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West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61 Page 5 of 34

proteinuria (males 11% and females 28%). Median proteinuria was 572 mg/day in males and 180 mg/day in
[11]
females . In 84 men and women with the N215S late-onset variant, the prevalence of proteinuria was not
[14]
different from the 167 non-N215S patients, 17.9% vs. 26.3%, respectively .
Hematuria
[20]
Microhematuria has been reported in Fabry disease, but its significance is uncertain . In other
[21]
podocytopathies, microhematuria has been associated with a worse renal prognosis . Whether this applies
to Fabry nephropathy is unknown.

Parapelvic cysts
Parapelvic cysts are common in Fabry nephropathy, and their prevalence increases with age to over 45% by
age 50 years in both men and women compared with a prevalence of 1%-6% in the general population .
[22]
Therefore, the detection of parapelvic cysts during kidney ultrasound should prompt the consideration of
Fabry disease. There is no association with decreased eGFR or proteinuria, suggesting that the parapelvic
cysts do not contribute to the progression of Fabry nephropathy. Glycosphingolipids have been implicated
in polycystic kidney disease, suggesting a role for Gb3 in parapelvic cyst formation in Fabry disease.

Tubular syndromes
Fanconi syndrome and nephrogenic diabetes insipidus are both rare complications of Fabry nephropathy,
with involvement of proximal and distal renal tubular epithelium, respectively [23,24] . They are most likely to
occur in males with classic Fabry phenotype. As they may be the presenting feature of Fabry disease,
nephrologists should be aware of this association.

Progressive CKD
In males with classical genotypes, progressive CKD is the norm, with most patients developing increasing
proteinuria and declining eGFR between the ages of 20 and 55 years. They will progress to ESRD unless they
die from another Fabry disease complication such as cardiomyopathy or stroke. Females with classical
genotypes are far less likely to progress to ESRD due to mosaicism and perhaps skewing of X chromosome.
Males with rare late-onset renal variants are also at high risk for ESRD, but there are few data as to this
subgroup. Males with the late-onset cardiac genotype face a risk of developing Fabry nephropathy,
particularly those with the N215S genotype. Females with late-onset cardiac variant disease probably have
minimal risk of developing advanced Fabry nephropathy.

In a referral population of 105 men at the NIH, prior to ERT, 74% developed CKD; only 19% received
angiotensin-converting enzyme inhibitors (ACEinh) or angiotensin receptor blockers (ARB) . CKD onset
[10]
was observed in 37%, at mean age 42 years (ranging from 19-54 years). Fifty percent of patients had
decreased GFR by the median age of 42. 23% started dialysis with an onset age range of 21-55 years; there
were kidney transplants in 14 patients. All patients who survived to age 55 started dialysis; all patients were
dead by age 60 years, with a mean age at death of 50 years.

In men with N215S late-onset variant, mean eGFR was no different from that of men with classic Fabry
disease; there was no difference in eGFR between women in these two groups, indicating that some late-
[12]
onset variants can have significant Fabry kidney disease .

eGFR slopes are higher in untreated males than in females, reflecting their different genotypes. There is a
range of slopes reflecting the effect of different variants as well as other factors such as hypertension, use of
ACEinh or ARB, proteinuria, and possible modifier genes and other factors. In males, mean GFR slopes
[27]
[10]
were reported as -12.2 , -3.85 , -7.0 , and -8.3 mL/min/1.73 m /yr . In females who did not reach
[25]
2
[26]