinalysis: a comprehensive review.Am Fam Physician. 2005; 71: 1153-1162PubMed Google Scholar Although patients with EB should undergo appropriate evaluation of microscopic hematuria given the known association with increased mortality from renal disease,3Fine J.D. Johnson L.B. Weiner M. et al.Inherited epidermolysis bullosa and the risk of death from renal disease: experience of the National Epidermolysis Bullosa Registry.Am J Kidney Dis. 2004; 44: 651-660Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar this study suggests that asymptomatic microhematuria may be a common, benign finding across EB subtypes. Furthermore, study is required to elucidate the underlying mechanism. Drs Gorell, Tang, and Chiou received salary support from the Epidermolysis Bullosa Medical Research Foundation, the Epidermolysis Bullosa Research Partnership, and were investigators for Phoenix Tissue Repair and Abeona Therapeutics Inc.