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Page 16 of 34 West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61

reduction in baseline uPCR was achieved in 75% of patients; eGFR slopes were significantly better than in
2
those patients who did not achieve the uPCR goal, -3.6 vs. -7.0 mL/min/1.73 m /yr, respectively. Low blood
pressure and hyperkalemia were limiting factors to the use of ACEinh and ARB in some patients.

There are no publications on the use of mineralocorticoid receptor antagonists (MRA) in Fabry
nephropathy. As a result, nephrologists must rely on data about many of these drugs from studies carried
out in other proteinuric diseases. Diabetic nephropathy may be a reasonable model for Fabry nephropathy
given the commonalities of metabolic disease, renal glycosphingolipid abnormalities, glomerular
hyperfiltration, hypertension, small vessel vasculopathy, and multisystem features with retinal, cardiac,
gastrointestinal disease and sensory neuropathy. There are reports of significant antiproteinuric effects in
[105]
diabetic nephropathy of MRAs such as spironolactone, eplerenone, and finerenone . Thiazide diuretics
[106]
may also have a modest effect . There are two reports of amiloride-induced reduction of proteinuria, one
in diabetic kidney disease and one in Fabry disease .
[107]
[108]
Newer agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2) are also of proven benefit in both
diabetic nephropathy and nondiabetic proteinuric kidney disease in terms of stabilization of eGFR and
[109]
reduction of proteinuria . Their benefits also extend to both systolic and diastolic heart failure, which can
complicate Fabry cardiomyopathy .
[110]

It should be noted that the benefits of MRAs and SGLT2 inhibitors are additive to those of ACEinh and
ARBs. While there are no data yet on the use of SGLT2 inhibitors in Fabry disease, there is a clinical trial in
the planning stage to study the effects of this drug on heart and kidney function in this condition.
(NCT05710367 clinicaltrials.gov)

Vitamin D and its analogs may also be considered for the treatment of proteinuria in Fabry nephropathy.
Vitamin D deficiency is common in Fabry disease; in one study, 46.8% of 77 patients had vitamin D
deficiency, even though half of those were already taking cholecalciferol . Vitamin D deficiency has been
[111]
identified as a factor worsening both kidney and heart disease in Fabry disease with increasing
proteinuria . In a human podocyte model exposed to lyso-Gb3, vitamin D receptor activation was also
[31]
shown to be of benefit through the blocking of an increase in secondary mediators of renal injury, such as
[65]
TGF-β1, induced by lyso-Gb3 . The addition of the vitamin D analog paricalcitol to ACEinh or ARB in a
randomized controlled trial in 15 adults with Fabry nephropathy further reduced proteinuria over 6 months
from a mean of 1.4 g/day to 0.4 g/day . Caution must be taken as secondary hypercalcemia with
[112]
worsening cardiac and renal function can occur with high-dose vitamin D . Vitamin D and its analogs
[113]
have also been used successfully to lower proteinuria in small short-term studies of diabetic nephropathy
and other proteinuric kidney diseases [114,115] . Overall, these data suggest that vitamin D deficiency should be
identified and corrected wherever possible and that low-dose vitamin D therapy can be added to reduce
proteinuria in Fabry nephropathy.

Adjunctive therapies
Other important therapies relate to minimizing risks for cardiovascular disease, such as dyslipidemia,
smoking, hypertension, and obesity. Blood pressure control can be challenging in patients with Fabry
disease due to significant variability, partially attributed to autonomic neuropathy present in some
patients . Ambulatory blood pressure monitoring can be useful to diagnose masked hypertension. Beta-
[116]
blocker use is to be avoided as this may worsen the resting sinus bradycardia that many adults with Fabry
disease exhibit .
[117]