Renal disease progression in patients with TTR amyloidosis Nikolay Bogush, MD, Rajiv Mundayat, MS, Moh-Lim Ong, MD, Shawn Robinson, MD, Stephen S. Gottlieb MD University of Maryland, Baltimore, MD USA

Background Kidney amyloid deposits are well documented in TTR amyloidosis Most of what is known about TTR renal disease is from small observational studies (less then 75 patients) These studies looked at patients with neurological or gastrointestinal symptoms No studies looked at patients with predominantly cardiac disease Hemodynamic effects of cardiac amyloidosis could impact renal function

Background (cont.) The incidence of renal disease has been reported as 13–50% in these patients The first manifestation of renal dysfunction is microalbuminuria Among patients with proteinuria, 18.8% progressed to ESRD within 5 years In a Portuguese cohort of 403 patients, approximately 1/3 had proteinuria, with 10% progressing to ESRD

Importance of understanding the renal impact of TTR Poor renal function is associated with high morbidity and mortality in patients with heart disease Better understanding of the incidence and progression of patients with amyloid kidney disease may improve treatment

Aims Identify the incidence of renal disease in TTR amyloid patients Determine if patients with cardiac phenotype are more prone to renal impairment compared to patients with neurologic phenotype Evaluate the rate of progression of renal disease in TTR amyloidosis Identify the incidence of proteinuria in these patients

Methods Data obtained from THAOS database Patients selected if the following were recorded: Age BMI Serum Cr at baseline and 1-year follow up 728 patients fulfilled the criteria and were included in the study What variables are reported on a sleep study report, and what do they mean? The key metric used to stratify OSA severity is the apnea–hypopnea index (AHI), defined as the number of episodes of apnea (cessation of airflow for at least 10 seconds) and hypopnea (airflow reduction for at least 10 seconds accompanied by either a 3% or 4% oxyhemoglobin desaturation or arousal from sleep) per hour of sleep. Of note, varying definitions of hypopnea (e.g., 3% vs. 4% desaturation) can lead to markedly different AHI calculations and can limit comparisons of polysomnography reports from different sleep laboratories. The AHI based on a 4% desaturation criteria for hypopnea has been more closely associated with cardiovascular risk (28) and is the metric preferred by the Centers for Medicare & Medicaid Services. However, this definition is more restrictive and may preclude the diagnosis among some patients with classic symptoms, but without significant oxyhemoglobin desaturations, who would benefit from therapy. Regardless of the hypopnea definition, OSA is defined as an AHI ≥ 5 events/h. Mild OSA is defined as an AHI ≥ 5 and < 15, moderate OSA as an AHI ≥ 15 and < 30, and severe OSA as an AHI ≥ 30. Sleep studies also collect other data that can provide important information about a patient’s sleep. Variables typically reported include but are not limited to total sleep time (or total recording time for home sleep tests), measures of sleep quality (sleep efficiency, wake time after sleep onset, quantity of sleep stages, and degree of overall sleep fragmentation), other measures of sleep-disordered breathing (number of central vs. obstructive respiratory events, frequency of oxyhemoglobin desaturation events, time spent with an oxyhemoglobin saturation < 90%, nadir oxyhemoglobin saturation), assessment of any EEG epileptiform activity, nocturnal arrhythmia, limb movements, and video/audio recording of sleep-related behaviors.

Methods (cont.) Patients divided into cardiac or neurologic phenotype Cardiac: Rhythm disturbance or heart failure without neurological or GI symptoms Neurologic: Walking disability of any severity, GI symptoms or other neurologic symptoms Mixed: A combination of symptoms Kidney disease: Consistent elevation of creatinine above the upper limit of normal at the institution Proteinuria: Protein/creatinine value > 45 mg/mmol or albumin/creatinine value > 30 mg/mmol

Patients included 94 Cardiac THAOS database 728 patients identified 495 Neurogenic 139 Mixed

Patient characteristics All Cardiac Neuro Mixed Age, years N 728 94 495 139 Mean ± SD 48 ± 17 67 ± 14 42 ± 13 57 ± 16 Median 43 71 37 59 Sex, n (%) Male 397 (55) 82 (87) 234 (47) 81 (58) Female 331 (45) 12 (13) 261 (53) 58 (42)

Presence of hypertension Cardiac phenotype Neurologic phenotype

Presence of diabetes mellitus Cardiac phenotype Neurologic phenotype

Echo characteristics Characteristic All Cardiac Neuro LV septum thickness N 127 54 73 Mean ± SD (median) 13.9 ± 4.6 (13) 17.9 ± 3.4 (18) 10.9 ± 2.7 (10) RV free wall thickness 44 8 36 6.9 ± 4.8 (6.2) 8.2 ± 1.6 (8.5) 6.6 ± 5.2 (6) LV systolic diameter 121 53 68 29.2 ± 5.7 (29) 31.8 ± 5.9 (32) 27.1 ± 4.7 (27) LV diastolic diameter 128 57 71 43.9 ± 5.6 (440 43.7 ± 5.7 (44) 44.0 ± 5.6 (44)

Presence of proteinuria Cardiac phenotype Neurologic phenotype

Laboratory values Characteristic All Cardiac Neuro Mixed Estimated GFR Mean ± SD 100 ± 40 68 ± 32 111± 36 78 ± 36 Median 100 62 108 73 Creatinine 0.94 ± 0.66 1.30 ± 0.48 0.80 ± 0.50 1.17 ± 1.0 0.81 1.2 0.76 0.92

Median age, GFR and presence of diabetes mellitus

Summary of ANCOVA: Baseline eGFR Cardiac (n = 94) Neurologic (n = 495) Cardiac vs. Neurologic P LS Means (SE) 98.79 (4.94) 105.43 (3.07) –6.64 (5.82) 0.15 95% CI* 89.07, 108.50 99.39, 111.46 –15.75, 2.47 Based on ANCOVA with age, gender, diabetes mellitus and hypertension at enrollment as covariates

Change in renal function Cardiac Neurologic Mixed Pre Post GFR 68 65 111 110 78 75 ΔGFR –3.1 –2.1 –3.2 Creatinine 1.30 1.33 0.80 0.83 1.17 1.16 ΔCreatinine +0.03 –0.01

Summary of ANCOVA: Change from baseline to Year 1 in eGFR Cardiac (n = 94) Neurologic (n = 495) Cardiac vs. Neurologic P LS Mean (SE) –7.49 (2.93) –5.22 (1.82) –2.27 (3.45) 0.41 95% CI* –13.24, –1.74 –8.78, –1.65 –7.67, 3.12 Based on ANCOVA with age, gender, diabetes mellitus and hypertension at enrollment as covariates

Summary Patients with cardiac phenotype are older than patients with neurologic phenotype and have a higher prevalence of diabetes Cardiac phenotype patients had a higher baseline creatinine and a lower GFR The incidence of proteinuria was higher in neurogenic phenotype

Summary (cont.) When adjusted for age, gender, diabetes and hypertension, no significant difference in GFR between the cardiac and neurogenic phenotype was found No significant difference was seen in the change in GFR or creatinine between the groups at 1-year follow up

Conclusions TTR cardiac amyloidosis does not appear to increase renal disease or changes in creatinine or GFR at 1-year follow up Lower GFR in cardiac TTR amyloidosis is probably due to comorbidities (HTN, DM and older age) Renal function might be differentially impacted in cardiac and neurologic amyloidosis