| Abstract|| |
The kidneys are affected in almost all patients with amyloid A in secondary amyloidosis (AA) amyloidosis but less frequently in immunoglobulin light chains in primary systemic amyloidosis (AL) amyloidosis. In this study, we present the incidence, etiology, clinical manifestations, biochemical features and clinical course of renal amyloidosis. We conducted a retrospective study on a group of 40 cases with renal biopsy-proven amyloidosis. They constituted 2.5% of the total cases of renal biopsies performed in the Theodor Bilharz Research Institute, Cairo, Egypt, during the period from February 2003 to May 2009. The mean age (30 males, ten females) was 36.51 ± 10.32 years. Thirty-two of the cases had secondary AA amyloidosis and eight cases had primary AL amyloidosis. The causes of secondary amyloidosis were as follows: 12 (30%) familial Mediterranean fever (FMF), eight (20%) pulmonary tuberculosis, four (10%) chronic osteomyelitis, four (10%) bronchiectasis, three (7%) rheumatoid arthritis and one (2%) rheumatic heart disease. The eight cases of primary AL amyloidosis comprised of five cases that were associated with myloma (13%) and three (8%) cases that were idiopathic. Among the 23 patients with AA amyloidosis, after six months of treatment with colchicine, the proteinuria improved, serum albumin level increased and edema disappeared in 13 patients. In four cases of AA amyloidosis who were clinically and biochemically normal after cholchicine therapy, a second renal biopsy disclosed decreased amyloid deposition compared with the first biopsy. In the three renal transplanted patients who had amyloidosis secondary to FMF and were treated with colchicines, AA amyloidosis did not recur in the transplanted kidney. It might be possible that in AL amyloidosis, treatment with methotrexate, melphalan and prednisolone may improve survival. The incidence of renal amyloidosis is increasing and colchicine can be used in secondary amyloidosis as it may have an effect on reducing the production of the amyloid precursor proteins and in reducing proteinuria.
|How to cite this article:|
Abdallah E, Waked E. Incidence and clinical outcome of renal amyloidosis: A retrospective study. Saudi J Kidney Dis Transpl 2013;24:950-8
|How to cite this URL:|
Abdallah E, Waked E. Incidence and clinical outcome of renal amyloidosis: A retrospective study. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2019 Jun 26];24:950-8. Available from: http://www.sjkdt.org/text.asp?2013/24/5/950/118094
| Introduction|| |
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 20 proteins capable of amyloid formation have been identified. They include immunoglobulin (Ig) light chains in primary systemic amyloidosis (AL), Ig heavy chain (AH), amyloid A in secondary amyloidosis (AA), beta2-microglobulin in dialysis-associated arthropathy (Ab2M) and amyloid beta protein (Ab) in Alzheimer's disease and Down's syndrome. There are also hereditary forms that include transthyretin (ATTR), apoli-poprotein A-I (AApoAI) and A-II (AApoAII), gelsolin (AGel), lysozyme (ALys), fibrinogen A-alfa chain (AFib) and others.  Another amyloidogenic protein is leukocyte chemotactic factor 2 (LECT2). ,
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 8-10 nm in diameter.
Initial investigations should confirm the diagnosis of amyloidosis on tissue biopsy, and this should be followed by investigations to establish the type of amyloid present, including quantitative serum-free light-chain (sFLC) assays. Response to treatment should be monitored with sFLC assays. The sFLC assays appear to be the most sensitive method for monitoring the clonal disease in AL amyloidosis patients. Treatment should be continued until the clonal disease has been suppressed by at least 50-75%, or until plateau. 
Clinically evident renal involvement mainly occurs in AL or AA amyloidosis. ,,,, Renal involvement can also occur in some hereditary forms of amyloidosis, most commonly in AFib, AApoAI, AApoAII, ALys and AGel. The deposition of Ab2m occurs in patients on prolonged maintenance dialysis but may not affect the kidney. 
The spectrum of renal symptoms and signs in amyloidosis is variable, such as isolated proteinuria, nephrotic syndrome, hypertension, hypotension and renal insufficiency. The kidneys are affected in almost all patients with AA amyloidosis, but less frequently in AL amyloidosis. ,
The therapeutic possibilities in the treatment of amyloidosis are restricted. As amyloidosis is caused by extracellular deposition of non-phagocytosable insoluble proteins, therapy should be aimed at increasing the cleavage of these amyloid fibrils proteins.
| Aim of the Study|| |
The aim of this study was to evaluate the incidence, etiology, clinical manifestations, biochemical features and clinical course of 40 cases with renal amyloidosis in our hospital and to ascertain the effect of colchicine in treatment.
| Patients and Methods|| |
Forty cases with renal biopsy-proven amyloidosis were included in this study during the period from February 2003 to May 2009 in the Theodor Bilharz Research Institute, Cairo, Egypt. They constituted 2.5% of the total number of renal biopsies performed in this institute during that period. Patients were divided into two groups. Group 1 consisted of 32 patients with secondary AA amyloidosis [12 with familial Mediterranean fever More Details (FMF), eight with tuberculosis (TB)], four with chronic osteomyelitis, four with bronchiectasis, three with rheumatoid arthritis and one with rheumatic heart disease) and Group 2 consisted of eight patients with primary AL amyloidosis. All 40 patients were subjected to detailed history and physical examination. Laboratory tests such as blood urea nitrogen (BUN), serum creatinine (Cr), sodium (Na), potassium (K), creatinine clearance (Ccr), 24-h urine protein and appearance of urinary sediment, Bence Jones proteins, complete blood picture (CBC), erythrocyte sedimentation rate (ESR), total cholesterol, total protein, albumin, protein electrophoresis, antinuclear antibody and rheumatoid factor were performed on all subjects. Bone marrow aspiration was performed when needed to determine the etiology of amyloidosis. Electrocardiogram, echocardiography and abdominal ultrasonography were used for further evaluation of the patients as and when needed.
Kidney biopsies had been performed on all patients. Biopsy samples were stained with Congo red stains. Potassium permanganate test was performed on all amyloid-positive materials. Potassium permanganate-sensitive samples were evaluated as AA amyloid. Additionally, the deposition of IgG, A, M and C3 were evaluated with an immunofluorescent method and an immunoperoxidase method. Bone radiographs, computerized tomographies and cultures were added in some patients when found necessary.
Twenty-three patients with AA amyloidosis secondary to TB, osteomyelitis, bronchiectasis and FMF with normal kidney function received colchicine. In four cases of AA amyloidosis who were clinically and biochemically normal after cholchicine therapy, a second renal biopsy was performed after obtaining their consent.
| Statistical Analysis|| |
The general data of the patients are expressed as means ± SD or percentage. Clinical variables were compared using the unpaired two-tailed t test. Correlation was assessed using Spearman's rank correlation coefficient. Analysis was performed using SPSS software, version 8.0 for windows (SPSS Inc., Chicago, IL, USA). Figures were tabulated using Microsoft Excel 2010. P-values <0.05 were considered significant.
| Results|| |
This study was performed on 40 cases of renal amyloidosis who had been diagnosed histologically. They constituted 2.5% of the total cases of renal biopsies. [Table 1] shows the demographic, clinical and biochemical characteristics of the studied patients. Of the 40 patients with renal amyloidosis, 30 were males and ten were females. Their mean age was 36.51 ± 10.32 years (R 17-74 years).
|Table 1: Demographic, clinical and biochemical characteristics of the studied patients.|
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In 32 patients, secondary AA amyloidosis was diagnosed and the associated diseases were FMF in 12 (30%), pulmonary TB in eight (20%), chronic osteomyelitis in four (10%), bronchiectasis in four (10%), rheumatoid arthritis in three (7%) and rheumatic heart disease in one (2%).
In eight cases, primary amyloidosis was suspected clinically [five cases diagnosed as myeloma-associated amyloidosis (13%) and three cases as idiopathic amyloidosis (8%)]. Primary diseases causing amyloidosis are shown in [Table 2]. Weakness or fatigue and weight loss were the most frequent initial symptoms. Weight loss occurred in more than 30% of the patients. Purpura, particularly in the lower and upper limbs, was noted in one patient. Echymosis was noted in one patient. Skeletal pain was a major symptom in five patients, and was usually related to lytic lesions or fractures associated with multiple myeloma. Pedal edema was noted in six patients. Dyspnea, paresthesias and syncope were noted in two patients. Macroglossia was present in one patient. Shoulder pad sign was not seen in any of our patients. The liver was palpable in 20% of the patients and the spleen was palpable in 10% of the patients.
|Table 2: The primary causes of renal amyloidosis and daily proteinuria distribution among the studied patients.|
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In these eight cases, serum and urine electrophoresis along with urine Bence Jones proteins were performed.  Radiological tests to find lytic lesions and osteoporosis and bone marrow for plasma cells were also performed. Acidified potassium permanganate treatment was carried out to determine whether the amyloidosis was of the AL or the AA type.  Cases were classified as primary amyloidosis when no known disease was associated or secondary when it was associated with a known disease.
Disease history was 13.2 ± 9.6 months in all patients; in group 1 it was 13.3 ± 8.3 months and in group 2 it was 13.4 ± 7.5 months. There were no significant differences between the groups (P = 0.0764). The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 120.76 ± 23.11 (R 77-177) mmHg and 74.75 ± 11.66 (R 37-96) mmHg. SBP and DBP were 122.43 ± 20.63 and 78.42 ± 12.15 mmHg in group 1 and 119.21 ± 24.31 and 72.11 ± 12.20 mmHg in group 2 patients, respectively. These values were also not significantly different.
Physical findings included edema, ascites, hepatomegaly and splenomegaly, and were found to be 93%, 40%, 20% and 10%, respectively. Hypertension (>140/90 mmHg) was found in 12.8% of the cases. The incidence of hypertension was 17% in patients with Ccr <30 mL/min and 7% in patients with Ccr >30 mL/ min). Hypotension was detected in four patients and serum albumin was less than 2.5 g/dL in these four patients (R 1.5-2.5 g/dL). The serum levels of albumin correlated significantly with SBP (P = 0.001) and DBP (P = 0.02). There were no correlation between BP and Ccr, proteinuria and duration of disease.
Proteinuria was the most frequent laboratory finding and had a variable spectrum, from asymptomatic proteinuria to severe nephrotic syndrome (mean 6.37 ± 3.53 g/daily, R 0.3-22.3 g/daily). The distribution of daily proteinuria is shown in [Table 2]. There was an important relationship between the daily proteinuria and the serum levels of albumin (P <0.026), total cholesterol (P <0.02), Hct (P <0.04) and duration of disease (P <0.05).
The mean value of Ccr was 48.2 ± 27.4 mL/ min in all patients; 49.3 ± 38.4 in group 1 and 47.23 ± 36.7 in group 2 patients. The distribution of Ccr and mean values of Ccr are shown in [Figure 1] and [Figure 2]. The mean serum albumin level was 2.5 ± 0.7 g/dL (R 0.6-5 g/dL). The mean values of Hct, WBC and ESR were 36 ± 63% (17-48%), 9840 ± 3533 (3000-17,621) mm 3 and 84 ± 25 (9-139) mm/h, respectively.
|Figure 1: Creatinine clearance values' distribution among the studied patients.|
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Bone marrow aspiration was normal in patients with AA amyloidosis, and showed plasma cells >10% in multiple myeloma and idiopathic AL amyloidosis. Immunofluorescent staining disclosed IgA (35%), IgG (49.7%), IgM (43%) and C3 (58.3%) with a non-linear pattern in the glomerulus, capillaries and mesangium.
Out of 23 patients with AA amyloidosis secondary to TB, osteomyelitis and bronchiectasis as well as FMF, in 13 patients, proteinuria improved, serum albumin level increased and edema disappeared after six months of treatment with colchicine. In four cases of AA amyloidosis who were clinically and biochemically normal after cholchicine therapy, a second renal biopsy revealed decreased amyloid deposition compared with the first biopsy. In three renal transplanted patients who had amyloidosis secondary to FMF and were treated with colchicine, AA amyloidosis did not recur in the transplanted kidney.
[Table 3] shows the changes in renal function of the patients and the mortality on follow-up. During follow-up, six patients died (five with AL and one with AA amyloidosis) and end stage-renal disease developed in nine patients (seven in AA and two in AL amyloidosis).
|Table 3: Changes in renal function of patients and mortality in follow-up.|
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| Discussion|| |
Secondary (AA) amyloidosis is a disorder characterized by the extracellular tissue deposition of fibrils that are composed of fragments of serum amyloid A (SAA) protein, an acute phase reactant. AA amyloidosis may complicate a number of chronic inflammatory conditions, including rheumatoid arthritis, juvenile chronic polyarthritis, ankylosing spondylitis, inflammatory bowel disease, familial periodic fever syndromes, chronic infections and certain neoplasms. 
Primary (AL) amyloidosis can present with a variety of systemic symptoms or signs, including heavy proteinuria (usually in the nephrotic range), edema, hepatosplenomegaly, unexplained heart failure and carpal tunnel syndrome. , Although virtually all patients have multisystem amyloid deposition, it is not uncommon to present with evidence of only one organ being affected. As an example, the absence of apparent extra-renal disease does not exclude AL amyloidosis as the cause of the nephrotic syndrome.  This is particularly true in nephrotic patients over the age of 50 years, up to 20% of whom may have AL amyloidosis. ,, The major diseases that may be linked to AL amyloidosis are multiple myeloma and Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma). 
In our study, we evaluated the incidence, etiology, clinical presentation and clinical outcome in patients with renal amyloidosis. In this present study, we had 40 cases of renal amyloidosis during a 6-year period, which formed 2.5% of the total renal biopsies performed during that period. The 1993 EDTA report on the management of renal failure  shows a low incidence of renal amyloidosis in Europe (~1%) in 1992. However, in some countries of Northern Europe, such as Finland, Norway and Sweden, the incidence is very high (19% of all new patients in Finland). In Finland, ~50% of all patients with amyloidosis are in the older age group (65 years or more). In contrast, renal amyloidosis is equally distributed in the different decades of the life in other European countries. The United Kingdom Medical Research Council's Glomerulonephritis Registry reports a frequency of 2.8% of renal amyloidosis among 3362 patients in whom one or two pathological renal biopsies were performed.  The Italian Registry of Renal Biopsies, which covers 71 actively participating renal units, reports a frequency of 2.5% of renal amyloidosis among 14,777 renal biopsies collected between 1987 and 1993. 
In the present study, the causes of secondary amyloidosis were as follows: 12 (30%) with FMF, eight (20%) with pulmonary TB, four (10%) with chronic osteomyelitis, four (10%) with bronchiectasis, three (7%) with rheumatoid arthritis, and one (2%) with rheumatic heart disease. The eight cases of primary AL amyloidosis comprised of five cases that were associated with myeloma (13%) and three (8%) cases that were idiopathic. In the developed countries, rheumatic diseases are the cause of secondary amyloidosis in 75% of the cases;  however, in this study, FMF and TB were the most important diseases. Similarly, reports from western countries are also available regarding the association of TB and renal amyloidosis. 
In another study,  29 cases of rheumatoid arthritis-associated amyloidosis were reported in a period of 11 years, and 83% of these cases had a survival of 42 ± 8 months. Researchers of yet another study found that 10.5% of the total rheumatoid arthritis patients had amyloidosis. The mean duration of rheumatoid arthritis was 15.4 years, and the presentation was mostly gastrointestinal (58.9%), renal (58.9%) and cardiac symptoms (39.5%), with a 4-year survival of 57.8%. 
In our study, proteinuria was the most frequent finding. Nephrotic range proteinuria was detected in 85% of the patients, as seen in other studies.  Indeed, Cohen  reported that asymptomatic proteinuria continued for years. In cases of FMF, it was reported that this takes three to five years. 
Hypotension is an important symptom causing severe morbidity. Autonomic neuropathy, hypoalbuminemia, cardiac dysfunction and peripheral vascular amyloidosis can cause hypotension.  In our study, the incidence of hypotension was 16%, and all hypotensive cases were hypoalbuminemic.
In our study, the incidence of hypertension was found to be 12.8%. Jansen  found hypertension in 11 of 53 patients. In patients with advanced renal failure, the incidence of hypertension was reported to be 35%.  We also found that hypertension was 17% in patients with Ccr <30 mL/min and 7% in patients with Ccr >30 mL/min.
After six months of treatment with colchicine in patients with AA amyloidosis secondary to TB, osteomyelitis and bronchiectasis as well as FMF, proteinuria improved, serum albumin level increased and edema disappeared in 13 patients. However, in patients with amyloidosis secondary to rheumatic diseases, colchicines therapy did not affect proteinuria. Saatci et al found that only 2.3% of the patients who were treated with colchicines developed recurrence of amyloidosis. 
Zemer et al  have stated that none of their patients developed amyloidosis after colchicine. Saatçi et al  found that increased beta 2 microglobulin excretion and microalbuminuria during the attacks decreases after the administration of colchicines; however, the mechanism of its effects remains to be eluciated. But, in addition to the effect of colchicines, spontaneous regression of glomerular pathologies or vascular lesions can cause a decrease in proteinuria.
In four cases of AA amyloidosis who were clinically and biochemically normal after cholchicine therapy, a second renal biopsy revealed decreased amyloid deposition as compared with their first biopsies. As known, colchicines can cause decreased secretion of amyloid A protein from the liver and decrease amyloid-enhancing factor such that stopping of the process can cause clinical improvement. At the least, it can be said that colchicine can be of use effectively in secondary amyloidosis.
In three renal transplanted patients who had amyloidosis secondary to FMF and were treated with colchicines, AA amyloidosis did not recur in the transplanted kidney, and this was consistent with other studies that have reported that colchicines (1.5 mg/day) prevented amyloid deposition in the transplanted kidney.  The recurrence of amyloidosis without colchicine therapy has been reported as 20%. 
A high incidence of primary amyloidosis in western countries might be due to the use of better diagnostic methods such as immunohistochemistry and histochemical staining, while in our study it is purely based on clinical details, exclusion of secondary causes and the use of potassium permanganate. Now, there are reports that suggest that clinical features are not sufficient to diagnose primary amyloidosis. 
Measurement of Ig sFLC assays in the serum has recently become possible as an alternative to the analysis of Bence Jones proteins in urine. These tests are used as an aid in the diagnosis and monitoring of multiple myeloma and related disorders. There are two types of Ig light chains produced in humans, designated by the Greek letters kappa (κ) and lambda (λ). Comparing the ratio of kappa/lambda free light chains in the serum of an individual with that measured in a number of subjects known to be disease free indicates whether the individual might have a plasma cell tumor such as multiple myeloma or AL amyloidosis. 
| Conclusion|| |
Renal amyloidosis is common and chronic infection is the main causative factor; hence, it should be treated to prevent the adverse complications of renal amyloidosis. Colchicines can be used in secondary renal amyloidosis.
| Recommendations|| |
Use of immunohistochemisty, histochemical staining and serum-free light chain assay in the diagnosis and monitoring of multiple myeloma and AL amyloidosis is recommended.
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Department of Nephrology, Theodor Bilharz Research Institute, Cairo
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]