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Page 6 of 34 West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61

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ESRD, eGFR slopes were the same as in the general population, at -1.02 and -0.83 mL/min/1.73 m /yr [25,28] .
[25]
Females who did reach ESRD had eGFR slopes similar to males at -3.05 mL/min/1.73 m /yr . Few of these
2
patients received ACEinh or ARB therapy.
Increasing proteinuria is associated with a marked decrease in eGFR whether or not patients are receiving
ERT [25,26] . Schiffmann (2009) reported worsening eGFR slope in untreated men with Fabry disease from -1.6
2
[25]
to -3.3 to -6.9 mL/min/1.73 m /yr as proteinuria increased from < 0.1 to ≥ 0.1- < 1.0 to ≥ 1.0 g/day .
Similarly, in women, the eGFR slope worsened from -0.6 to -2.2 to -4.6 mL/min/1.73 m /yr over the same
2
[25]
range of proteinuria. Men had a much greater decline in eGFR than women at all levels of proteinuria . In
108 ERT-treated men with proteinuria < 1 g/day, eGFR slopes were 1.0-2.0 mL/min/1.73 m /yr compared
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with eGFR slopes > 5 mL/min/1.73 m /yr for 38 patients with proteinuria ≥ 1 g/day .
[26]
2
Renal events defined as stage V CKD, dialysis, or kidney transplant were studied in 541 Fabry patients. Men
with classical phenotype had a much higher renal event rate than men with non-classical disease (P < 0.01)
and women with classical phenotype (P < 0.05) .
[29]
Risk factors for progressive CKD in Fabry disease include age, gender, classic phenotype, proteinuria, low
eGFR, hypertension, high plasma lyso-Gb3, very low α-Gal activity, conservative mutation, and vitamin D
deficiency [10,30,31] .

Chiorean et al. (2023) reported on a retrospective cluster analysis of pre-treatment Fabry disease patients
from a large US electronic health record network database. The prevalence of Fabry disease was 1 in
[32]
101,729 . They divided the 234 Fabry patients, mean age 46 years, into 7 clusters based on eGFR and age
patterns. Follow-up duration averaged 9.2 years. Data from 5 clusters were informative, with patients
showing eGFR slopes from -1.13 to -3.11 mL/min/1.73 m /yr. Prevalence of CKD stages II-V varied from
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17% to 77% across the clusters. Fabry complications varied between groups. This study shows the spectrum
of phenotypes in Fabry disease.

Cardiorenal syndrome (CRS) type 5 has been identified in Fabry disease, where concurrent diseases in the
kidney and heart contribute to pathology in other organs . Siegenthaler (2017) conducted a study on 104
[33]
adults with Fabry disease over a median of 105 months. Kaplan Meier analysis revealed that the survival rate
[34]
was lowest for the 28 patients with CRS, among whom six died . There is bilateral organ crosstalk through
various mechanisms that are activated as each organ is damaged by Fabry disease and begins to fail. As heart
function is progressively compromised by Fabry cardiomyopathy with both diastolic and systolic
dysfunction, this will lead to decreased kidney perfusion, which will, in turn, result in decreased eGFR and
worsening Fabry nephropathy. Alternately, as Fabry kidney disease progresses, there will be an
accumulation of salt and water, which will contribute to fluid overload and worsening heart failure. Anemia
and hypertension from kidney disease will increase left ventricular hypertrophy (LVH); metabolic acidosis
and various electrolyte disorders will contribute to decreased cardiac function and arrhythmias. The
activation of the renin-angiotensin system occurs in both kidney and heart diseases and is an important
avenue for intervention with ACEinh and ARB. Newer agents such as SGLT2 inhibitors will reduce
proteinuria, stabilize eGFR, and treat both systolic and diastolic heart failure, making them suitable for
[35]
managing CRS . Recognition of CRS is important given its poor prognosis, allowing for optimized therapy
for both kidney and heart conditions.