Chronic Kidney Disease in the U.S. Hemophilia Population: A Cohort Study

Introduction: Over a 3 year period, U.S. men with hemophilia were found to be 50 times more likely to die from renal disease than the general population (SMR 50; 95% CI 26.8-92.8) (Soucie et al., Blood 2000). Despite this finding, data regarding chronic kidney disease (CKD) and its risk factors in patients with hemophilia remain limited. The objective of this study is to determine the prevalence of CKD and CKD risk factors among older men with moderate and severe hemophilia.

Methods: A U.S. national study (ATHN-1) began enrollment in 10/2012. Inclusion criteria are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. In this extension study, CKD risk factors, historical creatinine levels, and history of renal events were obtained from patient interview and chart review after obtaining informed consent. Glomerular filtration rate (GFR) values were calculated using the CKD-EPI equation and compared to values in the general population using the NHANES dataset (Coresh et al., JAMA 2007). CKD is defined as the presence of either kidney damage or decreased kidney function with GFR < 60 ml/min/1.73 m2 for ≥ 3 months, irrespective of cause.

Results: As of 6/30/2017, data from 98/200 subjects from 18 U.S. Hemophilia Treatment Centers have been collected, and interim analysis is presented here. The majority were white (88; 89.8%) or African American (9; 9.2%). Mean current age was 64 years (SD: 5; range: 57-77). 37.8% (37/98) were on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Two (2.0%) had a current inhibitor. Viral infection was common: 35.7% currently had hepatitis C (HCV), and 17.4% HIV. Hypertension (HTN) was reported in 52.0% of subjects, 13.3% diabetes (DM), and average BMI was 28.1 kg/m² (35.7% obese). 6.1% (6/98) were found to have CVD (defined as angina, MI, TIA, or ischemic or embolic stroke).

Fasting blood work showed an abnormally elevated creatinine in 30.9% subjects (mean 1.1 mg/dl, SD 0.4). Mean historical maximum creatinine was 1.0 (range 0.6-4.8), with mean GFR 68 (range 12-126). 11.3% (8/71) met the definition of CKD. Stages of CKD by GFR in the hemophilia cohort were similar to the NHANES general population (p=0.60).

A history of hematuria was reported in 45.1% (41/91) of subjects, mostly at age under 20. 26.4% (24/91) of subjects had a history of nephrolithiasis, 57.1% (52/91) past use of NSAIDs, and 45.1% (41/91) antifibrinolytic agents. 15.4% (14/91) of subjects reported obstructive symptoms with urination; 14.3% (13/91) had benign prostate disease. 7.7% (7/91) of subjects had a history of intrinsic kidney disease. Of these, 28.6% (2/7) had a renal biopsy, 71.4% (5/7) had seen a nephrologist, and 14.3% (1/7) were on dialysis. The renal disease in these 7 subjects was related to: DM (3), HCV (2), HTN (1), and glomerulonephritis (1).

In our cohort, hemophilia subjects with CKD non-significantly trended to have increased DM (20% vs 8.2%), age ≥65 years (15.6% vs 7.7%), and HTN (14.6% vs 6.7%) compared to subjects without CKD. No other significant trends were identified, including no association with CVD, HCV, HIV, BMI or hematuria.

Conclusions: In this interim analysis of an ongoing national prospective cohort study, older men with moderate to severe hemophilia commonly report risk factors for CKD, including HTN (52.0%), DM (13.3%), viral infection (35.7% HCV, 17.4% HIV), and potential renal damaging medication use (57.1% past use of NSAIDs, 45.1% antifibrinolytic agents). Only 6.1% had CVD. Urological symptoms were also common, including hematuria (45.1%, with 26.4% reporting a history of nephrolithiasis); 15.4% of subjects reported obstructive symptoms with urination, and 14.3% had benign prostate disease.

In our cohort, 11.3% (8/71) subjects met the definition of CKD, defined as the presence of either kidney damage or GFR < 60 ml/min/1.73 m2 for ≥ 3 months. The distribution of GFR values appeared similar to the general population. As in the general population, hemophilia subjects with CKD non-significantly trended to have more DM, older age, and HTN compared to subjects without CKD. We plan to formally compare the prevalence of CKD and CKD risk factors with similarly aged men in the ARIC database once enrollment is complete, as understanding the risk factors that contribute to CKD is essential to halt its progression.