- Nelson Leung, MD
Nelson Leung, MD
- Professor of Medicine
- Mayo Clinic College of Medicine
- Robert A Kyle, MD
Robert A Kyle, MD
- Section Editor — Plasma Cell Disorders
- Professor of Medicine
- Mayo Medical School
- Gerald B Appel, MD
Gerald B Appel, MD
- Section Editor — Glomerular Diseases
- Professor of Medicine
- Columbia University College of Physicians and Surgeons
Amyloidosis is a group of diseases characterized by extracellular deposition of beta-sheet fibrils . In the systemic forms, the amyloid causes progressive organ dysfunction, leading to death of the patients. Over 30 proteins capable of amyloid formation have been identified . They include immunoglobulin (Ig) light chains (AL) and Ig heavy chains (AH) in primary systemic amyloidosis, amyloid A in secondary amyloidosis (AA), beta-2 microglobulin in dialysis-associated arthropathy (Ab2M), and amyloid beta protein (Ab) in Alzheimer disease and Down syndrome. There are also hereditary forms that include transthyretin (ATTR), apolipoprotein A-I (AApoAI) and A-II (AApoAII), gelsolin (AGel), lysozyme (ALys), fibrinogen A alpha chain (AFib), and others . Leukocyte chemotactic factor 2 (ALECT2) is an amyloidogenic protein for which the pathogenic mechanism is incompletely understood [4,5].
Amyloid fibrils can be identified in biopsy specimens both by their characteristic appearance on electron microscopy and by their ability to bind Congo red (leading to apple-green birefringence under polarized light) and thioflavine T (producing an intense yellow-green fluorescence) . They are randomly organized and are approximately 8 to 10 nanometers in diameter.
Amyloid fibrils also avidly bind a normal circulating protein of uncertain physiologic significance called serum amyloid P component (SAP) . This observation may be of diagnostic utility since tissue amyloid deposits can be detected by scintigraphy following intravenous injection of radiolabeled SAP . (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis (primary amyloidosis)", section on 'Serum amyloid P component scintigraphy'.)
Clinically evident renal involvement mainly occurs in AL or AA amyloidosis [1,7-10]. Renal involvement can also occur in some hereditary forms of amyloidosis, most commonly in AFib, AApoAI, AApoAII, ALys, and AGel, but it is rare in ATTR, especially the wild type. The deposition of Ab2m occurs in patients on prolonged maintenance dialysis; deposition in the kidney has been reported in autopsies but has no clinical significance . (See "Dialysis-related amyloidosis".)
This topic provides an overview of renal amyloidosis. A broad overview of amyloidosis, including diagnostic studies to determine the underlying etiology once a diagnosis of amyloidosis is confirmed, is presented elsewhere. (See "Overview of amyloidosis".)
- Glenner GG. Amyloid deposits and amyloidosis. The beta-fibrilloses (first of two parts). N Engl J Med 1980; 302:1283.
- Sipe JD, Benson MD, Buxbaum JN, et al. Nomenclature 2014: Amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid 2014; 21:221.
- Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med 2003; 349:583.
- Benson MD, James S, Scott K, et al. Leukocyte chemotactic factor 2: A novel renal amyloid protein. Kidney Int 2008; 74:218.
- Murphy CL, Wang S, Kestler D, et al. Leukocyte chemotactic factor 2 (LECT2)-associated renal amyloidosis: a case series. Am J Kidney Dis 2010; 56:1100.
- Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N Engl J Med 1990; 323:508.
- Kyle RA, Greipp PR. Amyloidosis (AL). Clinical and laboratory features in 229 cases. Mayo Clin Proc 1983; 58:665.
- Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32:45.
- Gertz MA, Lacy MQ, Dispenzieri A. Immunoglobulin light chain amyloidosis and the kidney. Kidney Int 2002; 61:1.
- Dember LM. Amyloidosis-associated kidney disease. J Am Soc Nephrol 2006; 17:3458.
- Vrana JA, Gamez JD, Madden BJ, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 2009; 114:4957.
- Sethi S, Theis JD, Leung N, et al. Mass spectrometry-based proteomic diagnosis of renal immunoglobulin heavy chain amyloidosis. Clin J Am Soc Nephrol 2010; 5:2180.
- Triger DR, Joekes AM. Renal amyloidosis--a fourteen-year follow-up. Q J Med 1973; 42:15.
- Palladini G, Merlini G. Current treatment of AL amyloidosis. Haematologica 2009; 94:1044.
- Wechalekar AD, Hawkins PN, Gillmore JD. Perspectives in treatment of AL amyloidosis. Br J Haematol 2008; 140:365.
- Uda H, Yokota A, Kobayashi K, et al. Two distinct clinical courses of renal involvement in rheumatoid patients with AA amyloidosis. J Rheumatol 2006; 33:1482.
- Moroni G, Banfi G, Maccario M, et al. Extracapillary glomerulonephritis and renal amyloidosis. Am J Kidney Dis 1996; 28:695.
- Falck HM, Törnroth T, Wegelius O. Predominantly vascular amyloid deposition in the kidney in patients with minimal or no proteinuria. Clin Nephrol 1983; 19:137.
- Westermark GT, Sletten K, Grubb A, Westermark P. AA-amyloidosis. Tissue component-specific association of various protein AA subspecies and evidence of a fourth SAA gene product. Am J Pathol 1990; 137:377.
- Eirin A, Irazabal MV, Gertz MA, et al. Clinical features of patients with immunoglobulin light chain amyloidosis (AL) with vascular-limited deposition in the kidney. Nephrol Dial Transplant 2012; 27:1097.
- Neugarten J, Gallo GR, Buxbaum J, et al. Amyloidosis in subcutaneous heroin abusers ("skin poppers' amyloidosis"). Am J Med 1986; 81:635.
- Orfila C, Lepert JC, Modesto A, et al. Fanconi's syndrome, kappa light-chain myeloma, non-amyloid fibrils and cytoplasmic crystals in renal tubular epithelium. Am J Nephrol 1991; 11:345.
- Sharma A, Bansal S, Jain R. Unique morphology of intratubular light chain casts in multiple myeloma: the amyloid cast nephropathy. Indian J Pathol Microbiol 2014; 57:629.
- Kato H, Fujigaki Y, Asakawa S, et al. Rapid Deterioration of the Renal Function Caused by the Coexistence of Intratubular Amyloidosis and Myeloma Cast Nephropathy. Intern Med 2015; 54:3023.
- Keeling J, Teng J, Herrera GA. AL-amyloidosis and light-chain deposition disease light chains induce divergent phenotypic transformations of human mesangial cells. Lab Invest 2004; 84:1322.
- Poshusta TL, Sikkink LA, Leung N, et al. Mutations in specific structural regions of immunoglobulin light chains are associated with free light chain levels in patients with AL amyloidosis. PLoS One 2009; 4:e5169.
- Gertz MA, Leung N, Lacy MQ, et al. Clinical outcome of immunoglobulin light chain amyloidosis affecting the kidney. Nephrol Dial Transplant 2009; 24:3132.
- Paueksakon P, Revelo MP, Horn RG, et al. Monoclonal gammopathy: significance and possible causality in renal disease. Am J Kidney Dis 2003; 42:87.
- Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002; 346:1786.
- Leung N, Dispenzieri A, Lacy MQ, et al. Severity of baseline proteinuria predicts renal response in immunoglobulin light chain-associated amyloidosis after autologous stem cell transplantation. Clin J Am Soc Nephrol 2007; 2:440.
- Skinner M, Sanchorawala V, Seldin DC, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 2004; 140:85.
- Sanchorawala V, Seldin DC, Magnani B, et al. Serum free light-chain responses after high-dose intravenous melphalan and autologous stem cell transplantation for AL (primary) amyloidosis. Bone Marrow Transplant 2005; 36:597.
- Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2006; 107:3378.
- Fadia A, Casserly LF, Sanchorawala V, et al. Incidence and outcome of acute renal failure complicating autologous stem cell transplantation for AL amyloidosis. Kidney Int 2003; 63:1868.
- Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine (Baltimore) 1991; 70:246.
- Ozen S. Renal amyloidosis in familial Mediterranean fever. Kidney Int 2004; 65:1118.
- Connolly JO, Gillmore JD, Lachmann HJ, et al. Renal amyloidosis in intravenous drug users. QJM 2006; 99:737.
- van der Hilst JC, Simon A, Drenth JP. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med 2005; 5:87.
- Simon A, van der Meer JW. Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol 2007; 292:R86.
- Uemichi T, Liepnieks JJ, Benson MD. Hereditary renal amyloidosis with a novel variant fibrinogen. J Clin Invest 1994; 93:731.
- Vigushin DM, Gough J, Allan D, et al. Familial nephropathic systemic amyloidosis caused by apolipoprotein AI variant Arg26. Q J Med 1994; 87:149.
- Valleix S, Drunat S, Philit JB, et al. Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family. Kidney Int 2002; 61:907.
- Yazaki M, Farrell SA, Benson MD. A novel lysozyme mutation Phe57Ile associated with hereditary renal amyloidosis. Kidney Int 2003; 63:1652.
- Picken MM, Linke RP. Nephrotic syndrome due to an amyloidogenic mutation in fibrinogen A alpha chain. J Am Soc Nephrol 2009; 20:1681.
- Gregorini G, Izzi C, Obici L, et al. Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis. J Am Soc Nephrol 2005; 16:3680.
- Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346:564.
- Sethi S, Theis JD, Shiller SM, et al. Medullary amyloidosis associated with apolipoprotein A-IV deposition. Kidney Int 2012; 81:201.
- Dasari S, Amin MS, Kurtin PJ, et al. Clinical, biopsy, and mass spectrometry characteristics of renal apolipoprotein A-IV amyloidosis. Kidney Int 2016; 90:658.
- Nasr SH, Dogan A, Larsen CP. Leukocyte Cell-Derived Chemotaxin 2-Associated Amyloidosis: A Recently Recognized Disease with Distinct Clinicopathologic Characteristics. Clin J Am Soc Nephrol 2015; 10:2084.
- Larsen CP, Kossmann RJ, Beggs ML, et al. Clinical, morphologic, and genetic features of renal leukocyte chemotactic factor 2 amyloidosis. Kidney Int 2014; 86:378.
- Mereuta OM, Theis JD, Vrana JA, et al. Leukocyte cell-derived chemotaxin 2 (LECT2)-associated amyloidosis is a frequent cause of hepatic amyloidosis in the United States. Blood 2014; 123:1479.
- Said SM, Sethi S, Valeri AM, et al. Characterization and outcomes of renal leukocyte chemotactic factor 2-associated amyloidosis. Kidney Int 2014; 86:370.
- Hutton HL, DeMarco ML, Magil AB, Taylor P. Renal leukocyte chemotactic factor 2 (LECT2) amyloidosis in First Nations people in Northern British Columbia, Canada: a report of 4 cases. Am J Kidney Dis 2014; 64:790.
- Moroni G, Banfi G, Montoli A, et al. Chronic dialysis in patients with systemic amyloidosis: the experience in northern Italy. Clin Nephrol 1992; 38:81.
- Bollée G, Guery B, Joly D, et al. Presentation and outcome of patients with systemic amyloidosis undergoing dialysis. Clin J Am Soc Nephrol 2008; 3:375.
- Pasternack A, Ahonen J, Kuhlbäck B. Renal transplantation in 45 patients with amyloidosis. Transplantation 1986; 42:598.
- Sobh M, Refaie A, Moustafa F, et al. Study of live donor kidney transplantation outcome in recipients with renal amyloidosis. Nephrol Dial Transplant 1994; 9:704.
- Sherif AM, Refaie AF, Sobh MA, et al. Long-term outcome of live donor kidney transplantation for renal amyloidosis. Am J Kidney Dis 2003; 42:370.
- Leung N, Lager DJ, Gertz MA, et al. Long-term outcome of renal transplantation in light-chain deposition disease. Am J Kidney Dis 2004; 43:147.
- Livneh A, Zemer D, Siegal B, et al. Colchicine prevents kidney transplant amyloidosis in familial Mediterranean fever. Nephron 1992; 60:418.
- Gillmore JD, Lachmann HJ, Rowczenio D, et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J Am Soc Nephrol 2009; 20:444.
- Leung N, Griffin MD, Dispenzieri A, et al. Living donor kidney and autologous stem cell transplantation for primary systemic amyloidosis (AL) with predominant renal involvement. Am J Transplant 2005; 5:1660.
- Casserly LF, Fadia A, Sanchorawala V, et al. High-dose intravenous melphalan with autologous stem cell transplantation in AL amyloidosis-associated end-stage renal disease. Kidney Int 2003; 63:1051.
- PATHOLOGY AND CLINICAL MANIFESTATIONS
- Light microscopy
- Clinical manifestations and site of deposition
- - Glomerular deposits
- - Crescentic glomerulonephritis
- - Vascular and tubular amyloid deposits
- - Intratubular amyloid cast nephropathy
- PRIMARY (AL) AMYLOIDOSIS
- Response to therapy
- SECONDARY (AA) AMYLOIDOSIS
- HEREDITARY RENAL AMYLOIDOSIS
- OTHER RENAL AMYLOIDOSES
- Apolipoprotein A-IV (AApoAIV) amyloidosis
- Leukocyte cell-derived chemotaxin 2-associated (ALECT2) amyloidosis
- DIALYSIS AND RENAL TRANSPLANTATION
- SUMMARY AND RECOMMENDATIONS