The value of estimated GFR in comparison to measured GFR for the assessment of renal function in adult patients with Fabry disease

Abstract Background. Renal disease is one of the major complications in Fabry disease, an X-linked lysosomal storage disease due to deficiency of the enzyme α-galactosidase A. The aim of our study was to determine the value of creatinine-, cystatin C- and beta-trace-based formulas for the estimation of glomerular filtration rate (eGFR) in Fabry patients. For comparison, the gold standard method 125I-labelled iothalamate/131I-labelled hippuran [measured GFR (mGFR)] was used. Methods. GFR was estimated by using 11 different formulas based on creatinine, cystatin C and beta-trace protein. Accuracy and precision, detection of early decline of renal function and follow-up of renal function by eGFR was compared to mGFR. Results. One hundred and thirty-six GFR measurements and plasma samples were available from 36 (20 male) Fabry patients, treated with agalsidase α or β with a median follow-up of 3.1 (range 1.5–5.2) years. Median mGFR was 97.3 (15.5–148.6) ml/min/1.73 m2 in males and 84.4 (23.0–131.0) ml/min/1.73 m2 in females at the start of follow-up. Conclusions. Although none of the investigated endogenous markers proved to be an equivalent substitute for mGFR in Fabry patients, the Stevens equation, a creatinine- and cystatin C-based formula, most closely approximated the mGFR. When a creatinine-based formula is preferred, considering that there is no standardized method available for cystatin C, the abbreviated Modification of Diet in Renal Disease (aMDRD) and the recently developed Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas had the best performance. In male Fabry patients, the aMDRD may overestimate GFR, especially in the higher ranges. In these cases, CKD-EPI may perform better. estimated GFR, Fabry disease, renal function Introduction Renal disease is one of the major complications in Fabry disease, an X-linked lysosomal storage disease due to deficiency of the enzyme α-galactosidase A [1,2]. Accumulation of several glycosphingolipids, the main compound being globotriaosylceramide (Gb3), occurs in various cell types. This results in complications of mainly vascular origin, of which progressive renal insufficiency, cardiac hypertrophy and cerebral infarctions are the most severe [3]. Due to the X-linked nature of the disease, males are most severely affected, but females can express symptoms as well. In the kidney, extensive storage has been identified in glomerular, tubular, vascular and interstitial cells [4]. Renal involvement can already be present during childhood. Before the era of enzyme replacement, the mean age of onset of clinical nephropathy [i.e. proteinuria or chronic kidney disease (CKD)] has been reported for male Fabry patients to occur at the age of 27 years [5]. Thereafter, the mean rate of glomerular filtration rate (GFR) decline was 12.2 ml/min/year. Overall, 13–23% of male Fabry patients and ∼3% of female patients developed end-stage renal disease (ESRD) [6–8]. Before the decline of renal function, hyperfiltration can be present early in the course of the disease [9]. Enzyme replacement therapy (ERT) is available since 2001, and improvement of cardiac disease and stability of renal disease are better achieved in patients with a preserved renal function [10,11]. Early detection of renal impairment is therefore important. Unfortunately, an easy and accurate method to assess renal function is lacking. GFR can be measured as the clearance of exogenous or endogenous filtration markers. The use of exogenous marker methods such as inulin clearance or nuclear methods is considered to be the gold standard for the assessment of renal function in Fabry patients [12]. However, these methods are expensive and time consuming. Creatinine is the most commonly used marker. Apart from the fact that creatinine is influenced by muscle mass, age, gender and race, loss of renal function may already have occurred without a significant rise in plasma creatinine. The Modification of Diet in Renal Disease (MDRD) and abbreviated MDRD (aMDRD) formulas [13,14], based on creatinine, are commonly used. A recent study showed that, by using the MDRD formula in Fabry patients, GFR is overestimated more specifically in male Fabry patients at the higher end of GFR range [15]. This hampers an early detection of a decline in renal function. Recently, a new formula, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), has been published, developed to assess GFR more accurately, especially in the higher ranges of GFR [16]. This formula may therefore be of additional value in Fabry disease. Cystatin C (cysC) is another endogenous marker. It is a low-molecular-weight protein (13.3 kDa), produced at a constant rate by all nucleated cells, and is freely filtered by the glomerulus and completely reabsorbed and broken down in the proximal tubule [17,18]. Its production is not influenced by gender, age, body weight or muscle mass [19,20], although it can be influenced by thyroid dysfunction [21–23] and large dosages of glucocorticoids [24–26]. CysC appears to be a more sensitive marker than creatinine to detect a decline in renal function and is reported to detect changes in GFR <80 ml/min [27]. To our knowledge, besides one review [12], only one study has been published investigating cysC in Fabry nephropathy [28], concluding that cysC is a sensitive and reliable marker. However, a reference method in that study was lacking. Beta-trace protein (βTP) is also advocated as an early marker for deterioration of renal function in the so-called ‘creatinine blind range’ [29–32]. βTP, also known as lipocalin-type prostaglandin D2 synthase, is a low-molecular-weight protein (22–26 kDa) [29] that is mainly produced in the central nervous system (leptomeninges, choroid plexus epithelium and oligodendrocytes). Furthermore, it is found in serum, urine, ascites and seminal plasma. Although a comparison between estimated glomerular filtration rates (eGFRs) using cysC and βTP in paediatric renal transplant patients showed no benefit of βTP over cysC [33], so far no studies have investigated the value of βTP as a parameter of renal function in patients with Fabry disease. The aim of the present study was to determine the value of creatinine-, cysC- and βTP-based formulas for the determination of GFR and the follow-up of renal function in Fabry patients in comparison to a gold standard method, consisting of a continuous infusion of 125I-labelled iothalamate in combination with 131I-labelled hippuran [34–36]. Materials and methods Patients The Academic Medical Center in Amsterdam is a tertiary referral centre for lysosomal storage diseases in the Netherlands, active since 1999. Currently, 100 Fabry adult patients are closely monitored in our outpatient clinic. Yearly, GFR measurement with125I-labelled iothalamate/131I-labelled hippuran is routinely performed in patients on ERT. All Fabry patients in whom three or more GFR measurements were available for f (...truncated)