Q J Med 2000; 93: 535-542
© 2000 Association of Physicians
Presentation, survival and prognostic markers in AA amyloidosis
From the Renal Unit, Glasgow Royal Infirmary, Glasgow, UK
Received 5 May 2000 and in revised form 13 June 2000
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Summary |
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We reviewed 43 patients with AA amyloidosis who presented to our unit between 1985–1999: 70% had an underlying chronic rheumatological diagnosis. Median (95% CI) patient survival from time of diagnosis was 52.9 months (9.4–96.6) and median renal survival was 18 months (3.2–32.8) Twenty-four patients have died; 42% of deaths were due to infection, while renal failure accounted for 12.5%. Presenting factors which adversely influenced outcome were a low serum albumin and a high 24-h urinary albumin excretion (p=0.007 and p=0.003, respectively). Stepwise multivariate regression analysis identified albuminuria and presenting creatinine clearance as significant predictors. (p=0.005 and p=0.035, respectively). Mean C-reactive protein (CRP) throughout follow-up correlated weakly but not significantly with survival off dialysis (p=0.06). Change in creatinine clearance correlated with albuminuria. (r2=40%, p=0.001)
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Introduction |
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AA amyloidosis is a relatively rare disease which may complicate chronic inflammatory diseases, chronic infections, familial Mediterranean fever and occasionally malignant diseases. Although amyloid deposition may be found in many organs, renal involvement dominates the clinical picture. Despite the fact that AA amyloidosis is a well-recognized complication of inflammatory diseases, there are few studies evaluating prognostic markers, natural history and treatment. We studied all patients presenting to our unit with AA amyloidosis over a 14-year period to evaluate these aspects.
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Methods |
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All patients who were referred to our renal unit and diagnosed as having AA amyloidosis and renal dysfunction during the period 1985–99 were included in this study. The patients were identified from our database by running a search for patients with a diagnosis of AA amyloidosis. The histological diagnosis of AA amyloidosis was made by the demonstration of amyloid deposits by Congo red staining on light microscopy, the demonstration of amyloid fibrils on electron microscopy, and in the majority of cases by a positive immunoperoxidase stain for amyloid A protein. Paraproteinaemia was excluded in all patients. Electronic patient records and case notes of patients with AA amyloidosis were examined, and demographic data at diagnosis were recorded, along with serum creatinine, haemoglobin, serum albumin and 24-h urine albumin excretion. The estimated creatinine clearance was calculated from the Cockcroft and Gault formula.1 We calculated the change in estimated creatinine clearance with time as a measure of deterioration in renal function. Note was made of immunosuppressive therapy prior to and during the study period. The average mean arterial pressure (MAP) and C-reactive protein (CRP) was calculated for the follow-up period. Monthly measurements were averaged to reduce bias from frequent recordings while patients were in-patients. CRP measurements at times of overt sepsis were excluded. The principal end-points were the start of renal replacement therapy (RRT) and death. Patients who were lost to follow-up or who had not reached both end-points were censored (for one or both end-points as appropriate) at their last follow-up or the end of the study period. A review of the literature was performed. The Medline database was searched from January 1966 to December 1999 using the terms amyloid and amyloidosis. Papers of interest were on aetiology, prognosis, drug treatment and the use of dialysis. The search was limited to English language, and case reports were not included. References quoted in the identified journals were also reviewed.
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Statistical analysis |
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Comparisons of means and medians were made using t tests and Kruskal-Wallis ANOVA, respectively.
2 analysis was used to compare categories and groupings. Survival curves were derived from Kaplan Meier technique and the importance of factors thought to effect survival was determined by Cox regression analysis. Correlations between rate of progression and different parameters were assessed by linear regression analysis, and results reported as r2 representing the coefficient of variation expressed as a percentage. |
Results |
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Forty-three patients were diagnosed with AA amyloidosis and renal dysfunction over the 14-year period from the beginning of 1985 until 1999. The male:female ratio was 1:1.8. The diagnosis was made on renal biopsy in 84% of patients while the remainder were diagnosed as a result of bone marrow (n=2), rectal (n=2) or skin (n=1) biopsies in patients with significant renal impairment associated with albuminuria. One patient was diagnosed by fat aspiration and one other patient had AA amyloid present on a ureteric biopsy performed at time of cystoscopy.
Of these 43 patients, 30 (70%) had a chronic rheumatological disorder: rheumatoid arthritis (22), juvenile chronic arthritis (3) or ankylosing spondylitis (5). The other causes included severe but apparently inactive pulmonary tuberculosis (6), Crohn's disease (1) and non-Hodgkin's lymphoma (1). No cause was found in the five remaining patients. All patients with chronic rheumatic disease had received non-steroidal anti-inflammatory drugs and the majority received second-line agents for their inflammatory arthritis. Fourteen patients received immunosuppressive treatment in an attempt to control the underlying disease process and/or reduce amyloid production. The immunosuppressive agents used were azathioprine (7), chlorambucil (4), cyclophosphamide (2) and methotrexate (1). One patient who received azathioprine was subsequently given cyclophosphamide and then methotrexate.
The personal and biochemical results at referral and outcome of patients are shown in Table 1
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Survival
Median patient survival (95% CI) from time of tissue diagnosis was 52.9 months (9.4–96.6). Median renal survival, i.e. patients alive and independent of renal replacement therapy, was only 18 months (3.2–32.8). Five-year patient survival was 43% (Figure 1
) whereas five-year renal survival was 31%. A median patient survival of 57.8 months (19.8–95.6) and renal survival of 25.2 months (3.1–60.5) were found in patients with a chronic rheumatological diagnosis. The six patients with tuberculosis as their underlying cause of AA amyloidosis fared particularly poorly, median patient survival was 0.66 months (0.35–0.97).
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We analysed the patients who reached an endpoint (n=27) and compared those who did so within 3 months of referral with patients who did so after 3 months. The characteristics of these groups are shown in Table 2
and described in the text. Patients with a poor prognosis were more likely to be male, have a non-rheumatological diagnosis and have more advanced renal disease. Median patient survival, excluding those who reached an endpoint within 3 months (n=28) was 94 months (38.7–149.3) and median renal survival in the same patients was 54.6 months (15.2–94).
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We also tried to identify factors at presentation which were associated with poor survival. We excluded patients who presented with a serum creatinine >300 µmol/l (n=13). Of the remaining 30 patients, 15 reached an endpoint. By univariate analysis, a low albumin and a high 24-h urine albumin excretion were significantly associated with a poor outcome. (p=0.007 and p=0.003, respectively) There was a trend for mCRP to be higher in the group reaching an endpoint, but it did not reach significance (p=0.057). There were no sex differences, no differences between rheumatological and non-rheumatological cases and no differences in mMAP, age or haemoglobin. In a stepwise multivariate regression analysis with survival off RRT as the dependent variable, only albuminuria and presenting creatinine clearance remained significant, if weak, predictors of survival (p=0.005, r2=9.6% and p=0.035, r2=1.7%, respectively).
Rate of progression of renal disease
We calculated the rate of deterioration of renal disease in 32 patients. We were unable to do so in the other patients, either because the patient's weight had not been recorded (n=5) or because follow-up was <1 month (n=6). The median change in creatinine clearance was -1.07ml/min/month (-18, 0). The rate of progression of renal disease had a strong negative correlation with serum albumin and MAP and a positive correlation with 24-h urine albumin. (r2 and p values: 47% and 0.001; 13.5% and 0.03; 40% and 0.001, respectively) (Table 3)
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Dialysis
Seventeen patients commenced renal replacement therapy. Median survival on dialysis (95% CI) was 8.3 months (0–25.4). Survival was particularly poor in males (n=6), in whom the median survival was 3.2 months (0.3–6.2) compared to a median female survival of 38.2 months (0.7–78.2) (p=0.005). This may reflect the different causes of amyloidosis: those patients with a chronic rheumatological diagnosis had a median survival of 32.2 months (0.7–63.7) compared to those with a non-rheumatological cause in whom survival was 3.2 months (0.6–7) (p=0.07). Age did not affect survival on dialysis.
Cause of death
Twenty-four patients died. The cause was unknown in three patients. Autopsies were performed on three patients only, so clinical criteria were used in the remainder. Infection was the cause of death in 10 patients; other causes were myocardial infarction (n=3), renal failure (n=3), pulmonary embolus (n=2), duodenal ulcer (n=1), acute myeloid leukaemia (n=1) and non-Hodgkin's lymphoma (n=1). Of the three patients who died from renal failure, two refused dialysis and the third patient wished to stop 1 month after starting. Of the 14 patients who received immunosuppressive agents, seven patients died. Infection was the cause in five, one patient died from a pulmonary embolus and one developed acute myeloid leukaemia and died after a bone-marrow transplant. There were no differences in sex, age, haemoglobin, serum albumin, albuminuria or serum creatinine at presentation between those patients dying of infection and those who died of another cause. There were also no differences in mean CRP and MAP or the use of immunosuppressive agents and number of chronic rheumatological diagnoses between the two groups. Details of the 10 patients who died from infection are shown in Table 4.
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Discussion |
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Unlike AL amyloidosis, AA amyloidosis has attracted very little attention, so even basic facts about its evolution are obscure. The renal and rheumatology units of Glasgow's Royal Infirmary serve a population of about 800 000 and the incidence in the west of Scotland is, therefore, about 3–4 per million per year. The causes of AA amyloidosis in Britain have changed markedly over the last three decades. A previous study from our unit between 1963 and 1973 identified 40 patients with renal amyloidosis, the cause of which was old pulmonary tuberculosis in 50%.2 The average age at diagnosis was 48 years and just over half were male. Similar results were reported from a unit in London, where 32 cases of AA amyloidosis were reported between 1958 and 1972 with an average age of 41 years, a male preponderance of 2:1, and only 12.5% of cases were attributed to chronic rheumatic disease.3 Between 1973 and 1983, 75 cases of AA amyloidosis were reported from Bristol and the average age was higher at 57 (18–81) years, 73% were secondary to chronic rheumatic disease and the sex ratio was 1.3:1 with more females affected.4 Our patients presented between 1985 and 1999, and the cause of amyloidosis, age of presentation and sex distribution were almost exactly the same. (70% rheumatological, 57 years old and 1.8:1) Therefore, with the elimination of tuberculosis as a cause of severe pulmonary scarring, chronic rheumatic disease has become the commonest cause of AA amyloidosis, and women are now more commonly affected. In our series, old pulmonary tuberculosis was still the cause in 14%. Unusually, no cause was found in five patients despite an extensive search.
There is a startling difference in the frequency of AA amyloidosis worldwide. A British study found it in 7.4% of patients with chronic juvenile chronic arthritis after 15 years, which is many times higher than the 0.1% recorded in equivalent patients in USA.5,6 Differences also exist for AA amyloidosis complicating rheumatoid arthritis: in Europe between 5–28% of patients with rheumatoid arthritis develop amyloidosis, with the highest incidence in Finland.7 A mortality study in Japan included autopsies on 1246 patients with rheumatoid arthritis; of these, 25.2% had amyloidosis.8 The reasons for the marked geographic differences are unclear.
However, the causes are similar. A report from the Mayo Clinic described the clinical features in 64 patients with AA amyloidosis who presented between 1956 and 1989.9 The three commonest causes were chronic rheumatological conditions (65%), chronic infections (17%) and chronic inflammatory bowel disease (9%). The chronic infections included bronchiectasis (n=5), osteomyelitis (n=5) and hidradenitis suppurativa (n=1). Thus, there are only minor differences in the causes of AA amyloidosis between British and American patients. There was an interesting lack of American patients with pulmonary tuberculosis. The authors noted that males were younger at diagnosis than females (51 vs. 64 years) and the female to male ratio was 1:1.5. Between 1985 and 1989 in Japan, 61.4% of cases of AA amyloidosis were associated with rheumatoid arthritis.8 Therefore, the disease appears to have a similar pattern in all three areas, but is less common in the USA.
The prognosis for patients with AA amyloidosis is difficult to determine from published series. It depends crucially on whether the report comes from a renal or a rheumatological unit. Reports from renal units give a median survival of 24–31 months,3,4,9 with one report quoting a median survival of 18 months from when the serum creatinine reached 150 µmol/l.10 Patients described in series from rheumatological units appear to have a better prognosis, with 5-year survival rates varying between 27% in untreated patients and 93% in treated patients.5,11–13 Even the statistics used by the different specialities make comparisons difficult, but patients attending rheumatologists appear to fare better unless they are untreated. The most likely reason for this is that these patients have less severe renal involvement at time of diagnosis. Renal function is not always recorded in these series but in the studies that commented on renal function the GFR was generally about 50–60 ml/min compared to 20–30 ml/min in renal series. (The median calculated creatinine clearance was 26 ml/min in our patients). Furthermore, most of these series were small. The median survival of our patients (52.9 months) is higher than reported results from other renal units only because all our patients were offered dialysis. Median survival without dialysis was 18 months which is comparable to previous reports.
The cause of death depends on the availability of dialysis. Generally renal failure and infection are the most common causes of death.11 In a Dutch study, 35% died from renal failure; the other causes included infection, gastrointestinal bleeding, bowel perforation and myocardial infarction.14 In the Bristol study, infection accounted for 24% of deaths,4 compared to 8.5% in the Mayo clinic9 and 19% in the London series.3 Our data show infection as a cause of death in 42%, while uraemia accounted for only 12.5% of deaths because of the increased availability of renal replacement therapy.
The survival of the 17 patients who started dialysis was poor, with a median survival of only 8.2 months. This is much worse than patients with other renal diagnoses. In Scotland, the median survival of all patients on dialysis with any renal diagnosis is 67 months (63, 72).15 However, survival on dialysis was better in patients with AA amyloidosis complicating a rheumatological disorder (n=11); these patients had a median survival on dialysis of 32.2 months. In the remaining six patients, old pulmonary tuberculosis was the most common diagnosis and survival was only 3.2 months. These patients had very poor respiratory function at presentation. Survival on dialysis varies world-wide: a large American study (n=321) found a median survival on dialysis of 20 months.16 The results of an Italian study were similar to ours: 41 patients with AA amyloidosis started dialysis, 14 patients died within one month, and in the remaining 27 patients, median survival was 25 months.17 A Spanish study (n=48) reported more encouraging results with a median survival of 52 months.18
We attempted to identify prognostic markers present at diagnosis. Fifteen of our 43 patients either commenced renal replacement therapy or died within 3 months. Their characteristics are shown in Table 2
. These patients were significantly older, had more advanced renal disease, higher albuminuria and a lower serum albumin. They were more likely to be male and have a non-rheumatological diagnoses. Late referral may have occurred because these patients had not been under as close medical supervision as the patients with rheumatological disorders or because they had more aggressive disease.
Prognosis was assessed in two ways: patient survival and rate of progression of renal failure. We studied patient survival in a group of 30 patients who had a serum creatinine of <300 µmol/l at presentation. A low serum albumin and a high 24-h urine albumin excretion were associated with a poor outcome by univariate analysis. Only a high 24-h urine albumin and a low creatinine clearance were identified as factors associated with poor survival by multivariate analysis. Other studies have identified serum creatinine at diagnosis and C-reactive protein (or serum amyloid A protein) during follow-up as prognostic makers.19,20 The Mayo Clinic study identified a raised serum creatinine and a low albumin as poor prognostic factors.9
The rate of loss of renal function was surprisingly fast, averaging 1.07 ml/min/month. This is equivalent to that found in untreated diabetics or patients with proteinuria of 4.5–7 g/day and not on ACE inhibitors.21,22 We measured albuminuria but, using a conversion factor of 5/3, the average proteinuria of our patients was estimated at 3.8 g/day. Thus, our patients fared marginally worse than predicted from their proteinuria alone. The rate of loss of function was negatively correlated with serum albumin and positively correlated with albuminuria (r2=47% and 40%, respectively). Proteinuria is a prognostic marker in almost all glomerulopathies, either because it reflects the severity of the initiating disease or because it is nephrotoxic per se.23Figure 2 illustrates the effect of albuminuria on survival off RRT. Median survival in patients presenting with albuminuria >2 g/day (n=23) was 2.63 months (0, 8.9) compared to 62.5 months (10.5, 114.87) in patients presenting with albuminuria <2 g/day (n=20) (p=0.004). Surprisingly, the rate of progression of renal failure was also negatively correlated with mMAP (r2=13.5%). This is the opposite of findings in other glomerulopathies. It may reflect involvement of other organs in patients with advanced disease such as the adrenals or heart. Nine patients had short synacthen tests performed; of these, only two were abnormal.
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The principal aim in treatment of patients with AA amyloidosis is to switch off production of the amyloidogenic protein (serum amyloid A protein) by controlling the underlying disease process. Unfortunately there are no good trials to assist clinical practice. There are several reports of a dramatic response to surgical resection of the cause of amyloidosis which establishes the principle that if the cause can be removed, the disease can be reversed.24–27 Unfortunately, these cases are exceptional, and medical treatment of chronic inflammatory conditions is the standard approach. Existing evidence applies to patients with rheumatological diseases. There is no evidence that second-line agents such as gold or penicillamine have a specific effect on amyloidogenesis, although there have been encouraging reports evaluating alkylating agents as ‘specific’ treatment of amyloidosis.5,11–13 These trials, however, have been criticized for design flaws such as the use of historical controls and heterogeneity of the ‘specific’ treatment used. However, despite these criticisms, they suggest that the use of immunosuppressive agents can improve prognosis. These studies are summarised in Table 5
. One study examined the use of chlorambucil and cyclophosphamide in 14 patients with a rheumatic disorder in 22 treatment periods. Renal function improved, stabilized or the rate of deterioration slowed in 19/22 treatment periods; in the other four treatment periods, renal function continued to deteriorate at a similar or faster rate. This group quoted a 5-year survival figure of 93%.12 A further report followed up eight cases of AA amyloidosis complicating juvenile chronic arthritis treated with chlorambucil. With treatment, improvement in the severity of JCA was seen in six patients but the other two patients were resistant. After a 10-year follow up, one chlorambucil-resistant patient had died of renal failure, two patients had persistent proteinuria, and five patients were free of proteinuria.28There are obvious concerns in using these agents in view of their potential toxicity and, given the variability of prognosis in AA amyloidosis, there is a risk of subjecting some patients to toxic treatment needlessly.
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We treated 14/30 rheumatological patients with a variety of drugs, of which azathioprine was the most commonly used. It was usually commenced in patients with raised CRP, and treatment did suppress the acute-phase response. There is no evidence that this group had an improved prognosis compared to the 16 untreated patients either in terms of improved survival or slower rate of progression. However, in this retrospective analysis, treatment was not given in a controlled manner, various treatments were used and for varying lengths of time. Therefore, this is weak evidence from which to draw any conclusions. While our results cannot claim to add information regarding the success or otherwise of immunosuppressive treatment, it is a concern that infection was a major cause of death. However, this was the case both in those who were treated with immunosuppressive agents and those who were not.
It is, therefore, important to identify patients with a poor prognosis at a stage when it may be possible to alter the disease process and in whom immunosuppressive treatment may be justified. Our results show that, as in other glomerulopathies, albuminuria is a very important predictor of poor outcome. Patients with ongoing inflammation and higher albumin excretion are at an increased risk, and may benefit from a trial of immunosuppressive agents. It is currently unknown if the use of immunosuppressive agents in more advanced renal disease e.g. creatinine >300 µmol/l is of any benefit. Multicentre trials to address these issues and incorporate the advances in immunosuppressive treatment are needed if we are to continue the progress in prevention and treatment of AA amyloidosis.
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Acknowledgments |
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We thank Dr J Hunter, Consultant Rheumatologist, for his helpful comments and advice.
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Notes |
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Address correspondence to Dr N. Joss, Renal Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF
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References |
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