Abstract
Background/Aim: Fabry disease, an X-linked lysosomal storage disorder, causes progressive globotriaosylceramide accumulation in cells throughout the body. Characteristic multiorgan manifestations include renal dysfunction (Fabry nephropathy) and associated urinary tract complications. Enzyme replacement therapy (ERT) has been available since 2001, but contemporary real-world data are lacking regarding Fabry nephropathy risks and treatment outcomes. Patients and Methods: This retrospective cohort study analyzed electronic medical records data for 10,637 Fabry disease patients from the TriNetX research database. Kidney and urinary tract outcomes were evaluated over two decades, 2000-2010 and 2011-2020. Outcomes assessed included chronic kidney disease (CKD), urinary tract infections, urinary incontinence, obstruction, renal insufficiency, and end-stage renal disease (ESRD). Results: The prevalence of stage 4-5 CKD nearly doubled between 2000-2010 and 2011-2020, while ESRD prevalence rose over 4-fold. Incidence rates showed similar marked elevations across renal and urologic complications. Females and Black patients experienced disproportionate escalations in kidney and urinary tract morbidity. Conclusion: This large cohort study revealed significantly increased Fabry nephropathy and associated urologic complications over the past two decades, contradicting expectations of reduced morbidity with ERT availability. The findings highlight needs to optimize screening, treatment strategies, monitoring practices, and address disparities to curb rising disease burden and improve patient outcomes.
Fabry disease results from mutations in the X-linked GLA gene encoding the lysosomal enzyme α-galactosidase A (α-Gal A) (1). Loss of α-Gal A activity leads to progressive accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (GL-3), in lysosomes of cells throughout the body (2-4). GL-3 accumulation and downstream inflammatory and fibrotic processes underlie the multiorgan pathology (4, 5). The kidney manifestations are referred to as Fabry nephropathy (6).
The earliest renal abnormalities include concentration defects, glomerular hyperfiltration, and microalbuminuria detectable in childhood and adolescence (7-9). Overt proteinuria typically arises in the second or third decade of life, followed by progressive decline in GFR with development of azotemia and hypertension in the third and fourth decades (10). Median age of developing ESRD is approximately 40 years in classically affected males (11, 12).
Heterozygous females exhibit significant phenotypic heterogeneity due to random X-chromosome inactivation (13). Later onset and slower progression of renal dysfunction is typical in females, but some develop severe manifestations resembling more affected males (14). Established risk factors for rapid progression in both sexes include greater baseline proteinuria, especially exceeding 1 g/day, reduced GFR <60 ml/min/1.73m2, and hypertension (15, 16).
Podocyte injury is central to the pathogenesis of Fabry nephropathy (17). GL-3 accumulation begins in utero and podocytes manifest greater GL-3 deposits compared to other renal cells (4). Podocytopathy likely directly causes proteinuria, whereas tubulointerstitial fibrosis represents a secondary lesion (18). Increased urinary podocyte loss correlates with clinical severity markers, supporting utility as a noninvasive prognostic biomarker (17). Characteristic pathological changes evolve over time, including GL-3 accumulation in glomerular, tubular, and vascular cells in early childhood (8). Glomerular sclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis develop subsequently. Ultimately end-stage kidney shows extensive sclerosis and fibrosis with relatively limited residual GL-3 deposits (19).
Given the non-specific early manifestations, the diagnosis of Fabry disease is often delayed, especially in females and milder phenotypes. Median delay between symptom onset and diagnosis is approximately 13 years in males and 16 years in females (15, 20). Increased awareness and higher clinical suspicion are needed. Initial screening relies on assay of α-Gal A activity in leukocytes or plasma and genetic testing for GLA mutations (21). Renal biopsy can confirm diagnostically significant GL-3 accumulation and fibrosis if the diagnosis is in question (19).
Enzyme replacement therapy (ERT) with recombinant α-Gal A became available in 2001 (22). Agalsidase alfa and agalsidase beta are administered intravenously at 0.2 mg/kg and 1.0 mg/kg, respectively, every 2 weeks (23). Both demonstrate GL-3 clearance from renal cells, particularly vascular endothelium, and stabilization of renal function in patients with preserved GFR and minimal proteinuria at treatment initiation (8, 24). However, ERT monotherapy does not significantly reduce proteinuria (8).
Fabry nephropathy remains a major cause of morbidity and mortality (15). For patients progressing to ESRD, dialysis and kidney transplantation are undertaken as in other forms of kidney disease (15, 25). Overall outcomes are optimized with a multidisciplinary care team, vigilance for extra-renal manifestations, focus on quality of life, and lifelong adherence to ERT if indicated (26).
This Global Cohort Study builds on this foundation by providing contemporary data on the incidence of renal complications in the era of ERT availability. Ongoing research on genotype-phenotype correlations, personalized regimens, and novel therapies offers hope of improving prognosis and longevity for Fabry patients.
Patients and Methods
We conducted a retrospective observational cohort study utilizing the TriNetX global federated research database. This database comprises real-time electronic medical records for approximately 140 million patients across 110 healthcare organizations, primarily in the United States, with additional data from centers in Australia, Germany, the UK, Italy, Singapore, Israel, and Taiwan (27).
Patient data within the TriNetX network remain anonymized to protect privacy. We identified all patients diagnosed with Fabry disease through June 25, 2023, using the International Classification of Diseases, Tenth Revision (ICD-10) code E75.21. We included patients based on documented phenotypic subtype, defined by the ICD-10 code E75.21 in combination with codes indicating ischemic heart disease (I20-I25), other forms of heart disease (I30-I5A), cerebrovascular disease (I60-I69), diseases of arteries and capillaries (I70-I79), acute and chronic kidney disease (N17-N19), paresthesia (R20.2), noninfective gastroenteritis (K52.9), keratoconus (H18.6), or complications of kidney transplantation (T86.1). Searches occurred from June 20 through July 31, 2023. At the time of search, 110 organizations had contributed data. As TriNetX provides only de-identified data, this study was exempt from ethical approval. Both TriNetX and contributing healthcare networks maintain compliance with the Health Insurance Portability and Accountability Act (HIPAA) to ensure data privacy and security (27, 28). We conducted this study in accordance with the Declaration of Helsinki ethical principles for medical research involving human subjects.
Study outcomes. We aimed to assess long-term kidney and urinary tract outcomes of Fabry disease patients over a 10-year follow-up period, analyzing data from 2000-2010 and 2011-2020. The outcomes included incidence and prevalence of chronic kidney disease (CKD), other obstructive and reflux uropathy (OORU), kidney stone (CK), ureteral stone (CU), disorder of the kidney and ureter (DKU), urinary tract infection (UTI), stress incontinence (SI), other specified urinary incontinence (OSUI), benign prostatic hyperplasia with lower urinary tract symptoms (BPHLUTS), unspecified urinary incontinence (UUI), urine retention (RU), stage 4 chronic kidney disease (CKD4), stage 5 chronic kidney disease (CKD5), and end stage renal disease (ESRD). Incidence rates were calculated per 100,000 person-years.
These conditions commonly affect Fabry disease patients, reflecting accumulation of pathological metabolites, inflammation, and fibrosis in the kidneys and urinary tract. We sought to characterize disease progression and changing risk profiles as patients age over the two decades analyzed.
Stratified analyses. To assess kidneys and urinary tract risk factors and the impact of patient characteristics on outcomes, we conducted stratified analyses of demographic and clinical variables. Specifically, patients were separated into age strata spanning 5-10 years, with narrower increments of 0-4, 5-9, and 10-14 years to closely analyze younger groups at and shortly following initial diagnosis. Male and female patients were analyzed separately to evaluate sex differences. Patients were also categorized into broad racial groups: White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and unknown race. Racial categories were broadly defined given variability in classifications across contributing sources. These stratified analyses aimed to determine how key patient attributes influence kidneys and urinary tract disease risks and outcomes over both periods to identify factors contributing to health disparities and shape targeted interventions.
Statistical analyses. We conducted a descriptive analysis of the data. Incidence rates of kidneys and urinary tract conditions of interest were calculated as the number of patients with events occurring during patient follow-up time at risk, divided by the total follow-up time in person-years (P-Y). Incidence rates were reported per 1,000 P-Y. Fabry disease patients who commenced with phenotype after the index date contributed person-time to both 2000-2010 and 2010-2020 cohorts.
Results
Baseline characteristics. A patient selection flowchart is shown in Figure 1. In total, 16,501 patients with Fabry disease were identified from the TriNetX database: 10,637 patients with Fabry disease at baseline and during follow-up. Follow-up duration was 10 years in two time periods, (2000 to 2010) and (2010 to 2020). Geographic distribution included 99% from US Regions: 49% Northeast (N=5,177), 11% Midwest (N=1,154), 24% South (N=2,577), 15% West (N=1,579), <1% Ex-US Regions (N=132).
Flow diagram of Fabry disease patients’ selection from TriNetX database.
Baseline characteristics are shown in Table I. This retrospective cohort included 10,637 patients with Fabry disease identified in the study database between 2000-2020. The majority were female (57%) and white (67%), with a mean age of 57.2 years. Complete data were available for 10,140 patients. Baseline characteristics revealed overweight BMI (mean 29.1 kg/m2), normal blood pressure (mean 127±74.9 mmHg), and typical lipid profiles. Kidney function markers showed normal mean creatinine (1.16 mg/dl) and calcium (9.36 mg/dl) levels. Complete blood count parameters were within normal limits. Liver enzymes and iron studies were also predominantly within expected ranges. These baseline characteristics portray a cohort with typical demographic and clinical parameters at Fabry diagnosis, providing context on prevalence of renal and urinary tract complications in a real-world global population with this disease over the past two decades. Analyzing this robust dataset can elucidate disease progression patterns and changing risk profiles related to kidney and urinary tract manifestations.
Baseline characteristics of patients with Fabry disease.
Incidence and prevalence of kidneys and urinary tract outcomes in patients with Fabry disease tracked to both 2000-2010 and 2010-2020 cohorts. The current study found a concerning rise in kidney and urinary tract morbidity among patients with Fabry disease over the past two decades. Between 2000-2010 and 2011-2020, the incidence and prevalence of nearly all measured renal and urologic outcomes increased markedly (Figure 2 and Figure 3). Specifically, the incidence proportion of obstruction of urine outflow rose over 5-fold from 0.4163 to 2.8369. Prevalence of this complication likewise rose substantially from 0.4422 to 3.1215. Significant increases were also observed for chronic kidney disease stages 3-5, end stage renal disease, overall chronic kidney disease, unspecified kidney dysfunction, urinary tract infections, stress urinary incontinence, overactive bladder, lower urinary tract symptoms associated with benign prostatic hyperplasia, urge urinary incontinence, and renal insufficiency. Of particular note, the prevalence of advanced chronic kidney disease stages 4 and 5 nearly doubled over the study period. End stage renal disease prevalence increased over 4-fold from 1.6129% to 6.0309%. Taken together, these concerning findings indicate a steep rise in renal and urinary tract morbidity in Fabry disease over the past 20 years.
Incidence of kidney and urinary tract complications in Fabry disease during 2000-2010 and 2011-2020 follow-up. CKD: Chronic kidney disease; OORU: other obstructive and reflux uropathy; CK: kidney stone; CU: ureteral stone, DKU: disorder of the kidney and ureter; UTI: urinary tract infection; SI: stress incontinence; OSUI: other specified urinary incontinence; BPHLUTS: benign prostatic hyperplasia with lower urinary tract symptoms; UUI: unspecified urinary incontinence; RU: urine retention; CKD4: stage 4 chronic kidney disease; CKD5: stage 5 chronic kidney disease; ESRD: end stage renal disease.
Prevalence of kidney and urinary tract complications in Fabry disease during 2000-2010 and 2011-2020 follow-up. CKD: Chronic kidney disease; OORU: other obstructive and reflux uropathy; CK: kidney stone; CU: ureteral stone, DKU: disorder of the kidney and ureter; UTI: urinary tract infection; SI: stress incontinence; OSUI: other specified urinary incontinence; BPHLUTS: benign prostatic hyperplasia with lower urinary tract symptoms; UUI: unspecified urinary incontinence; RU: urine retention; CKD4: stage 4 chronic kidney disease; CKD5: stage 5 chronic kidney disease; ESRD: end stage renal disease.
Incidence rates of 2000-2010 and 2010-2020 cohort’s follow-up in patients with Fabry disease. Our study found sizable increases in the incidence rates of kidney and urinary tract outcomes among patients with Fabry disease between 2000-2010 and 2011-2020. The incidence rate of obstruction of urine outflow (OORU) rose over 6-fold from 0.1490 to 0.9786 cases per 100,000 person-years. Similar considerable increases were observed for the incidence rates of chronic kidney disease stages 3-5, end stage renal disease, overall chronic kidney disease, unspecified kidney dysfunction, urinary tract infections, stress urinary incontinence, overactive bladder, lower urinary tract symptoms related to benign prostatic hyperplasia, urge urinary incontinence, and renal insufficiency. Of note, the incidence rate of chronic kidney disease stage 4 rose over 2-fold from 0.5883 to 1.3491 cases per 100,000 person-years. The incidence rate of end stage renal disease increased 3-fold from 0.5792 to 1.771 cases per 100,000 person-years between the two cohorts. Taken together, these findings point to an alarming rise in the incidence of renal and urinary tract morbidity among patients with Fabry disease over the past two decades.
Stratified analyses. This study found considerable increases in the incidence and prevalence of kidney and urinary tract complications in patients with Fabry disease between 2000-2010 and 2011-2020 (Figure 4). When stratified by age, the incidence and prevalence of most outcomes rose substantially from 2000-2010 to 2011-2020 across all age groups, but especially in patients aged 15-24, 35-54, and 70 and above. When stratified by sex, the incidence and prevalence of most outcomes increased over time for both females and males; however, the magnitude of increase tended to be greater for females. For example, the prevalence of stage 4 chronic kidney disease rose from 1.44% to 4.07% in females, compared to increases from 1.93% to 6.23% in males between the two cohorts. The prevalence of end stage renal disease increased over 3-fold in females (1.28% to 4.21%) but less than 2.5-fold in males (2.09% to 5.32%). Significant elevations also occurred across both sex for stress incontinence, benign prostatic hyperplasia, and unspecified urinary incontinence. When stratified by race, substantial increases in kidney and urinary tract complications emerged across racial groups. However, the magnitude of increase between the two cohorts tended to be greatest among Black/African American patients. For instance, the prevalence of chronic kidney disease rose from 18.29% to 44.15% in Black patients, compared to increases from 6.37% to 19.72% in Asian patients and from 6.92% to 21.73% in White patients. Taken together, these findings point to an alarming rise in renal and urologic morbidity in Fabry disease, particularly among females and Black/African American patients. Further research should explore reasons for these trends and strategies to improve outcomes.
Incidence rate of kidney and urinary tract complications in Fabry disease during 2000-2010 and 2011-2020 follow-up. CKD: Chronic kidney disease; OORU: other obstructive and reflux uropathy; CK: kidney stone; CU: ureteral stone, DKU: disorder of the kidney and ureter; UTI: urinary tract infection; SI: stress incontinence; OSUI: other specified urinary incontinence; BPHLUTS: benign prostatic hyperplasia with lower urinary tract symptoms; UUI: unspecified urinary incontinence; RU: urine retention; CKD4: stage 4 chronic kidney disease; CKD5: stage 5 chronic kidney disease; ESRD: end stage renal disease.
Discussion
This large retrospective cohort study analyzed electronic medical records data on 10,637 patients with Fabry disease from the TriNetX research database over two decades, 2000-2010 and 2011-2020. The objective was to evaluate long-term kidney and urinary tract outcomes and changing risk profiles. The key results demonstrate a steep rise in renal and urologic morbidity among patients with Fabry disease between these two periods.
These key findings contradict expectations that ERT would reduce renal complications (26, 29, 30). Instead, Fabry nephropathy and associated morbidity climbed steeply over the past two decades, especially among higher-risk subgroups. This study exposes deficiencies in contemporary treatment paradigms.
Rising renal morbidity in Fabry disease is concerning given the advent of ERT over 20 years ago (2, 31). These findings suggest moderate real-world effectiveness of current treatment paradigms. Several factors likely contribute, including diagnostic delays, suboptimal ERT regimens and adherence, inadequate control of proteinuria and other risk factors, and healthcare access disparities (32). The disproportionate escalation in renal complications among females and minorities warrants concerted attention. Targeted screening and interventions to improve ERT timeliness, dosing, monitoring, and multidisciplinary care for these higher-risk populations are needed.
This large cohort study provides a unique window into the contemporary burden of Fabry nephropathy in the context of ERT availability. The sample comprised over 10,000 patients with Fabry disease across over 100 healthcare organizations, mostly in the USA, strengthening generalizability. The findings raise concerns about increased renal morbidity that are likely applicable to Fabry populations in other nations with access to ERT. The analysis relied on real-world data, enhancing relevance to clinical practice settings. The inclusion of milder phenotypes and patients diagnosed later in life enhances representation of the full disease spectrum. The trends were consistent across age strata, both sexes, and diverse racial groups, supporting generalizability. Additionally, the rising ESRD prevalence may not be generalizable to all practice settings, as centers lacking multidisciplinary expertise may have lower treatment success rates. Nevertheless, this study provides a vital snapshot of real-world Fabry nephropathy outcomes that can inform quality improvement and health policy initiatives across diverse healthcare systems to address this serious disease complication.
This study has several limitations inherent to retrospective database analyses. The Fabry disease diagnosis relied on ICD coding, which can be prone to errors. The exact date of diagnosis was not captured, precluding assessing diagnostic delays. Detailed treatment data regarding ERT regimens and adherence were not available. Concomitant medications, blood pressure control, and other clinical variables were incompletely documented. Furthermore, the renal outcome definitions were based on diagnostic codes, which do not precisely correlate with measured glomerular filtration rate. Given the deidentified dataset, loss to follow-up bias cannot be excluded. The exact reasons for rising renal complications cannot be determined from this data source. Potential explanatory factors such as diagnostic delays, treatment gaps, inadequate ERT regimens, poor adherence, suboptimal concomitant therapy, and various demographic and psychosocial variables could not be directly analyzed. Additionally, the 2016 elimination of the Fabry disease ICD-9 code creates a limitation for continuous data capture across the transition from the 9th to 10th revision of codes. The cohorts included predominantly USA patients, with smaller samples from Australia, Germany, the U.K., and several other countries. While the sample size was large overall, smaller subgroup sizes may underpower some stratified analyses. Representation of non-White racial groups was limited. Finally, secular trends in CKD diagnosis and coding practices over the two decades may introduce bias towards higher outcome ascertainment in the later cohort.
In summary, this cohort study enables cautious extrapolation regarding increased Fabry nephropathy risks, particularly among female and minority patients. The findings have practice relevance highlighting needs to improve awareness, optimize screening and treatment protocols, enhance monitoring for complications, and reduce disparities. Further comparative effectiveness research in diverse settings is warranted to extend the implications of these crucial results.
Acknowledgements
The Authors are deeply grateful to the Center for Health Data Science, Chung Shan Medical University Hospital for their indispensable assistance with TriNetX.
Footnotes
Authors’ Contributions
THT, CHW, SLC, and JYH analyzed the data; DTB, YNH, and PHS wrote and revised the manuscript; PHS supervised the project at Chung Shan Medical University Hospital. To guarantee that any concerns about the accuracy or integrity of any portion of the work is properly examined and addressed, all Authors have approved the paper and agreed to be held responsible for all elements of the study.
Funding
This research was funded by grants from China Medical University Hospital and Chung Shan Medical University Hospital. At China Medical University Hospital, grant numbers DMR-109-052, DMR-109-180, DMR-110-063, and DMR-110-066 were awarded to CHW. Chung Shan Medical University Hospital provided funding through grant numbers CSH-2019-C-026 and CSH-2021-C-033, awarded to PHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of Interest
All Authors declare no conflicts of interest associated with this study.
- Received August 1, 2023.
- Revision received August 21, 2023.
- Accepted August 28, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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