Patterns and frequency of renal abnormalities in Fanconi anaemia: implications for long-term management
Fanconi anaemia (FA) is an inherited disease with bone marrow failure, variable congenital and developmental abnormalities, and cancer predisposition. With improved survival, non-haematological manifestations of FA become increasingly important for long-term management. While renal abnormalities are recognized, detailed data on patterns and frequency and implications for long-term management are sparse.
We reviewed clinical course and imaging findings of FA patients with respect to renal complications in our centre over a 25-year period to formulate some practical suggestions for guidelines for management of renal problems associated with FA.
Thirty patients including four sibling sets were reviewed. On imaging, 14 had evidence of anatomical abnormalities of the kidneys. Two cases with severe phenotype, including renal abnormalities, had chronic kidney disease (CKD) at diagnosis. Haematopoietic stem cell transplantation was complicated by significant acute kidney injury (AKI) in three cases. In three patients, there was CKD at long-term follow-up. All patients had normal blood pressure.
Evaluation of renal anatomy with ultrasound imaging is important at diagnostic workup of FA. While CKD is uncommon at diagnosis, our data suggests that the incidence of CKD increases with age, in particular after haematopoietic stem cell transplantation. Monitoring of renal function is essential for management of FA. Based on these long-term clinical observations, we formulate some practical guidelines for assessment and management of renal abnormalities in FA.
KeywordsFanconi anaemia Renal abnormalities Long-term follow-up
Fanconi anaemia (FA) is an inherited disease associated with variable congenital and developmental abnormalities, bone marrow failure, and cancer predisposition. FA results from defects in the FA/BRCA pathway for DNA interstrand crosslink (ICL) repair, in which multiple proteins encoded by the FA genes interact [1, 2]. Causative mutations have so far been reported in 22 FA genes (FANCA, -B, -C, -D1, -D2, -E, -F, -G, -I, -J, -L, -M, -N, -O, -P, -Q, -R, -S, -T, -U, -V, and -W) [1, 3, 4]. At a cellular level, FA is characterized by hypersensitivity to DNA crosslinking agents in terms of cell survival, arrest in the G2 phase of the cell cycle, and chromosomal breakage . The phenotype of FA can be extremely variable . Clinical manifestations commonly include radial ray abnormalities, short stature, microcephaly, and skin pigmentation. Bone marrow failure is very common, and historically, this has been the most relevant clinical manifestation . Over the last 20 years with improved outcome of haematopoietic stem cell transplantation (HSCT) and supportive treatment, the clinical course of FA has changed dramatically, and many individuals with FA now reach their third and fourth decade after correction of haematopoietic failure. For these patients, other problems associated with the underlying genetic defect become increasingly relevant for long-term management. Congenital abnormalities of the kidneys and the urinary tract (CAKUT) are well recognized in patients with FA, with a reported incidence of around 30% [5, 6, 7, 8]. However, detailed data with respect to patterns and frequency of abnormalities involving the kidneys are sparse. In addition, implications of renal abnormalities for the long-term management have not been fully assessed, and detailed guidelines for the diagnosis and management of renal abnormalities in FA have not been formulated. These should consider the inherited DNA repair defect and therefore minimize the use of X-rays, because of the potential harm caused in chromosomal instability syndromes such as FA . To address the relevance of patterns and frequency of renal abnormalities for long-term follow-up, we reviewed the incidence and patterns, and the clinical course of patients with FA in our centre together with available genetic data to aid the formulation of guidelines for the management of FA-associated renal problems.
Materials and methods
All patients diagnosed with FA based on clinical findings and demonstration of characteristic increased cellular mitomycin C sensitivity, in most cases complemented by mutational analysis, treated in our centre over the last 25 years were included. We retrospectively analyzed imaging and biochemical laboratory investigations at diagnosis and during their clinical course, including pre-, inter-, and post-HSCT and at long-term follow-up. Patients were grouped for presence and severity of FA-associated clinical features, including haematological, skeletal, central nervous system (CNS), and other abnormalities. Patients were classed as having a mild phenotype when in addition to haematological abnormalities at diagnosis only subtle microcephaly and short stature were present and no obvious radial ray abnormalities. Classical phenotype included radial ray abnormalities and bone marrow failure with typical skin pigmentations, short stature, and microcephaly. Patients were considered to have a severe phenotype when, in addition to the above, they exhibited extreme short stature and abnormalities also seen associated with the VACTER-L spectrum (vertebra, cardiac and trachea-esophageal malformations, limb malformations), and/or CNS, cardiac or anorectal abnormalities were present.
Clinical and genetic characterization of Fanconi anaemia patients studied
Multiple congenital abnormalities
Bone marrow failure evident < 5 years of age
Extreme short stature
FANCD1/BRCA2 - 1
FANCA - 1
FANCF - 2
Undetermined - 1
Bone marrow failure
Microcephaly radial ray abnormalities
Short stature and clinically subtle other abnormalities
FANCA - 13
FANCG - 3
FANCI - 1
Undetermined - 4
Subtle physical abnormalities
Bone marrow failure or hypoplasia
FANCD2 - 1
FANCA - 2
Undetermined - 1
All patients were investigated with renal ultrasound scan at presentation or early in the clinical course. Abnormalities were detected in 14 patients and included six dysplastic, three pelvic, two malrotated kidneys, and one each of crossed fused ectopia, horseshoe, and multi-cystic kidney (Supplemental Table 1, Supplemental Figure 1). A micturating cystourethrogram (MCUG) was performed in two male patients, one with a left pelvic kidney and hydronephrosis in the right kidney, and the other with bilateral renal dysplasia, which demonstrated vesicoureteral reflux (VUR) grade V and II (patient 3 and 23, Supplemental Figure 2A). DMSA (dimercaptosuccinic acid) scan was performed in three patients for assessment of split function, which demonstrated reduced differential renal function in two (patient 22 and 23, Supplemental Figure 2B). All of these abnormalities were managed conservatively. Four sibling sets were included in our study cohort, of which one pair had small dysplastic kidney in one sibling, which was further assessed by magnetic resonance (MR) imaging (patient 10, Supplemental Figure 3A and B). While most patients with severe phenotype had renal abnormalities, these were also detected patients with classic FA or with an otherwise subtle phenotype. There was no obvious correlation between kidney abnormality and mutational genotype.
Six patients had proven urinary tract infections (UTIs) in early childhood, requiring antibiotic treatment followed by prophylaxis. All patients with UTIs had abnormal anatomy on imaging, with MCUG findings documenting VUR in two male patients (patient 3 and 23), and reduced asymmetric kidney function on DMSA scanning in one patient (patient 22). The other three patients with UTIs had small dysplastic kidneys and a recto-vaginal fistula, horseshoe kidney, and fused ectopic kidneys (patients 1, 2, and 4).
Renal function at diagnosis
At diagnosis, chronic kidney disease (CKD) was noted in two cases. One case with severe phenotype and death from rapid leukaemic transformation had renal dysplasia on ultrasound scan with an estimated glomerular filtration rate (eGFR) of less than 15 ml/min/1.73m2 at presentation (patient 3) . The second case, also with severe phenotype including complex heart disease, had a left pelvic kidney with an eGFR of 30 ml/min/1.73m2. The level of renal function improved with management of the infant’s complex clinical needs including gut and heart surgery (patient 2).
Renal complications during HSCT
Of the 24 patients undergoing HSCT using sibling or matched unrelated cord blood or bone marrow, acute kidney injury (AKI) post-HSCT was seen in three patients (14%). All three patients had KDIGO (kidney disease improving global outcome) stage 1 AKI with rise > 1.5 × baseline serum creatinine. Two patients had dysplastic kidneys and one had normal kidneys on ultrasound. In all three patients, AKI was suspected to be related to toxicity from ciclosporin administration, despite absence of documented high trough levels. Renal function improved in all three after dose reduction or withdrawal of ciclosporin, and none required renal replacement therapy.
Outcome and follow-up
One case with severe phenotype and CKD diagnosis from extreme renal dysplasia and severe VUR died of leukaemic transformation at the age of 2 years (patient 3) . Two children died during HSCT of acute transplant-related complications with multi-organ failure, one of whom had a crossed fused ectopic kidney (patients 4 and 7). Seven children, including two who have undergone HSCT, are currently followed up for less than 5 years. Impaired renal function with CKD stage III was present in one child with severe phenotype before HSCT. This has to date been managed conservatively. All six others have normal renal function, including one child, who had one severely dysplastic non-functional kidney removed. On histological examination, this showed complete disorganization of the renal parenchyma with extensive fibrosis and partly cystically dilated tubules cuffed by primitive mesenchyme (patient 22, Supplemental Figure 4). Follow-up data longer than 5 years (range 5 to > 25 years) were available for 23 cases, of which three patients have not undergone HSCT, including a middle-aged female diagnosed in childhood with classic phenotype FA with a pelvic kidney and only subtle haematological abnormalities (patient 18) , and two are awaiting HSCT. During long-term follow-up after diagnosis and HSCT, three patients were noted to have biochemical evidence of CKD (eGFR 20–40 ml/min/1.73m2). All three had small dysplastic kidneys (patients 10, 14, and 21). All 30 patients had normal blood pressure at presentation and at follow-up.
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.
Compliance with ethical standards
The analysis was carried out with consent in accordance with the Declaration of Helsinki as an anonymized case review and as such had institutional review board approval.
Conflict of interest
The authors declare that they have no conflict of interest.
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