This study defines the natural history of the renal, cardiac and cerebrovascular complications in patients with Fabry disease before institution of ERT. Retrospective chart reviews, for a median of 12 years for each patient, described the progression of Fabry nephropathy, and the frequency and nature of life-threatening complications.
Males developed symptoms and were diagnosed earlier than females, and the majority of women were symptomatic with moderate to severe manifestations of Fabry disease. This may reflect an ascertainment bias inherent in the study design, but recent studies evaluating larger cohorts of females [8–12
] have found that they range from asymptomatic to as severe as males with Fabry disease. An important cause of phenotypic variation in females is presumably due to random X-inactivation [8
Rapid progression of the Fabry nephropathy was more prevalent among males than females, and older patients were more likely to have severe Fabry nephropathy at their first evaluation. Patients who developed ESRD had more rapid rates of progression than those who did not develop ESRD. Patients with advanced Fabry nephropathy (e.g. CKD) progressed more rapidly than those with baseline eGFR ≥60 ml/min/1.73 m2.
Branton et al
. reported a mean progression rate of −12.2 ml/min/year in 14 untreated male Fabry patients who had stage 3 CKD at baseline and progressed to ESRD [17
]. The progression rates ranged from −3.3 to −33.7 ml/ min/year, suggesting heterogeneity of the underlying processes. Progression may accelerate as nephropathy progresses, as the kidney function drops below a certain threshold. The progression rate should be monitored as an important outcome measure in Fabry nephropathy.
Overt proteinuria was an important finding in our study, and in a recent Fabry Registry study [10
], and was more prominent in males and females with CKD. Overt proteinuria was noted in 90% of males and all females who progressed to ESRD. Consistent with recent studies [18–22
], proteinuria was a risk factor for progression of nephropathy. Females had a similar association between baseline proteinuria and progression, but the slopes were less steep than those in males with similar levels of proteinuria.
Studies with ACE inhibitors showed that in type 1 diabetic [23
] and nondiabetic patients with proteinuric CKD [24,25
], reduction of proteinuria was associated with slowing of progression and lower risk of ESRD. Similar findings have been obtained with type 2 diabetic patients treated with angiotensin receptor blockers [26,27
]. Data from the Fabry patients in this study were mostly from the era before the frequent use of these agents; only about a third of patients with CKD received anti-proteinuric agents.
The progression rate of Fabry nephropathy for females with eGFR values ≥60 ml/min/1.73 m2 was −0.9 ml/ min/1.73 m2/year, similar to that of healthy women. In contrast, females with CKD progressed more rapidly (−2.1 ml/ min/1.73 m2/year). When stratified by baseline proteinuria, females with overt proteinuria had substantial progression rates. These results show that proteinuria significantly increases the rate of progression of Fabry nephropathy in females.
Placebo-controlled clinical trials and open-label extension studies in patients with Fabry disease have evaluated the effects of ERT with recombinant agalsidase alfa at 0.2 mg/kg every other week (EOW) [22
] and agalsidase beta at 1.0 mg/kg EOW [18
]. ERT stabilizes GFR in patients with early Fabry nephropathy (relatively normal GFR, minimal proteinuria) [20
] and clears GL-3 from renal cells [4
]. Moreover, slowing of disease progression also has been shown for patients with moderate renal disease [18
]. Early diagnosis, comprehensive evaluation of kidney function, aggressive management of the proteinuria and early initiation of ERT should optimize efforts to prevent or slow the progression of Fabry nephropathy [18
The present study confirms the high prevalence of cardiac events [8
], particularly of arrhythmias in Fabry patients. Only 2% of the patients had MIs while 13% had angina events. Comparison with non-matched data from the general adult US population (MIs, 5.5% of males, 3.4% of females; angina/coronary heart disease, 5.5% of males, 3.4% of females) [32
] suggests that angina events may occur more frequently in Fabry patients. While no paediatric females had a known arrhythmia event, arrhythmias were relatively common among males aged <18 years. Thus, cardiac evaluation should be routinely performed in teenage and older Fabry patients [33
The prevalence of TIAs and strokes was similar to other reports [8
]. Most strokes were ischaemic, and most were small vessel infarcts. The most common documented location was the middle cerebral distribution. Cardiac complications and hypertension, associated with CKD, are likely contributing factors in the aetiology of TIAs and stroke in Fabry patients [34
]. The ages at which males and females experienced cardiac events or strokes differed. On average, females had these events in their third or later decades of life, while males experienced them as early as in adolescence. Hypertension was more prevalent in males than in females. Whether hypertension is a risk factor for the occurrence of TIAs and stroke remains to be determined.
The mean age at death of 49.9 years for male patients was similar to that reported by others [17
], and represents a reduction of approximately 25 years compared to the US general population [35
]. For female patients, a median cumulative survival of 70 years has been previously reported approximating a reduction of 10 years as compared to the general population [35,36
]. Early recognition of childhood symptoms [37,38
], and timely therapeutic intervention offer the best hope for Fabry patients.
Although this study was carefully conducted with pre-defined analysis of the medical records of patients seen at expert centres, there are several evident limitations to this study that have to be acknowledged: (a) incomplete, inconsistent or erroneous documentation would decrease the power of subgroup analyses; (b) the fact that data were extracted from primary medical records over a 60-year span raises questions about validity and choice of endpoints. There have been changes in laboratory methods for measuring serum creatinine, and a central laboratory was not used for uniform analyses. Renal events were defined as an increase in measured serum creatinine by 50% to a value >1.4 mg/dl. Reference values have decreased over the years by 0.2–0.4 mg/dl, so the absolute change in kidney function cannot be over-interpreted other than to say that the 50% change in measured creatinine was an indication of significant decline in function; (c) similar concerns can be raised about using the extracted serum data to calculate eGFR precluding more detailed analysis of the eGFR data other than the dichotomous distinction between CKD (eGFR <60) and eGFR ≥60 ml/min/1.73 m2
. However, the source of variability is lessened by using the regression slopes of the change in eGFR over time; (d) despite the fairly robust size of the cohort, the numbers of patients in some categories (e.g. the patients who progressed to ESRD in Figure ) is too small to make meaningful comparisons between the categories; (e) a number of symptomatic complaints [e.g. premature (extra) beats] were retrospectively extracted from the medical records; (f) selection bias may well have influenced the inclusion of more severely affected individuals, and could have delayed the inclusion of female patients who were previously thought to be ‘carriers’ without important manifestations of Fabry disease and (g) the possibility that the regression slope of change in MDRD eGFR with time may underestimate the true rate of progressive loss of kidney function, especially if the GFR is relatively normal, is well described [39
]. As a consequence, Fabry patients with low-grade proteinuria and relatively normal GFR, such as those presented in Figure , may have greater rates of progression than would be estimated by the current methodology.
Within these considerations, this study extends the existing knowledge of the natural history of Fabry disease prior to the initiation of ERT and, in particular, describes the progression rates of the Fabry nephropathy for patients stratified by gender and baseline proteinuria.
In conclusion, male patients with Fabry disease typically progressed more rapidly than females, but a considerable number of female patients in fact do have progressive Fabry nephropathy. Higher baseline proteinuria, systemic hypertension and lower baseline eGFR were associated with progression of eGFR loss and are important in evaluating therapeutic expectations and the response to ERT and adjunctive therapies in Fabry disease.