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Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56 Page 13 of 29

equation to estimate GFR in adults with FD [167,168] . However, given that measured GFR by iohexol plasma
clearance and isotopic methods is more accurate, depending on local availability, the precise measurement
of the GFR is recommended for FD patients if the estimated GFR is > 60 mL/min/1.73 m 2[168] .

[169]
Cystatin C was proposed as a reliable marker of renal function [Table 4] . Cystatin C has been compared
with creatinine in the evaluation of renal function in a cohort of patients treated with agalsidase α for 4
years, with no significant change in creatinine or in creatinine-based estimated GFR, but with a significant
increase (just after only one year of ERT) in cystatin C and a concurrent decrease in estimated GFR by Hoek
[170]
equation (using cystatin C values). The authors concluded that cystatin C was an early marker for the
decline of GFR, but no gold standard precise measurement of GFR was used to support this conclusion .
[171]
[92]
This finding was further corroborated by another study .
Cystatin C-based estimation of GFR was compared with measured GFR in a relatively small validation study
(including several cystatin and creatinine-based equations). In contrast to that previously mentioned, Hoek
equation was less accurate than CKD-EPI creatinine2009 equation in detecting GFR decline during ERT, but
Stevens’ equation (a creatinine and cystatin C-based formula) was the one that most closely
[172]
approximated the measured GFR . However, Stevens’ equation development was based on serum cystatin
[173]
C assays in adults that were not traceable to standard reference material. Consequently, it is no longer
[167]
recommended by international chronic kidney disease (CKD) guidelines .
Albuminuria/proteinuria
Role in the identification of preclinical involvement
Total urinary protein and albumin excretion can be considered important biomarkers in FD nephropathy
[Table 4]. Proteinuria (> 150 mg/day) and albuminuria A2 are usually the first signs of renal
involvement [174-177] . The sensitivity of albuminuria seems superior to that of total urinary protein excretion in
detecting early renal involvement in FD . Thus, albuminuria remains the best existing marker to detect
[178]
early renal involvement, but the relevance of albuminuria A2 as a biomarker is largely based on validation
studies in the earlier stages of other nephropathy models. Moreover, in FD, nephropathy albuminuria may
result not only from glomerular damage of the filtration barrier, but also from tubular involvement with
decreased reabsorption of filtered albumin.

However, the usefulness of albuminuria and/or proteinuria in identifying incipient FD nephropathy is
questionable. Although there is a significant correlation between urinary protein excretion rates and foot
[16]
process width and fractional volume of Gb3 inclusions in the podocytes , FD nephropathy is clinically
silent for a long period and significant histological changes (including nonspecific degenerative lesions) may
occur without pathological albuminuria and/or proteinuria [15-20] . In incipient stages of FD nephropathy,
tubular reabsorption of albumin may overcome its increased excretion, limiting the sensitivity of this
biomarker.

Prognostic value and role in the evaluation of treatment response
Furthermore, proteinuria also seems to play an important role in FD nephropathy progression, even in
patients treated with ERT, because it is an independent risk factor affecting the extent of renal decline and is
one of the determinants of the success of ERT [12,178-185] . For both genders, the proportion of patients with
overt proteinuria (> 300 mg/day) and its magnitude and the prevalence of nephrotic range proteinuria are
higher with more advanced CKD stages [12,178] . Moreover, comparing the GFR decline stratified by baseline
proteinuria, higher baseline proteinuria levels were associated with more rapid GFR decline, but the patients
with higher baseline proteinuria were also older and with lower baseline GFR [12,179] . Notwithstanding this, in