The Changing Pattern of Renal Amyloidosis in Indian Subcontinent: Two Decades of Experience from a Single Center

Abstract

Background: Renal amyloidosis is a major cause of morbidity and mortality among the patients of systemic amyloidosis. The causes of amyloidosis vary from country to country and from time to time at individual center. Aim: This study investigates the changes in epidemiological and clinical profile of renal amyloidosis in recent years. Method: Cases of biopsy-proven renal amyloidosis from January 1992 to December 2010 were studied retrospectively. They were divided into two groups: 1990s (between 1992 and 2002) and 2000s (between 2003 and 2010). The clinical characteristics of patients were studied and compared between the groups. Result: A total of 2498 (974 in 1990s and 1524 in 2000s) renal biopsies was done during the 19-year period. The incidence of amyloidosis in 1990s and 2000s was 1.74% (n = 17) and 1.9% (n = 29), respectively (p > 0.05). We noted that the incidence of renal amyloidosis increased significantly (p < 0.05) among the females in 2000s. The mean age of patients in 2000s and 1990s was 38 ± 17.9 and 39.2 ± 19 years, respectively (p = 0.83). Renal insufficiency in patients with renal amyloidosis significantly increased (p < 0.05) in 2000s (n = 14; 48.2%) in comparison to 1990s (n = 2; 12.8%). Subnephrotic proteinuria was observed in 12.8% (n = 2) and 48.82% (n = 14) of patients in 1990s and 2000s, respectively (p < 0.05). Infection (n = 10; 58.8%) was the most common cause of secondary amyloidosis during the 1990s, whereas chronic inflammation (n = 14; 48.2%) was the most common cause in 2000s. In 1990s, the incidence of ankylosing spondylitis (AS) and rheumatoid arthritis (RA) was 11.7% (n = 2) and 5.8% (n = 1), respectively, but in 2000s, their respective incidence was 17.2% (n = 5) each. Multiple myeloma (MM) was the most common cause of amyloid light chain protein (AL) amyloidosis in both the groups. We observed systemic lupus erythromatosus (SLE)-related renal amyloidosis in two cases and Hodgkin lymphoma-associated amyloidosis in one case in 2000s. Conclusion: The overall incidence of renal amyloidosis showed little change from 1990s to 2000s. Chronic inflammatory diseases were the most common cause of renal amyloidosis in 2000s in contrast to infections in 1990s. Female gender was more affected in 2000s than in 1990s. Renal insufficiency and subnephrotic-range proteinuria were more frequent clinical manifestations of renal amyloidosis in recent years (2000s) in comparison to the earlier decade (1990s).

• amyloidosis
• chronic infection
• chronic inflammation
• myeloma
• proteinuria

INTRODUCTION

Amyloidosis constitutes a heterogeneous group of diseases characterized by extracellular deposit of amyloid protein that stains apple green with Congo red stain under birefringent light in different tissues and organs. In local amyloidosis, the amyloid deposit is confined to a particular organ or tissue. In systemic amyloidosis, deposits can be present in any or all of the viscera, connective tissue, and/or blood vessel walls. Acquired and hereditary diseases can lead to systemic amyloid associated (AA) amyloidosis, provided that they are associated with chronic inflammation or infections. Renal involvement is very frequent in systemic amyloidosis and is a major cause of morbidity and mortality.

In most published series from the developed countries, primary [amyloid light chain protein (AL)] amyloidosis comprises the majority of cases followed by secondary (AA) amyloidosis.^1,2 Unfortunately, only few epidemiological data on patients suffering from different types of amyloidosis with renal involvement are available in India.^3–6 In this study, we aimed to study the changing pattern of the renal amyloidosis with respect to epidemiological characteristics, etiological factors, and clinical presentations at our center in two study periods: 1990s (between 1992 and 2002) and 2000s (between 2003 and 2010).

MATERIALS AND METHODS

This retrospective study was conducted during the period from January 1992 to December 2010. Ultrasound-guided percutaneous renal biopsy was done under local anesthesia. Kidney tissue was preserved in 10% formalin and routine paraffin blocks were prepared. A 3-μm thick section was cut and stained with hematoxylin and eosin (H&E), Congo red, periodic acid Schiff (PAS), and acid fuchsin orange green (AFOG). Acidified potassium permanganate was used to identify AL or AA type.⁷ The facility for immunohistochemistry staining and immuno-fluorescence microscopy using specific antisera for AA and AL amyloid deposits is not yet available in our institute.

All the patients who underwent renal biopsy between January 1992 and December 2010 were searched for the presence of renal amyloidosis in biopsy. Patients with confirmed evidence of renal amyloidosis (Congo red positive) were included in this study. The medical records of the renal amyloidosis patients were reviewed in the Department of Nephrology. For each patient, detailed clinical history, physical examination findings, presence of amyloidogenic disease(s), and clinical manifestations of renal involvement at the time of biopsy were collected and analyzed. Nephrotic syndrome was defined as 24-h urinary protein excretion of >3.5 g. Renal insufficiency was defined as serum creatinine concentration of > 1.5 mg/dL. Cases were classified as primary amyloidosis when the disease was associated with AL deposits and secondary amyloidosis when it was associated with a known disease or AA deposits. Comparisons of the different characteristics of patients were done after dividing them in two groups: 1990s (1992–2002) and 2000s (2003–2010).

Statistical Analysis

Chi-square test was used to compare the different dichotomous variables. Yates’ correction was done when the variables are <5. Continuous variables were expressed in terms of mean ± SD. Unpaired Student’s t-test was used for statistical comparison of continuous variables. A statistical p-value of <0.05 was considered as significant.

RESULTS AND OBSERVATIONS

During the study period, a total of 2498 patients with clinical evidence of renal disease underwent renal biopsy at our center. Of these, 974 patients were biopsied during the year 1990s, whereas 1524 patients underwent biopsy during the year 2000s. The incidence of amyloidosis in 1990s and 2000s was 1.74% (n = 17) and 1.9% (n = 29), respectively (p > 0.05) (Table 1). The number of female patients with amyloidosis was 17.6% and 48.2% in 1990s and 2000s, respectively. Thus, amyloidosis in female patients was increased significantly in 2000s (p < 0.05). Patients in 2000s were slightly younger in regard to earlier decade; however, the difference was not statistically significant (t = 0.218, p = 0.83) (Table 1).

Table 1.  Demographic profile of amyloidosis patients in two study groups.

	1990s group	2000s group No. (%)	p-Value
Number of biopsies	974	1524
Amyloidosis nephropathy, number (%)	17 (1.75)	29 (1.9)	>0.05
Age range (years)	18–75	16–65
Mean age (years)	39.2 ± 19	38 ± 17.9	0.83^a
Female, number (%)	3 (17.6)	14 (48.20)	<0.05

Note: ^at = 0.215.

Peripheral edema of varying grade was present in all the patients. The frequency of subnephrotic-range proteinuria significantly increased (p < 0.05) in 2000s (n = 14; 48.2%) as compared to 1990s (n = 2; 12.8%), while other features were not much changed (Table 2). The incidence of renal dysfunction was 12.8% (n = 2) and 48.2% (n = 14) in 1990s and 2000s, respectively. Infection (n = 10; 58.8%) was the most common cause of systemic amyloidosis during the 1990s, whereas chronic inflammation (n = 14; 48.2%) was the most common cause in 2000s, but changes were not statistically significant (p > 0.05) (Table 3). However, subgroup analysis revealed that tuberculosis still remains the most common cause of amyloidosis in both the groups (35% and 24.1% in 1990s and 2000s, respectively), although the incidence of leprosy had dramatically deceased to 3.4% in 2000s from 23% in 1990s (Table 3). In 1990s, the incidence of ankylosing spondylitis (AS) and rheumatoid arthritis (RA) was 11.7% (n = 2) and 5.8% (n = 1), respectively, but in 2000s, their respective incidence was 17.2% each, showing an increasing incidence. However, these changes were not statistically significant (p > 0.05) between the two groups (Table 3). Amyloidosis related to systemic lupus erythromatosus (SLE) was seen in two cases in the 2000s group. The frequencies of AL amyloidosis related to multiple myeloma (MM) were 11.7% and 13.7%, Respectively, in 1990s and 2000s.

Table 2.  Clinical presentation of patients with renal amyloidosis in two periods (n = 46).

	1990s group^a	2000s group^b
Clinical features	No. (%)	No. (%)	p-Value
Edema	17 (100)	29 (100)	>0.05
Nephrotic syndrome	15 (88.23)	15 (51.7)	<0.05
Subnephrotic-range proteinuria	2 (12.8)	14 (48.2)
Renal insufficiency	2 (12.8)	14 (48.2)	<0.05
Hypertension	1 (5.8)	2 (6.8)	>0.05
Cardiac conduction defect	1 (5.8)	0 (0)
Hematuria	2 (11.6)	5 (17.2)	>0.05

Notes: ^a17 patients.

^b29 patients.

Table 3.  Underlying causes of amyloidosis in two group (n = 46).

		1990s group (n = 17)	2000s group (n = 29)
Underlying causes		No. (%)	No. (%)	p-Value
Infections	Tuberculosis	6 (35.29)	7 (24.1)
	Leprosy	4 (23.29)	1 (3.4)
	Repeated skin infection	0	1 (3.4)
	Bronchiectasis	0	1 (3.4)
	Total	10 (58.8%)	10 (34.4%)	>0.05
	Ankylosing spondylitis	2 (11.76)	5 (17.2)
Chronic inflammation	Rheumatoid arthritis	1 (5.8)	5 (17.2)
	Ulcerative colitis	1 (5.8)	2 (6.8)
	SLE	0 (0)	2 (6.8)
	Total	4 (23.5)	14 (48.2)	>0.05
	Multiple myeloma	2 (11.76)	4 (13.7)
Malignancies	Carcinoma rectum	1 (5.8)	0 (0)
	Hodgkin lymphoma	0 (0)	1 (3.4)
	Total	3 (17.6)	5 (17.2)	>0.05

Note: SLE, systemic lupus erythromatosus.

DISCUSSION

The kidney is a frequent site of amyloid deposition in both AL- and AA-type amyloidosis. Disruption of tissue architecture by amyloid deposits had long been accepted as the underlying mechanism of organ dysfunction in the amyloidosis. The literature on patients with renal amyloidosis and associated pathological conditions demonstrated a deceasing trend of earlier classic causes, for example, infectious and suppurative diseases, particularly tuberculosis, leprosy and osteomyelitis.^8–10 In addition, there has been emergence of new causes such as rheumatic and neoplastic diseases along with a proportional increase in primary amyloidosis and heredofamilial amyloidosis.^8–10

In this study, we found that there was slight increase in the incidence of renal amyloidosis from 1990s to 2000s (1.7–1.9%). This may be the result of increased uses of tissue biopsies and improvement in the staining techniques in recent years. However, the incidence is much lower than other studies from India where it ranges from 3.59% to 8%.^3–6 This lower incidence in our study may be due to better healthcare facility with effective treatment of amyloidogenic diseases in recent years. The incidence of renal amyloidosis is low in developed countries.^10,11 Esteve et al. of Spain in a 12-year survey reported an incidence of 4.6 cases of AL-type and 12.2 cases of AA-type amyloidosis per million population.¹² In the United States, 2% of all adult native renal biopsies were diagnosed as amyloidosis.¹³ The most important cause of lower incidence was attributed to the effective control of the infectious diseases causing amyloidosis. We observed younger patients of amyloidosis in the 2000s (38 ± 17.9 years) in comparison to 1990s (39.2 ± 19 years), although the difference was not significant. This may be due to increased awareness of health among the new generation, making people to seek early medical advice in comparison to older generation who were largely illiterate and ignorant about their health problem. Similar age pattern was noted in other Indian studies also in 1980s and 1990s.^3,4 However, the age of onset of amyloidosis was higher in developed countries.^10,12 This difference may be due to the fact that in developed countries the most common cause of systemic amyloidosis is primary amyloidosis, which usually occurs in the older age group.

We observed that males are more affected in both the groups similar to other Indian studies.^3,5 It may be a reflection of male-dominant nature of our society where males run the family and are more likely to expose to many risk factors for diseases, which can lead to amyloidosis, for example, tuberculosis. They also seek medical attention more often than their female counterparts. This pattern of male dominancy was found in other studies as well.^14,15 However, in 2000s, we found that incidence of amyloidosis in females was increased significantly (p < 0.05) in comparisons to 1990s, and it may be a reflection of two facts. First, females in our society are becoming more health concerned and seeking medical advice more often than they did in earlier decades. Second, chronic inflammatory conditions causing renal amyloidosis were increased in the second period of study and such amyloidogenic disorders are more prevalent in female (e.g., RA and SLE). In Italy and Japan, during the same decade, females were more affected.^11,16 However, there has been no change in the sex predilection in other regions.^17,18

Clinical manifestations of renal amyloidosis correlate with the amyloid distribution in different renal compartments. However, the reason for the preferential localization to one or the other compartment is not well established.¹⁸ In our study, all the patients had edema of varying degrees, but the incidence of subnephrotic-range proteinuria and renal insufficiency was significantly increased (p < 0.05) in recent years (2000s). This may be explained by more dense amyloid deposit in tubulointerstitial and vascular compartment compared to glomerular deposits as reported by Jérôme Verine et al.¹⁷ However, the reason for why such change in pattern of amyloid deposits occurred needs further study in a large cohort. In earlier study from our center, 8% of patients with amyloidosis were reported to have subnephrotic-range proteinuria.⁶ In a study in Germany during 1960–2007, it was reported that 20% of their patients had subnephrotic-range proteinuria.¹⁸ When amyloid deposits are confined to the tubulointerstitium or vasculature compartment of kidney, proteinuria is minimal and reduced glomerular filtration rate is the principal clinical manifestation.¹⁹ However, renal impairment tends to progress slowly when tubulointerstitial rather than glomerular deposition predominates. Vascular involvement is often accompanied by hypertension, an otherwise uncommon feature of amyloidosis. In our study, the incidence of renal insufficiency was increased in 2000s compared to 1990s (48.2% vs. 12.8%, respectively), which correspond to subnephrotic presentation, explaining the more extensive involvement of tubulointerstitium compartment. In a study in India during 1957–1979, renal dysfunction was noted in 30.5% of patients,³ whereas Shah et al., in a study during 1973–1992, found renal dysfunction in 55.51%.⁵ However, Jérôme Verine et al., in a study in France during 1990–2005, observed renal insufficiency in 75% of patients.¹⁷ The incidence of renal dysfunction in different studies during 1990s ranges from 16% to 53%.^11,14,15, We observed, the incidence of hypertension and hematuria was more common in 2000s compared to 1990s (6.8% and 17.2%, respectively). Chugh et al. found hypertension in 7.2% and most of these were in renal failure.³ However, higher incidence of hypertension (20–30%) was reported from others studies.^15,17 Helmut Hopfer et al., in their case series between 1960 and 2007, reported that 17.2% were hypertensives, and histologically amyloid deposit was found primarily in the vascular compartment of kidney.¹⁸

Etiologies of amyloidosis in Western countries have changed markedly during the last three decades. Primary amyloidosis is the most common cause of systemic amyloidosis in Western countries.^20,21 Whereas in developing countries including India, secondary amyloidosis still remains as the most common form, of which infection is the most common underlying etiology.^3–6 Etiological spectrum of renal amyloidosis was changing in our study in 2000s compared to 1990s. In 1990s, the most common cause of amyloidosis was chronic infection (58%), whereas in 2000s, it was the chronic inflammation (48.2%). However, on statistical calculation, the changes were not statistically significant (p > 0.05). In contrast, in developed countries, this changing pattern had already been prevailing since decades ago, and chronic inflammations have been the most common cause of renal amyloidosis.^10,22–24 The decline in the incidence of amyloidosis secondary to chronic infections had been largely attributed to the introduction of effective anti-tuberculosis and anti-leprosy chemotherapy and the improvement of standard of living of our population. However, after the subgroup analysis, tuberculosis still remains as the most common etiology in both the groups (35.29% and 24.1% in 1990s and 2000s, respectively), while the incidence of leprosy (23% in 1990s vs. 3.4% in 2000s) was markedly decreased. In other Indian studies, tuberculosis accounted for 55–79% of renal amyloidosis, but most of the studies were conducted in between1960s and1990s.^3–5,24 On other hand, in developed countries, tuberculosis accounted for 50–80% of secondary amyloidosis in 1940s and 1950s.^25–27

We observed that chronic inflammatory causes (RA, AS, etc.) were the major causes (48.2%) of secondary amyloidosis in 2000s, similar to Western countries. Recent increase in the incidence of chronic inflammatory causes was mostly contributed by RA, AS, and SLE. We reported that amyloid nephropathy was the cause of nephrotic syndrome in patients with AS in our previous studies.^28,29 In developed countries after 1940s and 1950s, RA has been the most common cause of secondary amyloidosis for decades, and it remains true till now.^10,22,26,27 In a recent study, Helmut Hopfer et al., in their series of cases between 1960 and 2007, reported that RA accounts for 22% of renal amyloidosis.¹⁸ In our study, we observed that MM remains the most common cause of AL amyloidosis in both the groups (11.7% and 13.7% in 1990s and 2000s, respectively). This finding is in accordance with other Indian studies.^3,5 The incidence of AL amyloidosis due to MM in developed countries varies between 4% and 26%.^10,18, We described a case of Hodgkin lymphoma presenting as nephrotic syndrome secondary to renal amyloidosis.³⁰

CONCLUSIONS

This study demonstrated that the pattern of renal amyloidosis with respect to etiology and clinical features was changing in recent years. Chronic inflammatory disease and AL amyloidosis have become the main causes of renal amyloidosis in 2000s as compared to infective causes in 1990s. The incidence of renal amyloidosis has increased in younger patients and females. We noted that subnephrotic proteinuria and renal insufficiency had become more frequent clinical manifestations of renal amyloidosis in 2000s compared to 1990s.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.