Renal Status and Hematuria in Older Patients with Hemophilia
Authors: Holme Pal André , Tait Robert Campbell , Combescure Christophe , Berntorp Erik , Tagliaferri Annarita , Staritz Peter , Schutgens Roger E.G. , Klamroth Robert , Marquardt Natascha , Rauchensteiner Stephan , De Moerloose Philippe 
Published: October 2019

Abstract
Background: It has been speculated that more episodes of hematuria in severe hemophilia might be a sign of increased renal disease, and that HIV or HCV infections might have a detrimental effect on the kidney*. Only a few comprehensive reports on the extent of renal disease in hemophilia have been published to date¨.
Aims: A cross-sectional study in Europe was conducted by the ADVANCE Working Group to investigate the extent of renal disease, creatinine clearance, hematuria episodes and Cystatin C values in a cohort of patients aged over 40 years with severe (<1% FVIII), moderate (1-5% FVIII) and mild (>5-40% FVIII) hemophilia.
Methods: Patient data from 16 centers were analyzed to describe the rate of renal disease as assessed by the treating physician, and also measured by serum creatinine, age adjusted creatinine clearance (CrCl), and available Cystatin C values at a single time point in a representative selection of patients; providing that IRB approval and patient consent was available.
Results: 509 patients with hemophilia were recruited (88% hemophilia A, 12% hemophilia B; 58% severe; 11% moderate, 31% mild). 35% of the total and 55% of the severe group was on prophylaxis. Median age was 52 years (range 35-98 years), 19% were HIV positive and the majority on HAART treatment. 71% were HCV seropositive, of whom 11% had reached natural clearance and 18.8% a persistent response. Significantly lower median BMI (25.3 vs. 26 kg/m²; P<0.0001) and waist circumference (95cm vs. 101cm) were seen in severe compared to mild hemophilia.
History of renal disease was found in 5.4% of cases, 2 had a history of kidney transplantation and none were currently on dialysis. Rates were not-significantly lower in severe compared with mild hemophilia (4.8% vs. 7.7%, p=0.29) and increased significantly with age (15.2% in those >70 years old, p=0.03*). Median creatinine clearance values (CrCl) were calculated from the serum creatinine values according to Cockroft Gault formula, and were significantly higher in severe hemophilia than mild (eGFR 116 ml/min vs. 106 ml/min; p=0.003). Cystatin C values were only measured for 23.6% of patients with more data available for severe/moderate than mild hemophilia (30% vs. 10%), but the values (Median=0.9, IQR: 0.78-1.07) were no different to normal in these age groups€. 54% had a history of macroscopic hematuria, with significantly more patients with hematuria history in severe disease (70% in severe vs. 27% in mild). The CrCl and renal disease status did not correlate with severity or number of macroscopic hematuria episodes (p=0.60).
Conclusion: Renal disease in hemophilia significantly increases with age but the rate does not differ between severe and mild hemophilia. Hematuria episodes do not appear to indicate or affect renal status in the majority$. HCV and HIV status looks to have an effect on BMI and might explain why better CrCl is shown in severe patients with hemophilia compared to mild.
Acknowledgment: The ADVANCE Working Group is supported by a scientific grant from Bayer HealthCare AG.

Disclosures
Klamroth: Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau; Biogen and SOBI: Honoraria, Speakers Bureau.