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.

Misdiagnosing renal amyloidosis as minimal change disease.

BACKGROUND: Minimal change disease (MCD) accounts for 10-15% of all adult nephrotic syndrome cases and requires normal renal histology by light microscopy and negative immunohistology. Foot process effacement on electron microscopy (EM) is typical. Renal amyloid deposits demonstrate pathognomonic green birefringence when viewed under cross-polarized light after staining tissue with Congo red (CR) and may reveal fibrils on EM. Late diagnosis and delayed treatment of renal amyloidosis negatively impact on renal and patient survival. METHODS: A retrospective analysis was performed on 2116 patients referred to the National Amyloidosis Centre between 2001 and 2013, in whom renal amyloidosis was confirmed histologically. Twenty-seven of these patients had renal histology initially interpreted to be MCD. RESULTS: Among 26 patients in whom biopsy specimens and/or reports were retrieved, the median age at MCD diagnosis was 62 years and presenting proteinuria averaged 7.8 g/24 h. The median time period between the two diagnoses was 241 days (range: 20-2632 days). MCD was diagnosed without CR in 17/26 (65%) biopsies, but all specimens contained amyloid on retrospective CR staining. MCD was diagnosed without EM in 17/26 (65%) cases and all of 10 such biopsies subsequently demonstrated fibrils. Sixteen patients were subjected to two or more renal biopsies when their proteinuria proved steroid refractory. CONCLUSION: This study highlights the need to stain renal biopsies from proteinuric adults with CR, examine them under cross-polarized light and perform EM wherever possible. If the suspicion of renal amyloidosis remains high, despite apparent negative histology, specimens should be reviewed at specialist centres before undertaking a second kidney biopsy.

Is extracellular volume expansion of peritoneal dialysis patients associated with greater urine output?

BACKGROUND AND OBJECTIVES: Residual renal function (RRF) is important for peritoneal dialysis (PD) technique failure and patient survival. Reduction in extracellular water (ECW) has been reported to reduce urine output. We audited volume status and RRF to determine whether ECW was linked to urinary output. METHODS: We retrospectively audited PD patients who had RRF and multiple frequency bioimpedance spectroscopy assessments. RESULTS: 550 patients were studied. Urine output was lower in males (p = 0.021), non-Caucasoids (p = 0.04), those prescribed antihypertensives (p < 0.001), and greater glucose dialysate usage (p < 0.001). Urine output was negatively associated with dialysis vintage (F = 40.7, ß -0.627, p < 0.001), and ECW (F = 33.7, ß -0.177, p < 0.001) and positively associated with intracellular volume (F = 34.6, ß 0.11, p < 0.001). CONCLUSIONS: RRF is important for successful PD, and ECW volume expansion may lead to better preservation of RRF in PD patients compared to haemodialysis. However, in our retrospective cross-sectional study, ECW expansion was associated with reduced urine output.

Proteomic Analysis for the Diagnosis of Fibrinogen Aα-chain Amyloidosis.

INTRODUCTION: Hereditary fibrinogen Aα-chain (AFib) amyloidosis is a relatively uncommon renal disease associated with a small number of pathogenic fibrinogen Aα (FibA) variants; wild-type FibA normally does not result in amyloid deposition. Proteomics is now routinely used to identify the amyloid type in clinical samples, and we report here our algorithm for identification of FibA in amyloid. METHODS: Proteomics data from 1001 Congo red-positive patient samples were examined using the Mascot search engine to interrogate the Swiss-Prot database and generate protein identity scores. An algorithm was applied to identify FibA as the amyloid protein based on Mascot scores. FibA variants were identified by appending the known amyloidogenic variant sequences to the Swiss-Prot database. RESULTS: AFib amyloid was identified by proteomics in 64 renal samples based on the Mascot scores relative to other amyloid proteins, the presence of a pathogenic variant, and coverage of the p.449-621 sequence. Contamination by blood could be excluded from a comparison of the FibA score with that of the fibrinogen ß and γ chains. The proteomics results were consistent with the clinical diagnosis. Four additional renal samples did not fulfill all the criteria using the algorithm but were adjudged as AFib amyloid based on a full assessment of the clinical and biochemical results. CONCLUSION: AFib amyloid can be identified reliably in glomerular amyloid by proteomics using a score-based algorithm. Proteomics data should be used as a guide to AFib diagnosis, with the results considered together with all available clinical and laboratory information.

Natural history and outcomes in localised immunoglobulin light-chain amyloidosis: a long-term observational study.

BACKGROUND: Localised immunoglobulin light-chain amyloidosis, involving one type of tissue, is rare. Little systematic data exists regarding clinical presentations, course or outcomes, or risk of progression to systemic amyloidosis. We aimed to report clinical features and outcomes of a large series of patients with localised light-chain amyloidosis. METHODS: We examined data for all patients with localised amyloidosis who were diagnosed, assessed, and followed at the UK National Amyloidosis Centre (NAC) between Jan 2, 1980, and Dec 15, 2011, from the NAC database and written records. The inclusion criteria was the presence of biopsy sample proven localised amyloidosis classified as biopsy proven amyloid deposition confined to one site or tissue proven by histology of the tissue examined), without any evidence of vital organ involvement, which was defined as cardiac, renal, or liver involvement or peripheral or autonomic neuropathy and treatment naive. FINDINGS: We identified 606 patients with biopsy proven localised amyloidosis (likely light-chain type in 98%) from 5050 newly diagnosed patients with all types of amyloidosis. Median age was 59·5 years (IQR 50·2-74·5). The most common sites included bladder (95; 16%), laryngeal or tonsillar (92; 15%), cutaneous (84; 14%), and pulmonary nodular (47; 8%). 121 (20%) had a monoclonal immunoglobulin or abnormal circulating free light chains. At median follow-up of 74·4 months (IQR 37·2-132·0), seven (1%) patients progressed to systemic immunoglobin light-chain amyloidosis. 270 (51%) patients had one repeated treatment intervention and 112 (21%) had more than one repeated treatment interventions (predominantly localised debulking). The estimated 5-year overall survival was 90·6% (95% CI 87·7-92·9) and 10-year overall survival was 80·3% (75·1-84·1). In patients aged 70 years or older, median overall survival was 12·1 years (95% CI 10·5-13·7). INTERPRETATION: Localised immunoglobulin light-chain amyloidosis has an excellent prognosis with no apparent effect on life expectancy. Evolution into systemic immunoglobulin light chain amyloidosis is very rare. FUNDING: None.

Recognizing isolated IgG4-related nephropathy.

IgG4-related tubulointerstitial nephritis is an uncommon cause of renal impairment. It has been associated with dysfunction in a number of other organs giving rise to the term IgG4-related systemic disease; organ involvement can occur metachronously, hence, making it more difficult to identify patients. The exact cause of this condition remains unknown. Here, we present a case of isolated renal involvement which demonstrates how particular biochemical, radiological and histopathological changes should raise the suspicion of IgG4-related nephropathy, especially when there is an absence of clues from any other organ.

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.

The effect of racial origin on total body water volume in peritoneal dialysis patients.

BACKGROUND AND OBJECTIVES: Peritoneal dialysis adequacy is typically assessed by urea clearance corrected for total body water (TBW) on the basis of anthropomorphic equations, which do not readily take into account changes in body composition, which may vary between ethnic groups. To determine whether ethnicity could affect estimates of peritoneal dialysis adequacy, we compared TBW estimated by anthropomorphic equations and that measured by multifrequency bioimpedance spectroscopy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We calculated TBW in 600 healthy adult peritoneal dialysis outpatient attending two tertiary university hospitals serving an inner-city multiethnic population who had TBW measured by multifrequency bioimpedance spectroscopy performed. RESULTS: 600 adult peritoneal dialysis patients were studied: mean age, 56.7 ± 0.6 years; 54.2% men; 29.7% diabetic; mean body mass index, 26.1 ± 0.2; 47.3% Caucasian; 29.2% South Asian; 12.8% African/Afro-Caribbean. Total body water was calculated using several anthropomorphic equations and was higher than that calculated MEASURED BY MF-BIS for all ethnic groups, apart from African/Afro-Caribbeans, with the greatest difference between Watson calculated TBW and multifrequency bioelectrical impedance spectroscopy 12.3 ± 0.6% for the South Asians, 9.0 ± 2.6% for Far Eastern Asians, 2.8 ± 0.6% Caucasians, and -0.2 ± 1.5% for African/Afro-Caribbeans. CONCLUSIONS: In this United Kingdom-based multiethnic population, body composition differed particularly for the South Asian patients compared with Caucasians and African/Afro-Caribbeans. Overestimation of TBW by anthropomorphic-based equations would lead to a lower calculation of Kt/V(urea), which may lead to changes in peritoneal dialysis prescription to achieve clinical standard targets and also affect studies examining the relationship between Kt/V and survival.