Natural history and outcome of light chain deposition disease.

Light chain deposition disease (LCDD) is characterized by the deposition of monotypic immunoglobulin light chains in the kidney, resulting in renal dysfunction. Fifty-three patients with biopsy-proven LCDD were prospectively followed at the UK National Amyloidosis Center. Median age at diagnosis was 56 years, and patients were followed for a median of 6.2 years (range, 1.1-14.0 years). Median renal survival from diagnosis by Kaplan-Meier analysis was 5.4 years, and median estimated patient survival was 14.0 years; 64% of patients were alive at censor. Sixty-two percent of patients required dialysis, and median survival from commencement of dialysis was 5.2 years. There was a strong association between hematologic response to chemotherapy and renal outcome, with a mean improvement in glomerular filtration rate (GFR) of 6.1 mL/min/year among those achieving a complete or very good partial hematologic response (VGPR) with chemotherapy, most of whom remained dialysis independent, compared with a mean GFR loss of 6.5 mL/min/year among those achieving only a partial or no hematologic response (P < .009), most of whom developed end-stage renal disease (ESRD; P = .005). Seven patients received a renal transplant, and among those whose underlying clonal disorder was in sustained remission, there was no recurrence of LCDD up to 9.7 years later. This study highlights the need to diagnose and treat LCDD early and to target at least a hematologic VGPR with chemotherapy, even among patients with advanced renal dysfunction, to delay progression to ESRD and prevent recurrence of LCDD in the renal allografts of those who subsequently receive a kidney transplant.

Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance in Cardiac Amyloidosis.

BACKGROUND: The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced by cardiac involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown. METHODS AND RESULTS: Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P<0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1-13.7; P<0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E', and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3-13.1; P<0.05). CONCLUSIONS: There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after adjustment for known prognostic factors.

A study of implanted cardiac rhythm recorders in advanced cardiac AL amyloidosis.

AIMS: AL amyloidosis may respond to chemotherapy but two-thirds of patients with severe cardiac involvement die within a year of diagnosis, purportedly from tachyarrhythmias or electromechanical dissociation. We sought to characterize the nature of cardiac arrhythmias in severe cardiac AL amyloidosis using implanted cardiac rhythm recorders. METHODS AND RESULTS: Implantable loop recorders (ILRs) were inserted within 24 h of baseline evaluation at the UK National Amyloidosis Centre, into 20 consecutive patients with newly diagnosed severe cardiac AL amyloidosis and symptoms of syncope or pre-syncope. Weekly ILR recordings and additional recordings at the time of symptoms were obtained. Median (range) follow-up from baseline was 308 (10-399) days. Thirteen patients died, and median survival in the whole cohort was 61 days from device insertion. In each of eight evaluable cases, death was heralded by bradycardia, usually associated with complete atrioventricular block (CAVB), followed shortly thereafter by pulseless electrical activity. Four patients received pacemakers, a median (range) of 7 (3-38) h after development of symptomatic CAVB, but these did not prevent rapid cardiac decompensation and death in three cases. Despite 272 loop recordings, there was only one episode of non-sustained ventricular tachycardia, which was preceded by severe bradycardia. Patients who died had significantly worse global left ventricular strain on echocardiography (P = 0.029) and reduced 6 min walk distance (P = 0.048) at baseline compared with survivors. CONCLUSIONS: The discovery that bradyarrhythmias heralded terminal cardiac decompensation in most patients with severe cardiac AL amyloidosis supports a study of prophylactic pacemaker insertion in this patient population.

Emerging treatments for amyloidosis.

Amyloidosis results from protein misfolding, and ongoing amyloid deposition can ultimately lead to organ failure and death. Historically, this is a group of diseases with limited treatment options and frequently poor prognosis. However, there are now 'targeted' therapeutics emerging in the form of stabilizers of the precursor protein, inhibitors of fibrillogenesis, fibril disruptors, and blockers of protein translation, transcription, and immunotherapy. We review many of these approaches that are currently being assessed in clinical trials.

Extracellular volume expansion in peritoneal dialysis patients.

INTRODUCTION: Cardiovascular mortality remains high among peritoneal dialysis (PD) patients. Several small studies have suggested that PD patients are volume expanded, and as such this could be a cardiovascular risk factor. We therefore wished to investigate factors which could lead to extracellular water (ECW) expansion. METHODS: Retrospective cross-sectional audit of 600 prevalent, adult PD patients attending two tertiary university PD centers, with corresponding assessments of PD adequacy, transport status, and multifrequency bioimpedance measurements of extracellular water to total body water (ECW/TBW). RESULTS: 600 PD patients, median age 57.5 (46.9-67.9) years, 54% male, 31% diabetic, 47.6% Caucasoid, median PD vintage 16 (3.7-38) months, (64% prescribed icodextrin, 34% hypertonic glucose dialysates, and 74% antihypertensive medications). Mean ECW 15.1±0.2 L, ICW 20±0.2 L, ECW/TBW ratio 0.437±0.007. On multivariate analysis %ECW/TBW was associated with age (F=13.1 ß=0.045 p=0.000), number of antihypertensive medications (F=10.3 ß=0.43 p=0.001), log CRP (F=12.9 ß=1.3 p=0.000), and negatively with serum albumin (F=25 ß=-0.22 p=0.000), and residual renal function (urine volume mL F=9.96 ß=-0.001 p=0.002) (weekly Kt/Vurine F=8.82 ß=-2.05, p=0.003). CONCLUSIONS: Overhydration as assessed by ECW/TBW is prevalent in adult PD patients, and is associated with loss of residual renal function, inflammation, malnutrition and hypertension - as assessed by antihypertensive medications. As this was a retrospective cross-sectional audit, whether loss of residual renal function, inflammation, and protein energy wasting lead to volume expansion remains to be determined in prospective longitudinal studies.