Renal and urinary tract abnormalities in FA are common, with previous studies suggesting that around one third of patients have structural renal abnormalities [
12,
13]. Our analysis identifies a prevalence of 50%, confirming the high frequency of earlier observations in what is, to our knowledge, the largest cohort specifically reporting renal aspects of FA. The patterns of abnormalities detected point to perturbed normal ascent of the embryonic kidney in FA and imply a potential role for the FA pathway in particular during early embryonal stages of kidney development. Further support for this hypothesis comes from a recent study reporting brca2/fancd1 deficiency in zebrafish leading to perturbed pronephros development [
14]. As in previous studies [
12], we did not identify an obvious correlation between genotype and presence of kidney abnormalities. Given the high incidence of renal abnormalities, anatomical and functional evaluation is important at diagnostic workup of FA. While obvious and significant renal dysfunction is uncommon at diagnosis, and in our cohort in all cases was associated with a severe phenotype, the high incidence of UTIs in our cohort, and findings of abnormal functional imaging suggests that children with FA may have compromised but compensated renal function. Published case reports support our findings that a minority of FA patients have severe renal problems at diagnosis, and CKD can be a serious complication of FA [
15]. For baseline renal assessment in FA, as summarized in Table
2, we would recommend ultrasound imaging accompanied by regular biochemical monitoring. Decisions with respect to additional radiological investigations would need to be taken on an individual basis. Mindful of the potential higher sensitivity to radiation, imaging could alternatively be carried out using MR (Supplemental Figure
3). Although there is no published experience specifically in FA, MR-urography has been used by us and others for reflux and assessment of renal function, avoiding ionizing radiation exposure [
16,
17]. In our cohort, renal impairment at diagnosis was seen in children with severe phenotype including early severe haematological complications. Early renal impairment might have some prognostic significance in general for FA that would need to be confirmed in larger patient groups. Only three patients in our study encountered renal complications acutely during HSCT, which is less than other FA patient cohorts described in the literature [
18]. While this might just reflect our selected patient population, we conclude that overall acute renal complications during HSCT are manageable in FA, but can also affect patients with normal kidneys on imaging. Renal sequelae have not specifically been studied with respect to the long-term outcome in FA, including non-transplanted patients and post-HSCT [
19]. Data from our cohort suggest that renal dysfunction post-HSCT might be more common in FA patients than reported for children transplanted for other indications [
20] and suggest that the incidence of renal dysfunction post-HSCT might increase with age in some cases of FA. However, most children maintained normal kidney function, and longer follow-up evaluation of larger groups of FA, and also of non-FA children with respect to renal health after HSCT, will be necessary to assess comprehensively the incidence and causation of renal dysfunction. Importantly, in our cohort, this also affected patients with normal renal anatomy on ultrasound imaging and normal kidney function at diagnosis of FA. An intrinsic increased sensitivity to genotoxic stress in kidneys of FA patients might underlie this observation, in particular as this has been observed in mice with FANCD2/FANCI-associated nuclease (FAN1) disruption, and renal sensitivity to genotoxic stress has been reported in response to cross-linking agents and other substances, such aristolochic acid [
21,
22]. More detailed prospective analysis of kidney function, also prospectively including urinary protein excretion pre- and post-HSCT, will be able to clarify biology and clinical relevance for children with FA.
Table 2
Pragmatic approach to assessment and management of renal manifestations of Fanconi anaemia
Assess renal function and biochemistry | Assess renal function and biochemistry | Assess renal function and biochemistry 6 monthly |
Ultrasound scan of urinary tract If abnormal consider individual need for further imaging, e.g. MR urography, DMSA scan Enhanced surveillance for UTI if CAKUT detected | Enhanced surveillance for UTI if CAKUT detected Consider use of antibiotic prophylaxis, in particular with VACTER-L-type abnormalities, complex abnormalities, and evidence of reflux | |
Blood pressure monitoring | Blood pressure monitoring | Blood pressure monitoring |
Renal disease is clearly important for the management of FA at diagnosis and early clinical course and during HSCT. Furthermore, renal function is also relevant for management of later complications in FA, such as other malignancies. With these points in mind, we suggest a few pragmatic guidelines for renal assessment of FA, as outlined in Table
2. Every patient should have imaging by ultrasound scan; further imaging may be necessary on an individual basis, but X-ray exposure should always be considered, and additional investigations justified. Close monitoring for UTIs in young children with a low threshold for antibiotic intervention and lifelong monitoring for renal function is important for long-term follow-up in FA.