Skip Navigation


NDT Advance Access originally published online on August 12, 2009
Nephrology Dialysis Transplantation 2009 24(10):2967-2969; doi:10.1093/ndt/gfp379
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/10/2967    most recent
gfp379v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ronco, P.
Right arrow Articles by Aucouturier, P.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ronco, P.
Right arrow Articles by Aucouturier, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Renal involvement in AL amyloidosis: the facts, the promise and the hope*

Pierre Ronco1,2,3 and Pierre Aucouturier2,4

1 INSERM UMR S 702 2 UPMC University, Paris 6 3 AP-HP, Hôpital Tenon, Service de Néphrologie et Dialyses 4 INSERM UMR S 938, Hôpital St Antoine, Paris, France

Correspondence and offprint requests to: Pierre Ronco; E-mail: pierre.ronco{at}tnn.aphp.fr

Keywords: AL amyloidosis; chemotherapy; dialysis; {lambda}-light chain; transplantation

AL amyloidosis is a devastating, multisystem disorder that often affects the kidney, with proteinuria and elevated serum creatinine being detected in 55% and 45% of patients at presentation [1]. Many patients will develop end-stage renal failure (ESRF). However, there is little information on the predictors of ESRF and the outcome of dialysis, although it is generally considered that the quality of life under dialysis is poor with a high rate of mortality.

The paper by Gertz et al. from the Mayo Clinic examines the long-term outcomes of 145 patients with biopsy-proven AL amyloidosis [2]. Eighty-four had renal amyloidosis and 35 were ultimately dialysis dependent. This is the largest series of patients with renal AL amyloidosis, with an Italian collaborative study that included 198 patients with AL amyloidosis [3]. The Mayo Clinic study provides three pieces of information (1) {lambda} light chain predicts increased likelihood of renal involvement, (2) high serum creatinine and daily proteinuria are predictors for dialysis, (3) median survival for patients starting dialysis is <1 year. These findings have important pathophysiological and therapeutic implications.



   Pathophysiology of amyloid deposition: still unresolved issues!
Top
 Pathophysiology of amyloid...
Kidney and life survival:...
 The hope of new...
 References
 
Determinant factors of amyloid are borne by the precursor light chain (LC), as suggested by recurrence in the renal graft and by induction of amyloid deposits in mice injected with LCs from patients with AL amyloidosis [4]. Pathophysiological studies are made difficult by the unique structural heterogeneity of the precursor, each monoclonal LC being different from all others (Figure 1).


Figure 1
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 A monoclonal immunoglobulin {lambda}-light chain includes a variable (VL) domain that is always different from one patient to another, and a constant domain. The VL domain is encoded after the rearrangement of a V and a J gene segment, and its variability is essentially restricted to three separate peptide portions termed ‘complementarity determining regions’ (CDR1, 2 and 3); the remaining VL sequence (‘framework regions’) supports the globular antiparallel beta-sheet structure of the domain. All structural determinants of amyloidogenic potential are borne by the VL domain, some in the CDRs that may influence the binding specificity, others in the framework regions where aminoacid substitutions may either increase the thermodynamic stability or favour dimerization.

 
Several LC characteristics are considered amyloidogenic. In AL amyloidosis, the {lambda} isotype is approximately 3- to 6-fold more frequent than the {kappa} isotype. A rarely expressed homology family of LC variable regions, the V{lambda}VI variability subgroup, is found only in amyloid-associated monoclonal immunoglobulins and represents 41% of amyloid LCs [5]. The essential role of the variable domain is further supported by analyses of extracted fibrils, which showed it to be the main amyloid constituent. This finding suggests a role of proteolysis in fibrillogenesis, and may partly account for the weak reactivity of anti-LC antibodies in some patients.

The search for primary sequence peculiarities of the LC variable domains led to disappointing conclusions, although an analysis of nearly 200 LC sequences identified 12 positions in {kappa}-chains and 12 in {lambda}-chains where certain aminoacid residues were associated with amyloidosis [6]. Because of their high dimerization constants, LCs from patients with AL amyloidosis could behave as antibodies for extracellular structures. This may also explain why {lambda}-chains, which are more prone to form dimers than {kappa}, are more frequent in amyloidosis.

Molecular bases of organ tropism in AL amyloidosis remain essentially unclear. Gertz et al. [2] first showed that patients with renal amyloid are far more likely to have a monoclonal {lambda} LC. The ratio of {lambda} to {kappa} patients in their cohort was 4:1 in patients with non-renal amyloid compared to 12:1 in those with renal amyloid (P = 0.02). Conversely, patients with {kappa} LCs are more likely to have dominant hepatic involvement [7]. The tropism of organ involvement may be influenced both by the germ line gene segment used for the LC variable region (VL) and by somatic mutations occurring in the secreting clone [8]. Patients expressing a monoclonal LC of the V{lambda}VI subgroup are more likely to present with dominant renal involvement, while cardiac and multisystem disease is less frequent [7]. Organ-specific environmental factors are also involved, including high intrarenal concentrations of urea that enhance fibril formation by reducing the nucleation lag time [9].

Five percent of the Mayo Clinic's patients [2] with apparently no renal manifestation, ultimately required dialysis. These patients may have had asymptomatic renal amyloid deposits at presentation. Tissue injury is mostly the consequence of extensive deposition of amyloid. However, at least in some tissues, the infiltration alone does not correlate well with the degree of organ failure or survival. This suggests that soluble LCs may exert direct cellular toxicity. LCs from AL-amyloid patients incubated with human mesangial cells induced a macrophage-like phenotype, whereas those from patients with non-amyloid deposition disease induced a myofibroblastic phenotype [10]. Infusion of LCs from patients with cardiac amyloidosis caused diastolic dysfunction in isolated mouse hearts [11].



   Kidney and life survival: Is renal replacement therapy worthwhile?
Top
 Pathophysiology of amyloid...
 Kidney and life survival:...
The hope of new...
 References
 
Gertz et al. [2] confirm the importance of cardiac involvement in predicting survival. Patients with renal AL amyloidosis had a better survival than patients without renal involvement (38 months versus 19 months; P = 0.05), mostly because of the higher prevalence of cardiac amyloidosis in patients without renal involvement. We recommend measuring N-terminal pro-brain natriuretic peptide (BNP) in all patients. BNP is a sensitive marker of myocardial dysfunction and response to treatment, and a powerful predictor of overall survival [12,13].

The management of patients with AL amyloidosis on haemodialysis is often complicated by persistent hypotension, gastrointestinal haemorrage, chronic diarrhoea and difficulties in the creation and maintenance of vascular access. Peritoneal dialysis could have several advantages avoiding vascular access and deleterious effects on blood pressure, but it may enhance malnutrition.

As in their previous publication in the early 1990s [14], Gertz et al. [2] reported a poor outcome for patients with AL amyloidosis on dialysis. The median survival from the start of dialysis was 10.4 months, with 20% of patients dying within the first month and only 12% having a 5-year survival. Major causes of death were cardiac, voluntary cessation of dialysis and gastrointestinal tract involvement. Given the poor outcome and quality of life, one could legitimately ask whether patients should be put on a chronic dialysis programme. However, in two studies dating from the early 1990s on heterogeneous cohorts of patients with AL or AA amyloidosis [15,16], patients’ median survival from dialysis initiation ranged from 25 to 52 months, respectively. In a recent study [17], including 19 patients with AL amyloidosis undergoing dialysis, the median survival was 26 months (extremes, one to 96 months). The difference in overall survival may be explained by substantial progress in chemotherapy, as patients from the Mayo Clinic were enrolled in therapeutic protocols between 1993 and 1997 with none of them receiving high-dose melphalan (HDM) [2], while French patients were seen between 1995 and 2005 and received dexamethasone-based regimen or HDM [17].

The outcome remains poor in patients with cardiac involvement that may benefit from heart and kidney transplantation, provided that the underlying clonal plasma cell disease has remitted following chemotherapy [18–21].



   The hope of new therapies
Top
 Pathophysiology of amyloid...
 Kidney and life survival:...
 The hope of new...
References
 
Given that amyloid deposits can regress, the objectives should be a complete haematologic remission assessed by measurement of serum-free LC [22,23]. Remission should be achieved as soon as possible to avoid early death related to cardiac involvement and/or extensive amyloidosis.

AL amyloidosis benefited greatly from major advances in the treatment of multiple myeloma. HDM (140–200 mg/m2) followed by autologous stem cell transplantation (ASCT) induces complete haematologic response and significant functional improvement in a substantial proportion of low-risk patients [24–27]. However, treatment-related mortality is higher than in ASCT-treated myeloma patients. Thus, an alternative to HDM/ASCT consists of oral melphalan (10 mg/m2/day) and dexamethasone administered at a high dosage (40 mg/day) in 4-day cycles each month (M/Dex). A recent randomized, multicentre trial showed no significant difference in complete haematologic response between M/Dex and HDM/ASCT [28]. Moreover, median survival was 56.9 months in the M/Dex group compared with 22.2 months in the HDM/ASCT group (P = 0.04). Renal responses occurred in ~25% of the patients in either group.

The following recommendations may be proposed: (1) patients with severe organ dysfunction should receive M/Dex as a first-line treatment and (2) patients with less severe disease are eligible for M/Dex or HDM/ASCT, still considered the reference treatment in experienced centres in the United States. In those who do not show haematologic responses after 3 to 6 months, treatment should be changed to alternatives such as lenalidomide (or thalidomide) or bortezomib-based regimens. These new regimens might become first-line reference treatments in the coming years.

With the eventual eradication of the LC secreting clone, regression of amyloid deposits can now be envisaged.

Conflict of interest statement. None declared.

(See related article by M. A. Gertz et al. Clinical outcome of immunoglobulin light chain amyloidosis affecting the kidney. Nephrol Dial Transplant 2009; 24: 3132–3137.)



   Notes
 
* Comment on Gertz et al. Clinical outcome of immunoglobulin light chain amyloidosis affecting the kidney. Nephrol Dial Transplant 2009; 24: 3132–3137. Back



   References
Top
 Pathophysiology of amyloid...
 Kidney and life survival:...
 The hope of new...
 References
 

  1. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol (1995) 32:45–59.[Web of Science][Medline]
  2. Gertz MA, Leung N, Lacy M, et al. Clinical outcome of immunoglobulin light chain amyloidosis affecting the kidney: mid june. Nephrol Dial Transplant (2009) 24:3132–3137.[Abstract/Free Full Text]
  3. Bergesio F, Ciciani AM, Manganaro M, et al, Immunopathology Group of the Italian Society of Nephrology. Renal involvement in systemic amyloidosis: an Italian collaborative study on survival and renal outcome. Nephrol Dial Transplant (2008) 23:941–951.[Abstract/Free Full Text]
  4. Solomon A, Weiss DT, Kattine AA. Nephrotoxic potential of Bence Jones proteins. N Engl J Med (1991) 324:1845–1851.[Abstract]
  5. Ozaki S, Abe M, Wolfenbarger D, et al. Preferential expression of human lambda-light-chain variable-region subgroups in multiple myeloma, AL amyloidosis, and Waldenström's macroglobulinemia. Clin Immunol Immunopathol (1994) 71:183–189.[CrossRef][Web of Science][Medline]
  6. Stevens FJ, Myatt EA, Chang CH, et al. A molecular model for self-assembly of amyloid fibrils: immunoglobulin light chains. Biochemistry (1995) 34:10697–10702.[CrossRef][Web of Science][Medline]
  7. Comenzo RL, Zhang Y, Martinez C, et al. The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden. Blood (2001) 98:714–720.[Abstract/Free Full Text]
  8. Enqvist S, Sletten K, Stevens FJ, et al. Germ line origin and somatic mutations determine the target tissues in systemic AL amyloidosis. PLoS ONE (2007) 2:e981.[CrossRef][Medline]
  9. Kim YS, Cape SP, Chi E, et al. Counteracting effects of renal solutes on amyloid fibril formation byimmunoglobulin light chains. J Biol Chem (2001) 276:1626–1633.[Abstract/Free Full Text]
  10. 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) 84:1322–1338.[CrossRef][Web of Science][Medline]
  11. Liao R, Jain M, Teller P, et al. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation (2001) 104:1594–1597.[Abstract/Free Full Text]
  12. Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood (2004) 103:2936–2938.[Abstract/Free Full Text]
  13. Palladini G, Campana C, Klersy C, et al. Serum N terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation (2003) 107:2440–2445.[Abstract/Free Full Text]
  14. Gertz MA, Kyle RA, O’Fallon WM. Dialysis support of patients with primary systemic amyloidosis. A study of 211 patients. Arch Intern Med (1992) 152:2245–2250.[Abstract/Free Full Text]
  15. Moroni G, Banfi G, Montoli A, et al. Chronic dialysis in patients with systemic amyloidosis: the experience in northern Italy. Clin Nephrol (1992) 38:81–85.[Web of Science][Medline]
  16. Martinez-Vea A, García C, Carreras M, et al. End-stage renal disease in systemic amyloidosis: clinical course and outcome on dialysis. Am J Nephrol (1990) 10:283–289.[Web of Science][Medline]
  17. Bollée G, Guery B, Joly D, et al. Presentation and outcome of patients with systemic amyloidosis undergoing dialysis. Clin J Am Soc Nephrol (2008) 3:375–381.[Abstract/Free Full Text]
  18. Mignot A, Bridoux F, Thierry A, et al. Successful heart transplantation following melphalan plus dexamethasone therapy in systemic AL amyloidosis. Haematologica (2008) 93:e32–e35.[Abstract/Free Full Text]
  19. Audard V, Matignon M, Weiss L, et al. Successful long-term outcome of the first combined heart and kidney transplant in a patient with systemic Al amyloidosis. Am J Transplant (2009) 9:236–240.[CrossRef][Web of Science][Medline]
  20. Mignot A, Varnous S, Redonnet M, et al. Heart transplantation in systemic(AL) amyloidosis: a retrospective study of eight French patients. Arch Cardiovasc Dis (2008) 101:523–532.[CrossRef][Web of Science][Medline]
  21. Lacy MQ, Dispenzieri A, Hayman SR, et al. Autologous stem cell transplant after heart transplant for light chain (Al)amyloid cardiomyopathy. J Heart Lung Transplant (2008) 27:823–829.[CrossRef][Web of Science][Medline]
  22. Lachmann HJ, Gallimore R, Gillmore JD, et al. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol (2003) 122:78–84.[CrossRef][Web of Science][Medline]
  23. Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involve-ment and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis. Am J Hematol (2005) 79:319–328.[CrossRef][Web of Science][Medline]
  24. Dhodapkar MV, Hussein MA, Rasmussen E, et al. Clinical efficacy of high-dose dexamethasone with maintenance dexamethasone/alpha interferon in patients with primary systemic amyloidosis: results of United States Intergroup Trial Southwest Oncology Group (SWOG) S9628. Blood (2004) 104:3520–3526.[Abstract/Free Full Text]
  25. Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood (2002) 99:4276–4282.[Abstract/Free Full Text]
  26. 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) 140:85–93.[Abstract/Free Full Text]
  27. Working Group of UK Myeloma Forum; British Committee for Standards in Haematology, British Society for Haematology. Guidelines on the diagnosis and management of AL amyloidosis. Br J Haematol (2004) 125:681–700.[CrossRef][Web of Science][Medline]
  28. Jaccard A, Moreau P, Leblond V, et al, Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med (2007) 357:1083–1093.[Abstract/Free Full Text]
Received for publication: 23. 6.09
Accepted in revised form: 6. 7.09


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/10/2967    most recent
gfp379v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ronco, P.
Right arrow Articles by Aucouturier, P.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ronco, P.
Right arrow Articles by Aucouturier, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?