Work-up of a Patient With FD
3.1 We recommend that the detailed baseline and follow-up data of all patients with established FD should be transferred to a central registry. (Ungraded statement)
3.2 We recommend baseline and subsequent yearly evaluation by a multidisciplinary team, including kidney function and albuminuria, in all patients with established FD (cardiology, neurology and nephrology). (Ungraded statement)
3.3 We recommend not considering female carriers for living donation, unless in exceptional cases. In these cases, we recommend a kidney biopsy to evaluate the risk for the donor and acceptor. (Ungraded statement)
Once an index patient is diagnosed, a baseline evaluation is indicated. As FD is a progressive multisystem disease, baseline evaluation is optimally performed by a multidisciplinary team (Table 1, adapted from Eng et al.). The baseline evaluation should be performed in male and all female carriers, as the phenotype can be equally severe.
As this document is written from the nephrology perspective, we will focus on renal involvement in what follows. For evaluation and pathophysiology of other organs, we refer to the guidelines of the respective subspecialities.
Renal involvement is a cardinal feature of FD. Gb-3 deposition in renal cells is progressive and begins early in life. Besides these deposits, pathogenic mechanisms result in glomerular ischaemia with subsequent glomerulosclerosis and tubular atrophy, even very early in the disease course. Vacuolization of podocytes and epithelial cells is a characteristic optical microscopy histological finding. These vacuoles are filled with deposits on electron microscopy, or following toluidine blue staining of samples prepared for electron microscopy. At an early stage, hyperfiltration may, as in diabetes, be the first sign of kidney damage.
As FD can progress subclinically, adolescent and adult patients should have urinary albumin measurement, as this is one of the first signs of Fabry nephropathy. We suggest assessing the amount of albumin normalized for creatinine on a fresh morning sample as diagnostic test. We suggest measuring urinary albumin rather than total protein, as it is more sensitive. Renal function can be assessed using serum creatinine and eventually formulas to translate serum creatinine to estimated clearances. Even in the absence of albuminuria or renal failure, all these parameters should be re-evaluated at least yearly in order to detect progressive disease.
Renal intracellular Gb-3 deposits may be present even in young children with normal GFR and minimal or absent micro-albuminuria. In a recent study of 14 young Fabry patients aged 4–19 years with normal GFR, there was an association between the volume of Gb-3 deposition in the podocytes, and age. The volume of Gb-3 deposition was also correlated with urinary protein excretion rates. Tøndel et al. found segmental foot process effacement in all young Fabry patients, despite the fact they were normo-albuminuric (below 30 mg/day). Thus, in the case of patients at risk of FD, any albuminuria, even if in the 'normal' range, should be considered as suspect.
Proteinuria progresses and correlates with and probably also contributes to the decline in renal function, e.g. male Fabry patients with a proteinuria >1 g/24 h had a greater yearly decline in renal function (−6.9 mL/min/1.73 m2) than patients with proteinuria between 0.1 and 1 g/24 h (−2.2 mL/min/1.73 m2) and patients with proteinuria <0.1 mg/24 h (−0.6 mL/min/1.73 m2). Other studies confirm that the urinary protein to urinary creatinine ratio (UP/Cr) is the most important indicator of renal disease progression. The yearly decline in renal function also correlates with GFR at presentation (in males, −3 mL/min/1.73 m2 with GFR >60 mL/min/1.73 m2 versus –6.8 mL/min/1.73 m2 with GFR ≤ 60 mL/min/1.73 m2; in females −0.9 mL/min/1.73 m2 versus − 2.1 mL/min/1.73 m2).
CKD Stage 5 usually develops between the third and the fifth decade, with a mean age at diagnosis of 38, but can appear as early as at the age of 16.[44,45] Interestingly, the mean age at initiation of RRT is similar for males and females, although the proportion of male versus female FD patients on RRT was 9 to 1.
Living related donation in FD can pose a problem if apparently asymptomatic female carriers consider donating a kidney. Even in the case of a normal renal function and in the absence of albuminuria, significant Gb-3 deposits can be abundant in a renal biopsy and thus female carriers are, in our opinion, not eligible for living kidney donation.
The Fabry population is small and heterogeneous which makes it difficult to study its natural course and to conduct larger-scale, placebo-controlled or open-label clinical trials. For these reasons, a high quality registry with all treated and untreated patients on a European scale, developed independently of industry, is highly desirable.
Nephrol Dial Transplant. 2013;28(3):505-517. © 2013
Oxford University Press