Conventional heart failure therapy in cardiac ATTR amyloidosis.

AIMS: The aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA). METHODS AND RESULTS: A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population [hazard ratio (HR) 0.77 (95% confidence interval (CI) 0.66-0.89), P < .001] and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) >40% [HR 0.75 (95% CI 0.63-0.90), P = .002]; and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% [HR 0.61 (95% CI 0.45-0.83), P = .002]. No convincing differences were found for treatment with ACEi/ARBs. CONCLUSION: Conventional heart failure medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.

Tc-99m labelled bone scintigraphy in suspected cardiac amyloidosis.

AIMS: To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease. METHODS AND RESULTS: A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM. CONCLUSION: The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.

Focal Segmental Glomerulosclerosis Complicating Therapy With Inotersen, an Antisense Oligonucleotide Inhibitor: A Case Report.

Inotersen is an antisense oligonucleotide inhibitor licensed for the treatment of polyneuropathy complicating hereditary transthyretin amyloidosis (ATTRv). Nephrotoxicity has been reported with inotersen, including progression to kidney failure. We describe what is to our knowledge the first reported case of inotersen-associated nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS) and review the literature concerning inotersen-induced nephrotoxicity. We report a woman in her early 30s with ATTRv associated with the V50M transthyretin (TTR) variant, who presented with nephrotic syndrome 7 months after commencement of inotersen. Renal histology demonstrated FSGS and scanty glomerular amyloid deposition. Discontinuation of inotersen alone resulted in complete clinical and biochemical resolution of nephrotic syndrome. Inotersen is associated with significant nephrotoxicity. In the phase 3 NEURO-TTR clinical trial, 3% of patients in the treatment arm developed a crescentic glomerulonephritis. All affected patients carried the V50M TTR variant, which is known to be associated with renal amyloid deposition. This case adds to the spectrum of kidney disease associated with inotersen and indicates that discontinuation of the drug alone may result in resolution of renal complications without additional immunosuppression. Monitoring of kidney function is essential in patients with ATTRv receiving inotersen, particularly if there is evidence of existing renal amyloid.

The effect of changing dialysate bicarbonate concentration on serum bicarbonate, body weight and normalized nitrogen appearance rate.

INTRODUCTION: Most hemodialysis machines deliver a fixed bicarbonate concentration. Higher concentrations may improve acidosis, but risk post-hemodialysis alkalosis, whereas lower concentrations potentially increase acidosis but reduce alkalosis. We reviewed the effects of lowering dialysate bicarbonate. METHODS: We reviewed peri-dialysis chemistries in patients switching to a lower bicarbonate dialysate at 4 time points over 19 months. RESULTS: We studied 126 patients, mean age 63.7 ± 16.3 years, 57.9% males. Post-hemodialysis alkalosis fell from 1.6 to 0.3% sessions, but pre-hemodialysis acidosis increased from 11.9 to 23.8% sessions (p = 0.005) reducing dialysate bicarbonate from 32 to 28 mmol/L. After 3 months, pre-hemodialysis serum bicarbonate fell (21.1 ± 2.3 to 19.8 ± 2.2 mmol/L), and post-hemodialysis (24.9 ± 2.1 to 22.5 ± 2.0 mmol/L, p < 0.001) with a fall in pre-hemodialysis weight from 74.6 ± 20.7 to 71.7 ± 18.2 kg, normalized protein nitrogen accumulation rate 0.8 ± 0.28 to 0.77 ± 0.2 g/kg/day, p < 0.05, and serum albumin 39.7 ± 4.2 to 37.7 ± 4.9 g/L, p < 0.001. Thereafter, apart from pre- and post-hemodialysis serum bicarbonate, weight and normalized protein nitrogen accumulation stabilized, although albumin remained lower (37.6 ± 4.0 g/L, p < 0.001). On multivariate logistic analysis, serum bicarbonate increased more with lower pre-hemodialysis bicarbonate standardized coefficient ß 0.5 (95% confidence interval -0.6 to -0.42), increased normalized protein nitrogen accumulation ß 0.2 (0.96 to 2.38), p < 0.001, and session time ß 0.09, (0.47 to 5.98), p < 0.022, and less with lower dialysate bicarbonate 0.0-0.23 (-1.54 to -0.74), p < 0.001. CONCLUSION: Increases in SE-Bic with hemodialysis, depend on the bicarbonate gradient, session time and nPNA. Lower D-Bic reduces post-hemodialysis alkalosis but increases pre-hemodialysis acidosis and may initially have adverse effects on weight and normalized protein nitrogen accumulation.

Characteristics and natural history of early-stage cardiac transthyretin amyloidosis.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized. METHODS AND RESULTS: A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23-20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297). CONCLUSION: Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.

Longitudinal strain is an independent predictor of survival and response to therapy in patients with systemic AL amyloidosis.

AIMS: Cardiac involvement, a major determinant of prognosis in AL (light-chain immunoglobulin) amyloidosis, is characterized by an impairment of longitudinal strain (LS%). We sought to evaluate the utility of LS% in a prospectively observed series of patients. METHODS AND RESULTS: A total of 915 serial newly diagnosed AL patients with comprehensive baseline assessments, inclusive of echocardiography, were included. A total of 628/915 (68.6%) patients had cardiac involvement. The LS% worsened with advancing cardiac stage with mean -21.1%, -17.1%, -12.9%, and -12.1% for stages I, II, IIIa, and IIIb, respectively (P < 0.0001). There was a highly significant worsening of overall survival (OS) with worsening LS% quartile: LS% ≤-16.2%: 80 months, -16.1% to -12.2%: 36 [95% confidence interval (CI) 20.9-51.1] months, -12.1% to -9.1%: 22 (95% CI 9.1-34.9) months, and ≥-9.0%: 5 (95% CI 3.2-6.8) months (P < 0.0001). Improvement in LS% was seen at 12 months in patients achieving a haematological complete response (CR) (median improvement from -13.8% to -14.9% in those with CR and difference between involved and uninvolved light chain <10 mg/L). Strain improvement was associated with improved OS (median not reached at 53 months vs. 72 months in patients without strain improvement, P = 0.007). Patients achieving an LS% improvement and a standard N-terminal pro-brain natriuretic peptide-based cardiac response survived longer than those achieving a biomarker-based cardiac response alone (P < 0.0001). CONCLUSION: Baseline LS% is a functional marker that correlates with worsening cardiac involvement and is predictive of survival. Baseline LS% and an absolute improvement in LS% are useful additional measures of prognosis and response to therapy in cardiac AL amyloidosis, respectively.

Cardiovascular magnetic resonance in light-chain amyloidosis to guide treatment.

AIMS: To assess the ability of cardiovascular magnetic resonance (CMR) to (i) measure changes in response to chemotherapy; (ii) assess the correlation between haematological response and changes in extracellular volume (ECV); and (iii) assess the association between changes in ECV and prognosis over and above existing predictors. METHODS AND RESULTS: In total, 176 patients with cardiac AL amyloidosis were assessed using serial N-terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography, free light chains and CMR with T1 and ECV mapping at diagnosis and subsequently 6, 12, and 24 months after starting chemotherapy. Haematological response was graded as complete response (CR), very good partial response (VGPR), partial response (PR), or no response (NR). CMR response was graded by changes in ECV as progression (≥0.05 increase), stable (<0.05 change), or regression (≥0.05 decrease). At 6 months, CMR regression was observed in 3% (all CR/VGPR) and CMR progression in 32% (61% in PR/NR; 39% CR/VGPR). After 1 year, 22% had regression (all CR/VGPR), and 22% had progression (63% in PR/NR; 37% CR/VGPR). At 2 years, 38% had regression (all CR/VGPR), and 14% had progression (80% in PR/NR; 20% CR/VGPR). Thirty-six (25%) patients died during follow-up (40 ± 15 months); CMR response at 6 months predicted death (progression hazard ratio 3.82; 95% confidence interval 1.95-7.49; P < 0.001) and remained prognostic after adjusting for haematological response, NT-proBNP and longitudinal strain (P < 0.01). CONCLUSIONS: Cardiac amyloid deposits frequently regress following chemotherapy, but only in patients who achieve CR or VGPR. Changes in ECV predict outcome after adjusting for known predictors.

Haematologic responses and survival do not significantly decrease with subsequent lines of therapy in systemic immunoglobulin light chain amyloidosis: results from an analysis of real-world longitudinal data.

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1 276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P = 0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent.

Renal transplant outcomes in amyloidosis.

BACKGROUND: Outcomes after renal transplantation have traditionally been poor in systemic amyloid A (AA) amyloidosis and systemic light chain (AL) amyloidosis, with high mortality and frequent recurrent disease. We sought to compare outcomes with matched transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy (DN), and identify factors predictive of outcomes. METHODS: We performed a retrospective cohort study of 51 systemic AL and 48 systemic AA amyloidosis patients undergoing renal transplantation. Matched groups were generated by propensity score matching. Patient and death-censored allograft survival were compared via Kaplan-Meier survival analyses, and assessment of clinicopathological features predicting outcomes via Cox proportional hazard analyses. RESULTS: One-, 5- and 10-year death-censored unadjusted graft survival was, respectively, 94, 91 and 78% for AA amyloidosis, and 98, 93 and 93% for AL amyloidosis; median patient survival was 13.1 and 7.9 years, respectively. Patient survival in AL and AA amyloidosis was comparable to DN, but poorer than ADPKD [hazard ratio (HR) = 3.12 and 3.09, respectively; P < 0.001]. Death-censored allograft survival was comparable between all groups. In AL amyloidosis, mortality was predicted by interventricular septum at end diastole (IVSd) thickness >12 mm (HR = 26.58; P = 0.03), while survival was predicted by haematologic response (very good partial or complete response; HR = 0.07; P = 0.018). In AA amyloidosis, recurrent amyloid was associated with elevated serum amyloid A concentration but not with outcomes. CONCLUSIONS: Renal transplantation outcomes for selected patients with AA and AL amyloidosis are comparable to those with DN. In AL amyloidosis, IVSd thickness and achievement of deep haematologic response pre-transplant profoundly impact patient survival.

Glucose absorption from peritoneal dialysate is associated with a gain in fat mass and a reduction in lean body mass in prevalent peritoneal dialysis patients.

The majority of peritoneal dialysates use glucose to generate an osmotic gradient for the convective removal of water and Na. Although glucose can potentially be absorbed, previous studies have failed to establish whether this leads to increased fat weight gain. We measured body composition using bioimpedance in peritoneal dialysis (PD) patients, electively starting PD, attending for their first assessment of peritoneal membrane function after 2-3 months, and then after 12 months. We studied 143 patients: eighty-nine (62·2 %) males, fifty-three (37·1 %) diabetics, mean age 61·3 (SD 14·9) years, with ninety (62·1 %) patients treated by automated PD cyclers with a daytime icodextrin exchange and thirty-seven (25·9 %) by continuous ambulatory PD. Median fat mass increased by 1·8 (-0·5 to 4·1) kg, whereas fat-free mass fell -1·3 (-2·9 to 1·0) kg, and the increase in fat mass was negatively associated with the fall in soft lean mass (r -0·41, P < 0·001). Increased fat mass was associated with measured peritoneal glucose absorption (r 0·69, P < 0·001), and glucose absorption was associated with the amount of 22·7 g/l glucose dialysate (OR 2·0, 95 % CI 1·5, 2·5, P < 0·001), peritoneal urea clearance (OR 9·5, 95 % CI 2·4, 37·1, P = 0·001) and male sex (OR 4·8, 95 % CI 1·5, 14·9, P = 0·008). We report an observational study in prevalent PD patients following body composition from their first assessment of PD membrane function for approximately 12 months, and despite the majority of patients prescribed icodextrin, we have demonstrated not only an association between intra-peritoneal glucose absorption and fat weight gain but also loss of fat-free mass.

Karyomegalic interstitial nephritis with a novel FAN1 gene mutation and concurrent ALECT2 amyloidosis.

BACKGROUND: Karyomegalic interstitial nephritis (KIN) is a rare hereditary cause of chronic kidney disease. It typically causes progressive renal impairment with haemoproteinuria requiring renal replacement therapy before 50 years of age. It has been associated with mutations in the Fanconi anaemia-associated nuclease 1 (FAN1) gene and has an autosomal recessive pattern of inheritance. Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is the third most common cause of amyloid nephropathy presenting with chronic kidney disease and variable proteinuria. We report a novel mutation in the FAN1 gene causing KIN and to our knowledge, the first case of concurrent KIN and ALECT. CASE PRESENTATION: We describe the case of 44 year old Pakistani woman, presenting with stage four non-proteinuric chronic kidney disease, and a brother on dialysis. Renal biopsy demonstrated KIN and concurrent ALECT2. Genetic sequencing identified a novel FAN1 mutation as the cause of her KIN and she is being managed conservatively for chronic kidney disease. Her brother also had KIN with no evidence of amyloidosis and is being worked up for kidney transplantation. CONCLUSION: This case highlights two rare causes of chronic kidney disease considered underdiagnosed in the wider population due to their lack of proteinuria, and may contribute to the cohort of patients reaching end stage renal disease without a renal biopsy. We report a novel mutation of the FAN1 gene causing KIN, and report the first case of concurrent KIN and ALECT2. This case highlights the importance of renal biopsy in chronic kidney disease of unclear aetiology which has resulted in a diagnosis with implications for kidney transplantation and family planning.

Tocilizumab (anti-IL-6) treatment for AA renal amyloidosis in a patient with advanced chronic kidney disease, a case report.

Systemic amyloid A amyloidosis is a progressive condition in which sustained elevation of serum amyloid A protein concentration leads to widespread amyloid deposition resulting in multiorgan failure without treatment. The kidney is the most commonly affected organ, and renal amyloid A amyloidosis can cause nephrotic syndrome and chronic kidney disease (CKD) leading to end stage kidney disease (ESKD). Serum Amyloid A protein is produced in the liver in response to chronic inflammation, specifically by inflammatory cytokines, especially IL-6. Tocilizumab, a monoclonal antibody that targets the interleukin-6 receptor, has increasingly been of interest in treating amyloid A amyloidosis. We present a case of a 79-year-old male with long-term seronegative polyarthritis who was referred with gradual decline in kidney function and nephrotic range proteinuria. His renal biopsy showed amyloid A amyloidosis with significant interstitial fibrosis and tubular atrophy. He was commenced on monthly tocilizumab infusions and peritoneal dialysis with good clinical response and rapid resolution of his nephrotic state. This case adds to the current literature on the benefits of tocilizumab in treating amyloid A amyloidosis in patients with advanced CKD.

When to Suspect and How to Approach a Diagnosis of Amyloidosis.

Diagnoses of amyloidosis, particularly transthyretin amyloid cardiomyopathy (ATTR-CM), are steadily increasing throughout the world, but the condition remains underdiagnosed. Patients with amyloidosis may present to a range of medical and surgical specialties, often with multisystemic disease, and a high index of clinical suspicion is required for diagnosis. Bone scintigraphy and cardiovascular magnetic resonance (CMR) imaging offer highly sensitive and specific imaging modalities for cardiac amyloidosis. Histological confirmation of amyloid deposition and amyloid type remains the cornerstone of diagnosis for most amyloid types, with transthyretin amyloid cardiomyopathy the exception, which may be diagnosed by validated nonbiopsy diagnostic criteria in the majority. Histological diagnosis of amyloid has been enhanced by laser capture microdissection and tandem mass spectrometry. Early diagnosis and treatment prior to the development of end-organ damage remains essential to improving morbidity and mortality for patients with amyloidosis.

The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre.

INTRODUCTION: Hereditary apolipoprotein A-I (AApoAI) amyloidosis is a rare heterogeneous disease with variable age of onset and organ involvement. There are few series detailing the natural history and outcomes of solid organ transplantation across a range of causative APOA1 gene mutations. METHODS: We identified all patients with AApoAI amyloidosis who presented to the National Amyloidosis Centre (NAC) between 1986 and 2019. RESULTS: In total, 57 patients with 14 different APOA1 mutations were identified including 18 patients who underwent renal transplantation (5 combined liver-kidney (LKT) and 2 combined heart-kidney (HKT) transplants). Median age of presentation was 43 years and median time from presentation to referral was 3 (0-31 years). Involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively. Renal amyloidosis was universal in association with the most commonly identified variant (Gly26Arg, n = 28). Across all variants, patients with renal amyloidosis had a median creatinine of 159 µmol/L and median urinary protein of 0.3 g/24 h at the time of diagnosis of AApoAI amyloidosis and median time from diagnosis to end-stage renal disease was 15.0 (95% CI: 10.0-20.0) years. Post-renal transplantation, median allograft survival was 22.0 (13.0-31.0) years. There was one early death following transplantation (infection-related at 2 months post-renal transplant) and no episodes of early rejection leading to graft failure. Liver transplantation led to regression of amyloid in all four cases in whom serial 123I-SAP scintigraphy was performed. CONCLUSIONS: AApoAI amyloidosis is a slowly progressive disease that is challenging to diagnose. The outcomes of transplantation are encouraging and graft survival is excellent.

Prognostic importance of the 6 min walk test in light chain (AL) amyloidosis.

OBJECTIVES: In AL amyloidosis, organ response assessment is based on surrogates (eg, cardiac biomarkers). An objective functional test, such as the 6 min walk test (6MWT), capturing overall clinical improvement, is required. We aimed to evaluate the prognostic impact of the 6MWT at baseline and change following chemotherapy. METHODS: This study evaluated the outcomes of patients who enrolled in a prospective observational study at the UK National Amyloidosis Centre (2012-2017). Patients underwent comprehensive assessments inclusive of blood testing, echocardiogram and 6MWT at baseline and annually thereafter. RESULTS: In total, 799 patients were included within the study. Median baseline 6 min walk distance (6MWD) was 362 m (IQR: 231 m). 6MWD progressively decreased with worsening cardiac disease stage (458 m, 404 m, 331 m and 168 m for cardiac Mayo stages I, II, IIIa and IIIb, respectively (p<0.0001)). In patients with a baseline 6MWT of ≥350 m, the median overall survival was not reached (vs 30.0 (95% CI 23.2 to 36.8) months if <350 m and 5.0 (95% CI 2.8 to 7.2) months if unable to attempt 6MWT (p<0.0001). Following chemotherapy, only patients in a complete haematological response improved their 6MWD by 12 months (p=0.001). Improvement in 6MWD prolonged survival in patients with cardiac amyloidosis (p=0.005). CONCLUSION: The 6MWT is prognostic in AL amyloidosis. A baseline distance of ≥350 m independently predicts better survival. These data suggest that 6MWT has utility in AL amyloidosis for baseline prognosis and assessing response.

Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretin amyloid cardiomyopathy.

OBJECTIVES: Wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is a progressive and fatal condition. Although prognosis can be determined at the time of diagnosis according to National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage, the clinical course varies substantially between individuals. There are currently no established measures of rate of disease progression. Through systematic analysis of functional, biochemical and echocardiographic disease-related variables we aimed to identify prognostic markers of disease progression in wtATTR-CM. METHODS: This is a retrospective observational study of 432 patients with wtATTR-CM diagnosed at the UK NAC, none of whom received disease-modifying therapy. The association between mortality from the 12-month timepoint and change from diagnosis to 12 months in a variety of disease-related variables was explored using Cox regression. RESULTS: Change in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) at 12 months from diagnosis was the strongest predictor of ongoing mortality and was independent of both change in other disease-related variables (HR 1.04 per 500 ng/L increase (95% CI 1.01 to 1.07); p=0.003) and a range of known prognostic variables at the time of diagnosis (HR 1.07 per 500 ng/L increase (95% CI 1.02 to 1.13); p=0.007). An increase in NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L during the first year of follow-up occurred in 45%, 35% and 16% of patients, respectively. CONCLUSION: Change in NT-proBNP concentration during the first year of follow-up is a powerful independent predictor of mortality in wtATTR-CM.

Cardiac transplantation in transthyretin amyloid cardiomyopathy: Outcomes from three decades of tertiary center experience.

Aims: Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive and fatal cardiomyopathy. Treatment options in patients with advanced ATTR-CM are limited to cardiac transplantation (CT). Despite case series demonstrating comparable outcomes with CT between patients with ATTR-CM and non-amyloid cardiomyopathies, ATTR-CM is considered to be a contraindication to CT in some centers, partly due to a perceived risk of amyloid recurrence in the allograft. We report long-term outcomes of CT in ATTR-CM at two tertiary centers. Materials and methods and Results: We retrospectively evaluated ATTR-CM patients across two tertiary centers who underwent transplantation between 1990 and 2020. Pre-transplantation characteristics were determined and outcomes were compared with a cohort of non-transplanted ATTR-CM patients. Fourteen (12 male, 2 female) patients with ATTR-CM underwent CT including 11 with wild-type ATTR-CM and 3 with variant ATTR-CM (ATTRv). Median age at CT was 62 years and median follow up post-CT was 66 months. One, three, and five-year survival was 100, 92, and 90%, respectively and the longest surviving patient was Censored > 19 years post CT. No patients had recurrence of amyloid in the cardiac allograft. Four patients died, including one with ATTRv-CM from complications of leptomeningeal amyloidosis. Survival among the cohort of patients who underwent CT was significantly prolonged compared to UK patients with ATTR-CM generally (p < 0.001) including those diagnosed under age 65 years (p = 0.008) or with early stage cardiomyopathy (p < 0.001). Conclusion: CT is well-tolerated, restores functional capacity and improves prognosis in ATTR-CM. The risk of amyloid recurrence in the cardiac allograft appears to be low.

The effect of glucose absorption from peritoneal dialysates on changes in lipid profiles in prevalent peritoneal dialysis patients.

The majority of peritoneal dialysates contain glucose, which can potentially be absorbed from the peritoneal cavity. Previous studies have reported an observation between dialysate glucose exposure and increases in total cholesterol (TC), low-density lipoproteins (LDLs) and triglycerides (TGs). As most of these studies reported glucose exposure in peritoneal dialysis (PD) patients treated by continuous ambulatory peritoneal dialysis (CAPD), we wished to determine whether measured peritoneal glucose absorption resulted in an increase in lipid profile with CAPD and automated PD (APD) cycler treatments. Glucose absorption was measured in 143 patients; 89 (62.2%) males, 53 (37.1%) diabetics, mean age 61.3 ± 14.9 years, with 90 (62.1%) using a daytime icodextrin exchange; 37 (25.9%) CAPD, attending for their first assessment of peritoneal membrane function, when PD prescriptions were then individualised for peritoneal transporter status and repeated after 12 months. Median glucose absorption was 172.5 (75.5-265.5) mmol/day. Although glycated haemoglobin increased (42 ± 16 to 45.4 ± 17.7 mmol/mol, p = 0.006), there was no change in TC (4.8 ± 1.3 to 4.7 ± 1.3 mmol/L), high-density lipoproteins (1.39 ± 0.45 to 1.33 ± 0.51 mmol/L), LDL (2.48 ± 1.12 to 2.21 ± 0.87 mmol/L) or TGs (2.0 (1.3-2.6) to 2.0 (1.3-2.8) mmol/L, adjusted p > 0.05). We found no association between glucose absorption and either lipid profiles or changes in serum lipids. In the current era of APD cyclers and icodextrin, PD prescriptions can be individualised to accommodate patients with a different peritoneal transport status, so that despite daily glucose absorption from dialysates, and a minor increase in glycated haemoglobin, we were unable to demonstrate any significant increase in standard lipid profiles.

Advances in Diagnosis and Treatment of Cardiac and Renal Amyloidosis.

Diagnoses of amyloidosis are increasing annually, and advances in bone scintigraphy and cardiac MRI accompanied by development of nonbiopsy diagnostic criteria have specifically led to a huge increase in transthyretin amyloidosis cardiomyopathy (ATTR-CM) diagnoses worldwide. Tafamidis use is increasing, and there are several ongoing phase III clinical trials of novel agents that promise to transform the treatment landscape for patients with ATTR-CM. In systemic light chain (AL) amyloidosis, more effective chemotherapeutic agents continue to improve patient outcomes. Accelerating the removal of amyloid deposits to accompany these therapies remains the holy grail. However, in the meantime, early diagnosis is undoubtedly key in improving patient outcomes.