Amyloidoses with renal involvement.
Modern amyloid nomenclature, based on the amyloid fibril proteins, includes 31 types of amyloidosis. Renal involvement is commonly seen in AA, AL, and several other hereditary and acquired amyloidoses. AA amyloidosis, constituting up to 45% of all systemic amyloidosis cases, is associated with wide variety of chronic inflammatory conditions. The precursor protein of the fibrils in AA amyloidosis is an apolipoprotein, called serum amyloid A, and produced in the liver in response to proinflammatory cytokines. AL amyloidosis is actually known to be the most common form of systemic amyloidosis in the Western countries. In this type of amyloidosis the precursor proteins are monoclonal immunoglobulin light chains, produced by plasma cell clone. Clinical diagnosis of AA and AL systemic amyloidosis is based on the presence of proteinuria or nephrotic syndrome and impaired kidney function in patients with extrarenal manifestations. Kidney biopsy is crucial for the diagnostics, and while Congo red staining with examination of Congo-positive material in the polarized light is confirmative for amyloidosis as such, immune staining, helpful to distinguish AA and AL types, guides treatment strategies. In cases when neither AA nor AL amyloidosis are confirmed, one should consider rare types of amyloidosis—ALECT2, AapolA, AFib or ALys.
- light chains
- serum amyloid A
- nephrotic syndrome
- kidney function
- kidney biopsy
Modern amyloid nomenclature, based on the amyloid fibril proteins, includes 31 types of amyloidosis . Renal involvement is commonly seen in AL, AH, AA, ALECT2, and several other hereditary and acquired amyloidoses [1, 2, 3, 4], main features are summarized in Table 1.
|Protein precursor||Fibril protein||Clinical setting||Kidney damage||Other target organs|
|Immunoglobulin light chain||AL||“Primary” amyloidosis, LPD||70%||All organs|
|Immunoglobulin heavy chain||AH||LPD||—||All organs|
|Serum amyloid A||AA||Chronic inflammation||90%||All organs except CNS|
|Leucocyte chemotactic factor-2||ALECT2||Not defined as acquired or hereditary||Primarily||Liver|
|Transthyretin||ATTR||Hereditary and acquired||Common||Heart, Eye, PNS, ANS, ligaments, tendon synovium, leptomeninges|
|Apolipoprotein A I||AapoAI||Hereditary||Common||Heart, liver, PNS, testis, larynx, skin|
|Apolipoprotein A II||AapoAII||Hereditary||Primarily||Many organs|
|Apolipoprotein A IV||AapoAIV||Acquired||Primarily||—|
We describe below two most common types of amyloidosis, damaging kidneys—AA amyloidosis and AL amyloidosis.
2. AA amyloidosis
The precursor protein of the fibrils in AA amyloidosis is an apolipoprotein, called serum amyloid A, and produced in the liver in response to proinflammatory cytokines. AA amyloidosis, constituting up to 45% of all systemic amyloidosis cases, is associated with wide variety of chronic inflammatory conditions [5, 6, 7], summarized in the Table 2.
|Infectious conditions with persistent inflammation||Chronic non-infectious diseases with persistent inflammation|
|Conditions predisposing to chronic infections||Arthritis|
|Immunodeficiency’s predisposing to chronic infections||Bowel diseases|
|Chronic infections||Other diseases|
|Hereditary autoinflammatory syndromes|
Rheumatoid arthritis, if poorly controlled, still remains one of the most common inflammatory diseases, associated with AA amyloidosis (Figure 2).
However, many other conditions, listed in Table 2, may be causative for AA amyloidosis. Frequency of the diseases, associated with AA amyloidosis in the patients, followed in our unit, is shown in Table 3.
|Associated disease||Patients (N)||%|
|Crohn’s disease/ulcerative colitis||3||2.0|
|Chronic cutaneous ulcers||3||2.0|
|Sclerosing angiomatoid nodular transformation of the spleen||1||0.7|
Worthy to note, that beyond traditional causes, several rare conditions, such as sarcoidosis, cystic fibrosis and Castleman’s disease, complicated by AA amyloidosis, might be seen in the real practice (Figures 3 and 4).
Presence of NS or proteinuria in patients with the history of any kind of chronic inflammatory conditions, indicates a high “suspicion index’ with AA amyloidosis. The diagnosis demands pathology confirmation with kidney biopsy, demonstrating not only positive Congo red staining of the material, infiltrating kidney tissue (see Figure 1), but also apple-green birefringence in polarized light (Figure 7) and serum amyloid A expression (Figure 8).
Treatment goal in patients with AA amyloidosis is a complete control of the inflammatory process . Due to the various characters of the underlying diseases, treatment may include surgery, antibiotics, anti-TNF agents, colchicine and several novel drugs. Kidney transplantation for the patients with the end stage of renal disease (ESRD) is an important option and may be considered if a stable control of the underlying disease has been achieved.
3. AL amyloidosis
The precursor proteins of the fibrils in AL amyloidosis are monoclonal immunoglobulin light chains, produced by plasma cell clone. AL amyloidosis, which is the most prevalent type of systemic amyloidosis in the Western countries, sometimes is associated with B cell lymphoproliferative disorders—multiple myeloma, Waldenström macroglobulinemia and non-Hodgkin lymphomas [9, 10, 11, 12, 13, 14]. However usually AL amyloidosis is associated with low-grade plasma cell clone and do not meet the criteria for multiple myeloma or lymphoplasmacytic lymphoma, therefore formerly it was known as “primary” [15, 16, 17, 18].
In the real practice, among 128 patients with biopsy-proven AL amyloidosis, followed in our unit, 25 were diagnosed with multiple myeloma, 1—with Waldenström macroglobulinemia, and 102—with AL amyloidosis (“primary”).
Kidneys and heart are the main sites of involvement in AL amyloidosis with the occurrence up to 70% of cases. Renal involvement typically presents with proteinuria or NS, which is manifested in more than 50% of patients at the time of diagnosis, and impaired kidney function progressing towards ESRD in about 20% of cases over time [19, 20, 21].
Kidney biopsy is usually indicated for significant proteinuria and/or renal insufficiency in patients with signs and symptoms of heart, liver, tongue, intestine, peripheral and autonomous nervous system and soft tissues damage (Figures 12–17).
Monoclonal protein studies should be performed to match the monoclonal protein in circulation with the monoclonal deposits in the kidney (Figure 18).
Different treatment regimens had been used since 1997, when melphalan was introduced—melphalan and prednisone (MP), melphalan and dexamethasone (MD), and high dose melphalan with autologous stem cell transplantation (ASCT). Currently recommended treatment for AL amyloidosis, including cyclophosphamide-thalidomide-dexamethasone (CTD), bortezomib-dexamethasone (BD), cyclophosphamide-bortezomib-dexamethasone(CBD) regimens with relatively fast hematological response were adopted from multiple myeloma treatment protocols . In our experience of treatment of systemic “primary” AL amyloidosis with kidney involvement using different regimens over almost three decades, cumulative survival did not differ statistically between melphalan-based and bortezomib-based regimens (Figure 19) .
Clinical diagnosis of AA and AL systemic amyloidosis, most often affecting kidneys, is based on the presence of proteinuria or nephrotic syndrome and impaired kidney function in patients with extrarenal manifestations. Kidney biopsy is crucial for the diagnostics, and while Congo red staining with examination of Congo-positive material in the polarized light is confirmative for amyloidosis as such, immunofluorescence and immunohistochemistry technics are helpful to distinguish AA and AL types. Differential diagnostics of AA and AL types guides the treatment strategies. In cases when neither AA nor AL amyloidosis are confirmed, one should consider rare types of amyloidosis, based on the presence of renal involvement—ALECT2, AapolA I, II and IV, AFib or ALys amyloidosis.
Author thanks doctors Olga Vorobova, Ekaterina Stolyarevich, Vladimir Bedin, Mikhail Tavobilov, Evgeny Shutov, Eugene Nikitin, Marina Rybakova and Igor Miloserdov for their help in diagnostics and treatment of the patients.
Conflict of interest
Author declares no conflict of interests.