| Abstract|| |
The kidney is the most common organ involved in systemic amyloidosis. We aimed to study etiology and clinicopathological profile of renal amyloidosis. This was a retrospective study of 40 consecutive adult patients with biopsy-proven renal amyloidosis evaluated over a period of two years. Emphasis was given to describing the clinical presentation, renal function, proteinuria, type of amyloidosis, and its etiology. Mean age of the study cohort was 44 ± 15 years (with a male-to-female ratio of 3:1). Amyloid A (AA) amyloidosis was the most common type of amyloidosis observed in 72.5% of cases. Amyloid light chain (AL) amyloidosis accounted for 17.5% of cases, and the rest remained undetermined. AA amyloidosis had widespread age distribution while AL amyloidosis was confined to those >40 years. Proteinuria was the most common renal manifestation observed in all patients. Nephrotic syndrome was seen in 70% of patients. Mean 24 h proteinuria was 6.4 g. Renal failure was the second most common manifestation seen in 70% of patients, of whom 21.4% required hemodialysis. Tuberculosis (TB) accounted for 90% cases of AA amyloidosis. The most prevalent form was pulmonary TB while the rest accounted for by rheumatoid arthritis and bronchiectasis. Among patients with TB induced amyloidosis, 61.5% had received adequate treatment for TB in the past. All patients with AL amyloidosis had nephrotic range proteinuria, five had renal failure out of which two required dialysis. Cardiac involvement was seen in two patients. AA amyloidosis was the most common type of renal amyloidosis in the present study and pulmonary TB was the most common etiology.
|How to cite this article:|
Engineer DP, Kute VB, Patel HV, Shah PR. Clinical and laboratory profile of renal amyloidosis: A single-center experience. Saudi J Kidney Dis Transpl 2018;29:1065-72
|How to cite this URL:|
Engineer DP, Kute VB, Patel HV, Shah PR. Clinical and laboratory profile of renal amyloidosis: A single-center experience. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2020 Jun 4];29:1065-72. Available from: http://www.sjkdt.org/text.asp?2018/29/5/1065/243966
| Introduction|| |
Amyloidosis represents group of disorders characterized by extracellular deposition of circulating protein in the form of fibrils with typical β-pleated sheet configuration. Amyloid deposits are identified histologically by their typical orange-red appearance under light microscopy and apple-green birefringence under polarized light when stained with congo red dye., With the help of mass spectroscopy (MS) based proteomics, 30 amyloidogenic proteins have been identified. Systemic amyloidosis can involve any organ, but the kidney is the most commonly involved organ. Two most common types of renal amyloidosis seen in clinical practice are amyloid A (AA) amyloidosis and amyloid light chain (AL) amyloidosis. AA amyloidosis occurs due to deposition of serum amyloid associated protein in association with chronic inflammatory diseases. Etiologies of AA amyloidosis include chronic inflammatory arthritis, chronic infections [tuberculosis (TB), bronchiectasis, osteomyelitis, and others], autoinflammatory disorders (familial Mediterranean fever, Muckle well syndrome and others), inflammatory bowel disease and others (castle man disease, vasculitis, and others). Majority cases of AL amyloidosis are due to deposition of amyloidogenic immunoglobulin (Ig) light chains secondary to plasma cell dyscrasias. Rarely monoclonal heavy chains alone or in association with light chains are precursors of amyloidosis leading to AH or AHL amyloidosis, respectively. Other rare types of renal amyloidosis are those derived from fibrinogen A α chain (AFib), apolipoprotein (Apo) AI0, Apo AII, or Apo AIV (AApo AI/AII/AIV), transthyretin (ATTR), and lysozyme, gelsolin. According to studies from western countries, AL amyloidosis is the most common type followed by AA amyloidosis. However, studies from India had described AA amyloidosis as the most common type of renal amyloidosis.,,,
| Subjects and Methods|| |
This was a prospective study of patients with biopsy-proven renal amyloidosis over a period of two years (2010–2011) at our institute. Patients included in this study presented with nephrotic syndrome, subnephrotic proteinuria or unexplained renal failure.
Detailed clinical history with emphasis on the past or present history of TB, chronic infection and chronic inflammatory disease was obtained.
All patients underwent the following tests: complete blood count, erythrocyte sedimentation rate, urinalysis, 24 h urine protein estimation, renal function test, liver function test, chest X-ray, electrocardiogram, two-dimensional echocardiogram, coagulation study, ultrasound abdomen, skeleton survey (X-ray of dorsolumbosacral spine, pelvis, and skull), and serum protein electrophoresis. Sputum examination for acid-fast bacilli (AFB), serum-free light chain assay and bone marrow biopsy were done when required.
All patients had renal biopsies processed for light microscopy (LM) and immunofluorescence (IF). Tissue was stained with hematoxylin and eosin, periodic acid–schiff stain, jones’ silver stain, masson’s trichrome stain, congo red, and serum AA (SAA) for LM study. IF study was done using polyclonal antisera against human IgG, IgM, IgA, C3, C1q, kappa and lambda light chains. Biopsy findings were reported by the nephropathologist of the institution.
All patients were treated with salt restriction, diuretics, and antihypertensive (when required). Angiotensin receptor blocker was prescribed to all patients except those requiring initiation of hemodialysis (HD) and those who are hyperkalemic (serum potassium >5.1 mEq/L). HD was done as per standard indication. For AA amyloidosis-specific treatment was directed to underlying chronic infective/inflammatory disorder. AL amyloidosis was treated in consultation with the oncologist. Treatment regimens used were melphalan with dexamethasone, lenalidomide with dexamethasone, and bortezomib with dexamethasone.
Clinical and laboratory variables were defined as below:
Nephrotic syndrome – nephrotic proteinuria (≥3.5 g/24 h), hypoalbuminemia (serum albumin ≤2.5 g/dL) and edema
Sub nephrotic proteinuria – 24-h urine protein between 300 mg and 3500 mg
Microscopic hematuria – Three or more red blood cells per high power field in centrifuged urine examined microscopically
Renal failure – serum creatinine >1.5 mg/dL
Hypertension – systolic blood pressure (BP) ≥140 mm Hg and/or diastolic BP ≥90 mm Hg
Hypotension – systolic BP <100 mm Hg
Anemia – hemoglobin (Hb) concentration <13 g% in males and <12 g% in females
Hypercholesterolemia. – serum total cholesterol >200 mg/dL
AL amyloidosis – the presence of amyloidrelated renal syndrome (proteinuria and/or renal failure), positive amyloid staining by congo red stain, evidence that amyloid is light chain related established by direct examination and/or evidence of monoclonal plasma cell proliferation disorder (monoclonal band on serum protein electrophoresis, abnormal serum-free light chain ratio, clonal plasma cells in bone marrow)
AA amyloidosis – presence of amyloid-related renal syndrome, positive amyloid staining by congo red stain, positive staining of amyloid deposition with SAA stain and the presence of past/active chronic infective/inflammatory disease
Undetermined type – cases not fitting in the definition of AL or AA amyloidosis
Sputum positive pulmonary TB – patient with symptoms suggestive of pulmonary TB with at least one of two sputum positive of AFB
Sputum negative pulmonary TB – patient with symptoms suggestive of pulmonary TB with two negative sputum for AFB and chest X-ray suggestive of TB
Multiple Myeloma (International Myeloma working group) (all of the below)
- Bone marrow plasma cells ≥10%
- Presence of serum and/or urinary monoclonal protein
- Evidence of lytic bone lesion, anemia, hypercalcemia, or renal failure that is attributable to underlying plasma cell proliferation disorder.
Cardiac involvement in AL amyloidosis – Mean left ventricular wall thickness (septum and posterior wall) >12 mm in the absence of hypertension or other potential causes of left ventricular hypertrophy.
| Statistical Analysis|| |
Data were expressed as the mean ± standard deviation (SD) or frequency in percentage. Comparison between types of amyloidosis was carried out using Kruskal–Wallis test (for continuous variable) and Chi-square test (for categorical variables). P<0.05 was considered as statistically significant. All analyses were performed with Statistical Package for the Social Sciences (SPSS) software version 14.0 statistic software (SPSS, Inc., Chicago, IL., United States).
| Results|| |
Clinical and pathological profile of patients with renal amyloidosis is summarized in [Table 1]. In our study, the most affected age group was 20–39 years (42.5%) followed by 40–59 years (30%) and then >60 years (25%). Among AA amyloidosis, most common affected age groups were 20–39 years and 40–59 years, whereas AL amyloidosis was only confined to those older than 40 years.
Proteinuria was the most common clinical presentation seen in all patients. Among patients with nephrotic proteinuria (n = 31), 28 met the definition of the nephrotic syndrome. Eight patients had proteinuria >10 g. The second most common presentation was renal failure (28 patients), of which 21.4% (6 patients) required dialysis. Eighty percent of patients were anemic with mean Hb of 10.4 g% (SD, 2). Hypotension was noted in six patients with postural hypotension in one case.
In the present study, the most common etiologic factor was TB (65%). Other etiologies were rheumatoid arthritis (5%) and chronic lung infection (2.5%). Etiology of amyloidosis was unidentified in 10% of patients. Most common etiology of AA amyloidosis was TB (90% cases), with pulmonary affection in all except one patient with spinal TB.
Analysis of patients with amyloidosis due to TB [Table 2] showed that the most common affected age group was 20–39 years. The interval between the diagnosis of TB and amyloidosis was variable ranging from six months to 30 years with a median of 2.5 years. Most patients were diagnosed with TB within three years before detection of amyloidosis and had received adequate antitubercular treatment.
|Table 2: Clinical and pathological profile of AA amyloidosis associated with tuberculosis.|
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As shown in [Table 1], AL amyloidosis was the second most common type. Nephrotic range proteinuria was universal with two patients having proteinuria of >10 g a day. Two out of five patients with renal failure required HD. Anemia was also a prevalent feature (6 patients). One patient had hypotension on presentation. Two patients had cardiac involvement as per two-dimensional echocardiography criteria. Out of seven AL amyloidosis patients, only one patient had multiple myeloma with the monoclonal band on serum protein electrophoresis. This patient had 35% abnormal plasma cells on bone marrow examination and lytic lesions in the spine. Immunofluorescence showed positive staining for λ light chain antisera in two cases and for both к and λ light chain antisera in five cases. Overproduction of λ light chain was universal feature of AL amyloidosis with the mean free light ratio (к/λ) of 0.12 (SD, 0.02).
Renal biopsy-related bleeding complications were seen in five patients. Four patients had gross hematuria, of whom, two had bladder clot which required cystoscopic evacuation. One patient had perinephric hematoma which was managed conservatively. Three of these patients had AA amyloidosis and two had AL amyloidosis. All patients with biopsy-related bleeding complication had renal failure with median serum creatinine of 6.63 mg/dL (range, 4.48–10.85 mg/dL).
| Discussion|| |
In this study, 40 cases of renal amyloidosis were studied in two years with a biopsy incidence of 5.7% of total native renal biopsies. Biopsy incidence of renal amyloidosis in studies from India ranges from 1.7% to 8.5% and has shown declining trend.,,, In a study by Chugh et al during 1957–1979, biopsy incidence of renal amyloidosis was 8.5%. In study by Shah et al from Nair Hospital during 1973–1992, biopsy incidence of renal amyloidosis was 3.6%. Mehta et al during the period of 1968–1986 reported biopsy incidence of 4%. In recent studies by Prakash et al, biopsy incidence of renal amyloidosis was 1.7% in the study group of 1992–2002 and 1.9% in the study group of 2003–2012. Abdallah et al from Egypt and Tsai et al from China reported biopsy incidence of renal amyloidosis of 2.5% and 0.68%, respectively.,
Abdallah from Kuwait and Alwahaibi from Oman reported amyloidosis as histopathological diagnosis in 2.3% and 0.5% of total renal biopsies, respectively., In renal biopsy study by Nishi from Japan, renal amyloidosis accounted for 1.3% of total biopsies done. Dasanayaka from Srilanka and Absar from Pakistan, renal amyloidosis accounted for 0.5% and 4% of cases, respectively., In the largest clinicopathologic series of renal amyloidosis (474 patients, 2007–2011) from Mayo clinic laboratory, biopsy incidence of renal amyloidosis was 2.1%. It is evident that incidence of renal amyloidosis in the study was higher than recent Indian study, Chinese study and series from Mayo Clinic.,, Incidence of amyloidosis in our study was also higher than the Japanese study, study from Oman, Kuwait, Srilanka, and Pakistan.,,,, One important reason for higher biopsy incidence of amyloidosis is the persistence of TB in lower socioeconomic class despite overall reduction in TB mortality, incidence and prevalence in India.,, TB was the most common etiology of renal amyloidosis in the present study and being a government funded specialty research institute, we had a selection bias with majority patient from lower socioeconomic strata.
In the present study, males were predominantly affected which corroborate with other Indian studies, study from Egypt and Mayo clinic.,,,,, This pattern seems to be due to higher TB prevalence in males as TB was the most common cause of amyloidosis in our study. In this study, male predominance was also noted in AL amyloidosis.
AA amyloidosis is the most common type of renal amyloidosis in the present study with TB as its most common etiology. Indian studies conducted between 1960 and 1990 have reported TB as the etiology of renal amyloidosis in 51%–65% cases.,, Recent study by Jaiprakash has also described TB as the most common etiology of renal amyloidosis but with lower incidence (35.29% in 1990s and 24.1% in 2000s). This highlights persisting TB burden in the country. Development of renal amyloidosis despite adequate treatment signifies the need for aggressive primary and secondary prevention efforts with early diagnosis and management. This is in sharp contrast to studies from developed countries, where AL amyloidosis is the most common type and chronic inflammatory diseases are the most common cause of AA amyloidosis.,, Study by Elbis Ahbap from Turkey has shown familial Mediterranean fever as the most common cause of AA renal amyloidosis. In the present study, other uncommon etiologies of AA amyloidosis were rheumatoid arthritis and chronic bronchiectasis. This is in contrast with the study by Jaiprakash where chronic inflammatory diseases (rheumatoid arthritis, ankylosing spondylitis, etc.) were responsible for 48% cases of renal amyloidosis in 2000s study group.
Pulmonary TB was the most common type of TB responsible for AA renal amyloidosis in the current study which corroborate with study by Shah, Chugh, and Abdallah.,, In the present study, almost all have pulmonary TB except one with spinal TB whereas in study by Chugh et al, 81.1% had pulmonary TB and rest had lymph node or abdominal TB. In study by Shah et al 85.7% had pulmonary TB and rest had spinal, miliary, and lymph node TB. As observed by our study, Dixit et al similarly noted predominant involvement of young male patients by TB-related amyloidosis. Interval between onset of TB and amyloidosis has shown a wide range across studies which is like our finding (range 6 months–30 years). The reported intervals were 1–30 years (mean 6.92 years), 2 months–31 years, 5 months–25 years, 2 months–7 years, 2 months–6 years and 6 months–43 years (mean 17 years), 1–6 years (mean 2 years) by Chugh et al, Mehta et al, Shah et al, Dixit et al, Gupta et al, Kennedy et al and Erk et al respectively.,,,,,, In the present study, majority had received adequate treatment for TB which is in contrast to study by Dixit where most were inadequately treated. In our study, type of amyloidosis was unclassified in four cases (10%) due to the lack of availability of Laser microdissection/MS (LMD/MS). These cases neither had associated systemic disease nor had any evidence of monoclonal disease on serum-free light chain assay/bone marrow examination. IF or SAA IHC stain also did not help to differentiate the type of amyloidosis. These cases may be uncommon type of amyloidosis like those derived from AFib, Apo AI0, Apo AII, or Apo AIV (AApo AI/AII/ AIV), ATTR or may be cases of AL amyloidosis missed by IF. Study from Mayo clinic reported that LMD/MS was needed to determine the origin of amyloid in 16% cases and IF failed to diagnose 7.3% of AL amyloidosis.
Nephrotic syndrome was the most common presentation across all studies with prevalence varying from 52.3% to 88.23%.,,,,, Another common manifestation was renal failure which in our study was much higher (75%) than other Indian studies (Chugh et al – 30.5%, Shah et al – 42.18%, Mehta et al – 44.2%, Jaiprakash – 12.8%).,,,, Hypertension was found in 12.8% of patients in a study by Abdallah, 7.3% of patients in study by Chugh et al, 9.38% of patients in study by Shah et al, 7.7% in a study by Mehta et al and 10% in the present study. In the present study, 15% of patients had hypotension which is comparable to study by Emad Abdallah but higher than reported by Chugh et al (7.3%) and Mehta et al (6.7%).,,,
In this study, proportion of AL amyloidosis was quite higher than other Indian studies (In a study by Chugh et al – 12.9%, Shah et al – 11.99%, Mehta et al – 11.5%). This rise seems to be due to increased true incidence, improved diagnostics or reduced AA amyloidosis cases.
The study did not show excess bleeding complications after renal biopsy in amyloidosis cases. Bleeding complications after renal biopsy were seen in five patients (12.5 %). Several studies have shown a high risk of bleeding complications (up to 50%) after renal biopsy in patients with renal amyloidosis., However, these studies have included small numbers of patients with renal amyloidosis. In the largest clinical series (101 cases), renal amyloidosis did not increase the risk of bleeding post renal biopsy as compared to controls.
| Limitations|| |
Being a single-center study from governmentfunded super specialty institute, we have selection bias of including patients predominantly from lower socioeconomic class. Due to the lack of availability of LMD/MS, type of amyloidosis remained unidentified in four cases. Details regarding adequacy of antitubercular treatment was based on patient recall which may be inaccurate.
| Conclusion|| |
AA amyloidosis was the most common type of renal amyloidosis in present study. TB was the most common etiology and amyloidosis developed despite adequate antitubercular treatment. Prevalence of AL amyloidosis noted in our study was higher than previous Indian studies. Small proportion of renal amyloidosis remained unclassified.
Conflict on interest: None declared.
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Dr. Divyesh P Engineer
Department of Nephrology and Clinical Transplantation, Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat
[Table 1], [Table 2]