The CKD-EPI-Cystatin C Equation For The Estimation Of Glomerular Filtration Rate Detects Higher Number Of Patients With Thalassemia Major and Renal Impairment, Before and After Treatment With Deferasirox; Is It Time To Change From MDRD To CKD-EPI-Cystatin C equation In Thalassemia?

Patients with thalassemia major (TM) often develop organ damage, such as liver, heart or endocrine insufficiency. However, there is very little published data for the kidney function of TM patients and even less information on the changes of estimated glomerular filtration rate (eGFR) under chelation therapy. Recent reports suggest that approximately 20% of the adults with TM show a slow, but progressive decline in eGFR, estimated by the MDRD formula, which is based mainly on serum creatinine (sCr). As sCr seems to underestimate the prevalence of renal impairment (RI), novel markers of renal injury are used for the more precise evaluation of GFR, including cystatin-C (CysC). Recently, the CKD-EPI investigators have reported that a combined sCr-CysC (CKD-EPI-sCr-CysC) equation correlated more accurately with GFR than equations based on either of these markers alone (CKD-EPI or CKD-EPI-CysC, respectively; Inker et al, NEJM 2012]. Our aim was to prospectively evaluate, for the first time, the CKD-EPI-CysC formulae (with or without sCr) in TM patients who receive deferasirox and to compare them with other equations for the eGRF.

We studied 54 TM (19M/35F) patients who received deferasirox at the standard dosage. CysC was measured before (baseline) and then every six months post-deferasirox, using a latex particle-enhanced nephelometric immunoassay (Dade Behring, Liederbach, Germany). The eGFR was estimated by the MDRD, the CKD-EPI, the CKD-EPI-CysC and the CKD-EPI-sCr-CysC equations. Patients were divided in the 5 CKD stages of the KDIGO classification, according to their eGFR (stage 1: eGFR >90 ml/min/1.73 m²; stage 2: 60-89 ml/min/1.73m²; stage 3: 30-59 ml/min/1.73m²; stage 4: 15-29 ml/min/1.73 m²; stage 5:<15 ml/min/1.73m²or on dialysis).

The median age was 41 years (range: 28-67 years). At baseline, TM patients had elevated values of Cys-C compared to controls (n=27; mean±SD: 0.93±0.26 mg/l vs. 0.76±0.11 mg/l, p<0.001). Specifically, 24/54 patients (44.4%) had higher Cys-C values than the upper normal limit (0.95 mg/L), while no patient had increased levels of sCr. The median values for eGFR at baseline calculated by the MDRD, CKD-EPI, CKD-EPI-CysC and CKD-EPI-sCr-CysC equations were 107.5, 113, 100 and 107 ml/min/1.73m², respectively. For each studied equation, the number of patients with RI stage 3-5 (i.e. eGFR<60 ml/min/1.73m²) was 7.4% for MDRD vs. 1.9% for CKD-EPI vs. 14.8% for CKD-EPI-CysC vs. 5.6 % for CKD-EPI-sCr-CysC (p<0.01; table). Concordance for CKD stage allocation for the 4 equations of estimating eGFR was 85.2% for MDRD vs. CKD-EPI, 66.6% for MDRD vs. CKD-EPI-CysC and 77.7% for MDRD vs. CKD-EPI-sCr-CysC.

After 6 and 12 months of therapy with deferasirox, we observed an increase of CysC (mean±SD: 1.12±0.34 mg/l and 1.12±0.37 mg/l, respectively; p<0.01 compared to baseline for both time-points). After 12 months of deferasirox administration, 34/54 patients (63%) had increased CysC values, and only one high sCr. The median values for eGFR after 12 months calculated by the MDRD, CKD-EPI, CKD-EPI-CysC and CKD-EPI-sCr-CysC equations were 91, 106, 77 and 89 ml/min/1.73m², respectively (p<0.01 for all comparisons to baseline). For each studied equation, the number of patients with RI stage 3-5 was 14.8% for MDRD vs. 11.1% for CKD-EPI vs. 27.8% for CKD-EPI-CysC vs. 16.7 % for CKD-EPI-sCr-CysC (p<0.01; table). CKD stage was upgraded in 12 (22.2%), 7 (12.9%), 25 (46.3%) and 14 (25.9%) patients according to MDRD, CKD-EPI, CKD-EPI-CysC and CKD-EPI-sCr-CysC equations, respectively, suggesting a deterioration of renal function post-deferasirox.

Our study suggests that the CKD-EPI-CysC equation detects more TM patients with RI compared to equations that include sCr. Based on this equation, approximately 15% of patients at baseline and 28% after 12 months of deferasirox therapy present with CKD stage 3. We propose the broader use of CKD-EPI-CysC equation for eGFR in TM as this equation can detect earlier renal damage in this sensitive cohort of patients.

No relevant conflicts of interest to declare.