Fabry Nephropathy: Screening, Diagnosis, and Treatment

Methods

A literature search was conducted using the PubMed database (most recent search July 2012). The search term used was 'Fabry Disease' with limits: 'Humans', 'Clinical Trial', 'Meta-Analysis', 'Practice Guideline', 'Randomized Controlled Trial', 'Review', 'English', 'French'. A total of 357 articles were retrieved; the articles were classified to the following topics (one paper can be attributed to more than one classification):

epidemiology, screening studies;
diagnostic methods;
Fabry nephropathy: natural history, complications (hypertension), mechanisms, renal pathology;
treatment of Fabry nephropathy; with ERT, ACEi and ARB, RRT; efficacy and safety issues.

Articles out of scope and review articles that presented no new data were excluded. Articles on experimental, non-registered treatments were also excluded.

The reference lists of the identified relevant studies were manually searched for additional citations.

After all relevant publications were retrieved, a consensus meeting was held with all co-authors. The resulting paper was sent for internal review before submission, as explained in the 'instructions to authors' section of the ERBP website.^[7]

Table 1. Proposed assessments in FD patients (reproduced with permission from Eng *et al*. [39])
Organ system	Assessment	Recommendation
General	General status, school or work performance, sports, depression, anxiety, drug use, pedigree update, somatic growth	Baseline (at first visit), every 6 months
	Complete physical examination SF-36®Health Survey, or PedsQL™ Measurement Mode	Baseline, every 6 months
	Genetic counselling	Baseline, every 6 months for new issues
	Genotype	If not previously determined
Kidney	Serum electrolytes, creatinine, BUN; 24-h urine or spot urine for total protein/creatinine, albumin/creatine, sodium, creatinine	Baseline, every 3 months if CKD Stage 1 or 2 and >1
		g/day of proteinuria or CKD Stage 4
		Every 6 months if CKD Stage 3
		Every 12 months if CKD Stage 1 or 2 and <1 g/day of proteinuria
Cardiac	Palpitations, angina	Baseline, every 6 months
	Blood pressure, rhythm	Every evaluation visit
	ECG, echocardiography 2D with Doppler	Baseline, every other year for patients ≤35 years of age, every year thereafter
	Holter monitoring, 30-day event monitoring	If an arrhythmia is suspected or palpitations are present
	MRI, strain rate imaging	Optional
	Coronary angiography	If clinical signs of angina
Neurologic	Acroparesthesias, fatigue, fever, sweating, heat and cold intolerance, joint pains, stroke-related symptoms, TIA	Baseline, every 6 months
	Neurologic exam, Brief Pain or McGill Pain Inventory	Baseline, every 6 months
	Brain MRI without contrast	Baseline, at the time of a TIA or stroke event or in females to document CNS involvement
	Magnetic resonance angiography	If cerebral vasculopathy should be excluded
	Cold and heat intolerance, pain, vibratory thresholds, sweat output, post-ganglionic sudomotor function, superficial skin blood flow	When available
	Co-morbid stroke risk factors: cholesterol (Total, LDL, HDL), triglycerides	Annually
	Lipoprotein A, total plasma homocysteine, factor V Leiden (G1691A), Protein C, Protein S, prothrombin G20210A, antithrombin III, abticardiolipin antibody, lupus anticoagulant	At baseline, single assessment
ENT	Tinnitus, hearing loss, vertigo, dizziness	Baseline, every 6 months
	Audiometry, tympanometry, otoacoustic emissions	Baseline, and yearly thereafter
Ophthalmologic	Visual disturbances, light sensitivity	Baseline, every 6 months
	General pohtalmologic exam (slit-lamp, direct ophtalmoscopy, best corrected visual acuity, visual fields)	Baseline, every 12 months
	Retinal disfunction testing (ERG, colour vision testing, visual-evoked potentials, retinal angiography), tear secretion testing	If clinically indicated
Pulmonology	Cough, exertional dyspnoea, wheezing, exercise intolerance	Baseline, every 6 months
	Spirometry, including response to bronchodilators, treadmill exercise testing, oximetry, chest X-ray	Baseline, every 2 years or more frequently for clinical indications
Gastrointestinal	Postprandial abdominal pain, bloating, diarrhoea, nausea, vomiting, early satiety, difficulty gaining weight	Baseline, every 6 months
	Endoscopic or radiographic evaluations	If symptoms persist or worsen despite treatment
Skeletal	Bone mineral density	Baseline

Table 1. Proposed assessments in FD patients (reproduced with permission from Eng et al. [39])

Organ system

Assessment

Recommendation

General

General status, school or work performance, sports, depression, anxiety, drug use, pedigree update, somatic growth

Baseline (at first visit), every 6 months

Complete physical examination SF-36®Health Survey, or PedsQL™ Measurement Mode

Baseline, every 6 months

Genetic counselling

Baseline, every 6 months for new issues

Genotype

If not previously determined

Kidney

Serum electrolytes, creatinine, BUN; 24-h urine or spot urine for total protein/creatinine, albumin/creatine, sodium, creatinine

Baseline, every 3 months if CKD Stage 1 or 2 and >1

g/day of proteinuria or CKD Stage 4

Every 6 months if CKD Stage 3

Every 12 months if CKD Stage 1 or 2 and <1 g/day of proteinuria

Cardiac

Palpitations, angina

Baseline, every 6 months

Blood pressure, rhythm

Every evaluation visit

ECG, echocardiography 2D with Doppler

Baseline, every other year for patients ≤35 years of age, every year thereafter

Holter monitoring, 30-day event monitoring

If an arrhythmia is suspected or palpitations are present

MRI, strain rate imaging

Optional

Coronary angiography

If clinical signs of angina

Neurologic

Acroparesthesias, fatigue, fever, sweating, heat and cold intolerance, joint pains, stroke-related symptoms, TIA

Baseline, every 6 months

Neurologic exam, Brief Pain or McGill Pain Inventory

Baseline, every 6 months

Brain MRI without contrast

Baseline, at the time of a TIA or stroke event or in females to document CNS involvement

Magnetic resonance angiography

If cerebral vasculopathy should be excluded

Cold and heat intolerance, pain, vibratory thresholds, sweat output, post-ganglionic sudomotor function, superficial skin blood flow

When available

Co-morbid stroke risk factors: cholesterol (Total, LDL, HDL), triglycerides

Annually

Lipoprotein A, total plasma homocysteine, factor V Leiden (G1691A), Protein C, Protein S, prothrombin G20210A, antithrombin III, abticardiolipin antibody, lupus anticoagulant

At baseline, single assessment

ENT

Tinnitus, hearing loss, vertigo, dizziness

Baseline, every 6 months

Audiometry, tympanometry, otoacoustic emissions

Baseline, and yearly thereafter

Ophthalmologic

Visual disturbances, light sensitivity

Baseline, every 6 months

General pohtalmologic exam (slit-lamp, direct ophtalmoscopy, best corrected visual acuity, visual fields)

Baseline, every 12 months

Retinal disfunction testing (ERG, colour vision testing, visual-evoked potentials, retinal angiography), tear secretion testing

If clinically indicated

Pulmonology

Cough, exertional dyspnoea, wheezing, exercise intolerance

Baseline, every 6 months

Spirometry, including response to bronchodilators, treadmill exercise testing, oximetry, chest X-ray

Baseline, every 2 years or more frequently for clinical indications

Gastrointestinal

Postprandial abdominal pain, bloating, diarrhoea, nausea, vomiting, early satiety, difficulty gaining weight

Baseline, every 6 months

Endoscopic or radiographic evaluations

If symptoms persist or worsen despite treatment

Skeletal

Bone mineral density

Baseline

Table 2. Randomized controlled trials in ERT; data concerning the kidney, reproduced from Dib *et al*. [52]
Comparison I: Agalsidase alpha versus placebo	Agalsidase alpha (n)	Mean (SD)	Placebo (n)	Mean (SD)	Mean difference, 95% CI
Urinary sediment Gb3
Schiffmann 2001 up to 6 months	14	1683 (1657)	11	2495 (1104)	−812,00 (−1897.83, 273.83)
Kidney Gb3
Schiffmann 2001 up to 6 months	14	15.6 (5.98)	11	18.1 (10.54)	−2.5 (−9.47, 4.47)
Creatinine clearance
Schiffmann 2001 up to 6 months	13	94.8 (27.76)	11	84.5 (35.15)	10.30 (−15.37, 35.97)
Insulin clearance
Schiffmann 2001 up to 6 months	13	71 (16.11)	11	71.5 (32.03)	−0.50 (−21.36, 20.36)
Mesangial widening
Schiffmann 2001 up to 6 months	12	25.7 (20.78)	9	40.4 (28.5)	−14.70 (−36.72, 7.32)
Glomeruli with segmental sclerosis
Schiffmann 2001 up to 6 months	12	6.8 (8.66)	9	3 (5.7)	3.80 (−2.35, 9.95)
Obsolescent glomeruli
Schiffmann 2001 up to 6 months	12	19.5 (20.78)	9	13 (15.3)	6.50 (−8.93, 21.93)

Comparison II: Agalsidase beta versus placebo	Agalsidase beta (n)	Mean (SD)	Placebo (n)	Mean (SD)	Mean difference, 95% CI
Renal microvascular endothelial deposits
Eng 2001 up to 6 months	29	0.4 (0.7)	29	2.1 (0.8)	−1.7 (2.09, −1.31)
Renal events
Banikazemi 2007 intention-to-treat	10/51		7/31	13 (15.3)	0.87 (0.37, 2.04)

Table 2. Randomized controlled trials in ERT; data concerning the kidney, reproduced from Dib et al. [52]

Comparison I: Agalsidase alpha versus placebo

Agalsidase alpha (n)

Mean (SD)

Placebo (n)

Mean (SD)

Mean difference, 95% CI

Urinary sediment Gb3