Kidney and anemia in familial amyloidosis type I

Beirão, Idalina; Lobato, Luísa; Costa, Paulo; Fonseca, Isabel; Mendes, Paula; Silva, Ana Martins; Bravo, Fernanda; Cabrita, António; Porto, Graça

doi:10.1111/j.1523-1755.2004.00971.x

Cited by 26 publications

(36 citation statements)

References 21 publications

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“…The clearance of phosphatidylserine exposing erythrocytes should lead to anemia. Sequelae of amyloidosis indeed include anemia [54][55][56], which may at least in theory result from amyloid induced eryptosis and subsequent clearance of eryptotic erythrocytes from circulating blood. Amyloid binding has been shown to enhance phagocytosis of erythrocytes in the spleen [57].…”

Section: Discussionmentioning

confidence: 99%

Amyloid Induced Suicidal Erythrocyte Death

Nicolay

Gatz

Liebig

et al. 2007

Cell Physiol Biochem

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Amyloid peptides are known to induce apoptosis in a wide variety of cells. Erythrocytes may similarly undergo suicidal death or eryptosis, which is characterized by scrambling of the cell membrane with subsequent exposure of phosphatidylserine (PS) at the cell surface. Eryptosis is triggered by increase of cytosolic Ca²⁺ activity and by activation of acid sphingomyelinase with subsequent formation of ceramide. Triggers of eryptosis include energy depletion and isosmotic cell shrinkage (replacement of extracellular Cl^- by impermeable gluconate for 24 h). The present study explored whether amyloid peptide Aβ _1-42 could trigger eryptosis and to possibly identify underlying mechanisms. Erythrocytes from healthy volunteers were exposed to amyloid and PS-exposure (annexin V binding), cell volume (forward scatter), cytosolic Ca²⁺ activity (Fluo3 fluorescence) and ceramide formation (anti-ceramide antibody) were determined by FACS analysis. Exposure of erythrocytes to the amyloid peptide Aβ _1-42 (? 0.5 µM) for 24 h significantly triggered annexin V binding, an effect mimicked to a lesser extent by the amyloid peptide Aβ _1-40 (1 µM). Aβ _1-42 (? 1.0 µM) further significantly decreased forward scatter of erythrocytes. The effect of Aβ _1-42 (? 0.5 µM) on erythrocyte annexin V binding was paralleled by formation of ceramide but not by significant increase of cytosolic Ca²⁺ activity. The presence of Aβ _1-42 further significantly enhanced the eryptosis following Cl^- depletion but not of glucose depletion for 24 hours. The present observations disclose a novel action of Aβ _1-42, which may well contribute to the pathophysiological effects of amyloid peptides, such as vascular complications in Alzheimer''s disease.

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Section: Discussionmentioning

confidence: 99%

Amyloid Induced Suicidal Erythrocyte Death

Nicolay

Gatz

Liebig

et al. 2007

Cell Physiol Biochem

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“…A small number of ATTR V30M cases, especially late-onset cases, may present with heart failure (28). Precocious anemia, unrelated to renal manifestations, is conferred by low erythropoietin levels (29,30). It was suggested that the distal nephron is the major site of erythropoietin production in ATTR (31).…”

Section: Clinical Presentationmentioning

confidence: 99%

Transthyretin Amyloidosis and the Kidney

Lobato

Rocha

2012

Clinical Journal of the American Society of Nephrology

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122

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SummaryThe amyloidoses are protein-misfolding disorders associated with progressive organ dysfunction. Immunoglobulin light chain is the most common, amyloid A the longest recognized, and transthyretin-associated amyloidosis (ATTR) the most frequent inherited systemic form. Although ATTR, an autosomal-dominant disease, is associated with at least 100 different transthyretin (TTR) mutations, the single amino-acid substitution of methionine for valine at position 30 is the most common mutation. Each variant has a different organ involvement, although clinical differences attributed to environmental and genetic factors exist within the same mutation. Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features. This review combines clinical and laboratory findings of renal involvement from the main geographic regions of disease occurrence and for different mutations of TTR. Fifteen nephropathic variants have been described, but the TTR V30M mutation is the best documented. Nephropathy affects patients with late-onset neuropathy, low penetrance in the family, and cardiac dysrhythmias. Microalbuminuria can be the disorder's first presentation, even before the onset of neuropathy. Amyloid renal deposits commonly occur, even in the absence of urinary abnormalities. The experience with renal replacement therapy is based on hemodialysis, which is associated with poor survival. Because TTR is synthesized mainly in the liver, liver transplantation has been considered an acceptable treatment; simultaneous liver-kidney transplantation is recommended to avoid recurrence of nephropathy. In addition, the kidney-safety profile of new drugs in development may soon be available.

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“…Low EPO production is an early event in FAP TTR V30M and may precede clinical disease [4]. Similarly, medullary involvement can be clinically silent and be present in asymptomatic carriers.…”

Section: Discussionmentioning

confidence: 99%

“…The serum EPO levels were compared with the expected levels, estimated according to the logarithmic regression equation of EPO against Hb in control subjects [4]. An observed/expected ratio was used to evaluate if EPO production is appropriate to the Hb level.…”

Section: Methodsmentioning

confidence: 99%

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Low Erythropoietin Production in Familial Amyloidosis TTR V30M Is Not Related with Renal Congophilic Amyloid Deposition

Beirão¹,

Moreira

Porto

et al. 2008

Nephron Clin Pract

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Background: Anemia with low serum erythropoietin (EPO) is common in Portuguese transthyretin V30M amyloid polyneuropathy (FAP). Low EPO production can be observed before clinical disease. Renal amyloidosis is observed in FAP, mainly in the medulla. Renal manifestations correlate with glomerular and vascular involvement, but not with tubulointerstitial deposition. To evaluate the potential role of renal amyloid deposits in the genesis of the EPO defect in FAP, we analyzed the renal biopsies of 12 patients (5 males, 7 females, aged from 29 to 54 years) with a clinical evolution varying from 3 to 12 (mean 5.4 ± 2.8) years. Methods: Formalin-fixed, paraffin-embedded sections of renal biopsies were stained by Congo red. Amyloid deposits were assessed by a semiquantitative method based on the percentage of amyloid deposition in each renal structure. Hemoglobin, creatinine, urea, EPO and proteinuria were concomitantly evaluated and correlated with the pathological findings. Results: Renal amyloid deposits were observed in all biopsies analyzed, independently of the neuropathy score. Low serum EPO levels were not related with either the amount of amyloid deposition or the renal clinical manifestations. Conclusion: Impairment of EPO production in FAP is not directly related to renal amyloid deposits and more studies are needed to clarify this question.

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Kidney and anemia in familial amyloidosis type I

Abstract: Anemia in FAP type I is a common manifestation. The results clearly suggest a defective endogenous Epo production in the genesis of the anemia.

Cited by 26 publications

References 21 publications

Amyloid Induced Suicidal Erythrocyte Death

Amyloid Induced Suicidal Erythrocyte Death

Transthyretin Amyloidosis and the Kidney

Low Erythropoietin Production in Familial Amyloidosis TTR V30M Is Not Related with Renal Congophilic Amyloid Deposition

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