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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 54  |  Issue : 1  |  Page : 3-6
Immunoglobulin M nephropathy nephropathy in adults and adolescents in India: A single-center study of natural history


1 Department of Pathology, Laboratory Medicine and Transfusion Services and Department of Immunohematology, Institute of Kidney Diseases and Research Centre and Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, India
2 Department of Nephrology and Transplantation Medicine, Institute of Kidney Diseases and Research Centre and Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, India

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Date of Web Publication7-Mar-2011
 

   Abstract 

Background: Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis (GN) usually presenting clinically as steroid resistant/dependent nephrotic syndrome (NS) with pathology of mesangial proliferative GN or focal and segmental glomerulosclerosis with diffuse predominant mesangial IgM deposits. Not much information is available about its natural history. This is the first Indian study to our knowledge on IgMN in adults and adolescents. Materials and Methods: We evaluated renal biopsies performed at our center between January,'04 to September,'09. Biopsies of all adolescents and adults were evaluated for IgMN and we studied their age, gender distribution, blood pressure (BP), disease duration, steroid/immunosuppressive management and serial serum creatinine (SCr), urinary proteins, and BP values. Patients with other systemic diseases/infections and children were excluded. Results: IgMN constituted 4.3% of 2702 adult renal biopsies. No significant gender predilection was noted. Males presented at average age of 23.1 years, females at 30 years. Steroid-dependent NS was the commonest presentation noted in 75% followed by steroid-resistant NS. Hypertension was noted in 10% patients. Mesangial proliferative GN (MePGN) was commonest histopathological finding noted in 74.4%, followed by focal segmental glomerulosclerosis (FSGS) in 16.2%, and minimal change disease (MCD) in 9.4% biopsies. Sole IgM deposits were noted in 88.5%. All MCD, 35.6% MePGN reached remission, FSGS progressed to renal failure by 1 year. Hypertension, proteinuria, interstitial fibrosis, and FSGS were bad prognosticators. Conclusions: This is the first Indian study of IgMN in adults and adolescents carried out over a period of 5.8 years, which has shown that hypertension, proteinuria, and interstitial fibrosis at presentation have bad prognosis.

Keywords: Hypertension, IgM nephropathy, mesangial proliferative glomerulonephritis, nephrotic syndrome, proteinuria

How to cite this article:
Singhai A M, Vanikar A V, Goplani K R, Kanodia K V, Patel R D, Suthar K S, Patel H V, Gumber M R, Shah P R, Trivedi H L. Immunoglobulin M nephropathy nephropathy in adults and adolescents in India: A single-center study of natural history. Indian J Pathol Microbiol 2011;54:3-6

How to cite this URL:
Singhai A M, Vanikar A V, Goplani K R, Kanodia K V, Patel R D, Suthar K S, Patel H V, Gumber M R, Shah P R, Trivedi H L. Immunoglobulin M nephropathy nephropathy in adults and adolescents in India: A single-center study of natural history. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 Nov 12];54:3-6. Available from: http://www.ijpmonline.org/text.asp?2011/54/1/3/77315



   Introduction Top


Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis (GN) characterized by primary mesangioproliferative GN (MePGN) on light microscopy with sole or dominant diffuse, granular IgM deposits within the mesangium on immunofluorescent (IF) microscopy and clinically presenting with steroid-resistant/dependent proteinuria, having no associated systemic disorders/disease. [1],[2] However morphological picture may vary from no glomerular abnormalities to segmental or global glomerulosclerosis. IgMN was first described as a distinct entity in 1978 by Cohen et al.[1] Although this glomerulopathy, which is not uncommon and is disturbing to the patient and family due to its steroid-dependence/resistance, there are not many studies describing its natural history.


   Aims Top


We carried out a retrospective analysis of native renal biopsies to find out the incidence and natural history of IgMN in adults and adolescents in Western India.


   Materials and Methods Top


Patients

A total of 2928 native renal biopsies of patients who presented at our center from January, 2004, to September, 2009, were evaluated. We included all patients aged 13 years and above, who were steroid-dependent/resistant nephrotic, or with nephrotic-nephritic syndrome. Patients with associated/other systemic diseases like systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus, hepatitis, HIV infection, and paraproteinemia were excluded from the study.

Clinicopathological Evaluation

Clinical history and findings of age, gender, hypertension, quantitative proteinuria, and serum creatinine (SCr) were considered for evaluation.

Definition [3]

Steroid-resistant nephrotic syndrome (NS) was defined as per standard International Study of Kidney Diseases in Children (ISKDC) criteria as "no change or increased proteinuria compared to baseline, with maximum dose of prednisone of 1 mg/kg BW/day or 80 mg/day within 8 weeks of starting treatment."

Laboratory Studies

All the biopsies subjected to 3-μ thick paraffin sections for light microscopy (LM) were stained by hematoxylin and eosin, periodic acid Schiff, Jone's silver methaneamine, and Gomori's trichrome stains. Biopsies were evaluated for mesangial cell proliferation, segmental/focal global sclerosis, tubular atrophy and degeneration, interstitial fibrosis and inflammation, and fibrointimal proliferation in vessels. Changes were graded as unremarkable, mild, moderate, or marked. A biopsy was considered adequate if it contained ≥7 glomeruli in LM and 2 glomeruli in IF studies. For direct IF studies, we used anti-human IgA, IgG, IgM, C1q, C3, albumin and fibrinogen antisera (Dako, USA) on 3-μ thick frozen sections. Glomerular IF findings were graded as trace, +1, +2, +3, and +4 and intensity of ≥+2 was considered as positive.

Statistical Analysis

Student's paired t test was performed to compare the SCr and 24-h urinary protein leak of normotensive MePGN patients with hypertensive MePGN group and with focal segmental glomerulosclerosis (FSGS) group. The P value of <0.05 was considered significant.

Observations

Incidence pattern and clinical presentation [Table 1].
Table 1: Demographics of different patterns of IgMN

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Out of 2928 biopsies, 142 (4.85%) were diagnosed as IgMN, out of which 82.4% (n = 117) were in the age group of 13-78 years (mean age: 29 years). Out of 2702 biopsies in this age group, IgMN constituted 4.3%. The disease had no significant gender predilection; male-to-female ratio was 1.1:1. Average age at presentation in males was 23.1 years as compared to females in whom it was 30.4 years. Steroid-dependent NS was commonest presentation noted in 75.4% followed by steroid-resistant NS in 19.7% and nephrotic/nephritic presentation noted in 4.9% patients. Hypertension was noted in 10.3% (n = 12) patients. Average duration of steroid intake in the form of prednisone, in dose of 30 mg/day (range 5-60 mg/day), was for 80.2 weeks (range 2-636 weeks). Mean SCr was 1.46±1.6 mg/dL. In males, it was found to be 1.60±0.10 mg/dL and in females, 1.22 ± 0.43 mg/dL. BP was higher in FSGS group as compared with minimal change disease (MCD) and MePGN groups. The average blood pressure (BP) was 110/76 mmHg (range 100/70-140/90 mmHg) in patients with MCD and MePGN as compared to those with FSGS whose average BP was 140/90 mmHg (range 120/80-160/100 mmHg) at the time of diagnosis. The average urinary protein leak per 24 h was 0.95 g in MCD group followed by 2.54 g in MePGN group and 5.3 g in FSGS group.

Renal Histopathological Pattern

The commonest pattern was MePGN [Figure 1]a observed in 74.4% (n = 87), followed by FSGS noted in 16.2% (n = 19) and MCD was seen in 9.4% biopsies (n = 11). Some of these also had combined lesions like acute tubular necrosis or moderate fibrointimal proliferation in vessels. In all lesions, chronicity in the form of interstitial fibrosis and tubular atrophy with/without fibrointimal proliferation in blood vessels correlated with the severity of lesion. Thus FSGS patients were the worst affected and MCD, the least. A detailed summary of the LM findings is listed in [Table 2].
Figure 1: (a) IgMN with mesangial proliferative glomerulonephritis; H and E stain, ×200, (b) direct immunofluorescence showing predominant mesangial IgM deposits (+2) on staining with anti-human IgM anti-serum.

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Table 2: Detailed histopathological findings in IgM nephropathy cases

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Associated Immunoglobulins

IgM was the predominant immunoglobulin deposited in 50-100% of mesangial regions in coarse granular pattern of all glomeruli with the intensity ranging from +2 to +4 [Figure 1]b. In cases with associated IgA deposits, if IgM deposits were predominant then only the lesion was labeled as IgMN. IgM alone was noted in 88.7% (n = 126) biopsies. The other associated deposits were C3 in 4.9% (n = 7), C3 + IgG in 2.8% (n = 4), IgG in 2.1% (n = 3), and IgA in 1.4% (n = 2) biopsies. There was no correlation between codeposits of immunoglobulins and clinical or histopathological presentation of the disease.

Prognostic Indicators

Over an average follow-up of 29.4 months (range 1-70 months), 2.3% (n = 2) patients in MePGN group, and 15.8% (n = 3) in FSGS had reached end-stage renal disease noted by rise in SCr above 4 mg% in follow-up of 6-9 months in the former and in 1.2 years in the later (range 7 months to 2 years) postbiopsy. These patients had higher proteinuria and BP than others and their histological changes of tubular atrophy and interstitial fibrosis were also more than 50% at the time of biopsy. They were treated with prednisone, 40-60 mg/day ± CsA to which they did not respond. Two patients, one each from MePGN and FSGS group was given cyclophosphamide, to which they did not respond.

All the patients in MCD group had complete remission over an average 9 months (range 3.5-12 months) postbiopsy and were doing well over an average follow-up 36 months (range 3-69 months) with mean SCr, 0.81 mg% (0.68-1.68 mg%). In MePGN, 35.6% (n = 31) patients achieved remission over an average follow-up of 8 months (range 6-12 months) and their mean SCr was 1.06 mg% (range 0.71-1.04 mg%) over an average follow-up of 3 years (range 6-54 months). In FSGS group, there was no remission.

The remaining 62.1% (n = 54) patients in MePGN over an average follow-up of 3 years (range 2-66 months) were maintaining stable renal functions with mean SCr 1.05 mg% (range 0.69-2.24 mg%), minimal proteinuria (0 to <300 mg/24 h) on average prednisone, 20 mg/day (range 5-60 mg/day); two patients required cyclosporin A (CsA). In FSGS group also, 84.2% (n = 16) were maintaining stable renal functions with mean SCr 1.87 mg% (range 0.9-2.54 mg%), minimal proteinuria (0 to <300 mg/24 h) on average prednisone, 30 mg/day (range 20-60 mg/day).

With respect to clinical and lab findings, hypertension and proteinuria were poor prognostic indicators whereas SCr, gender, and duration of illness had no prognostic value [Figure 1] and [Figure 2]. Mean SCr (in mg%) in MePGN group at 1 year, 2 years, 3 years, and 4 years follow-up since biopsy were 1.08 ± 0.53, 0.96 ± 0.33, 0.99 ± 0.43, and 1.06 ± 0.46, respectively, whereas in MePGN group with hypertension at 1 year, 2 years, and 3 years follow-up since biopsy were 3.65 ± 2.87, 3.3 ± 1.66, 4.64 ± 1.19, respectively, and at 4 years they were all under dialysis care; hence SCr was irrelevant. In FSGS group, mean SCr (in mg%) at 1 year and 2 years follow-up since biopsy were 3.65 ± 0.53 and 2.19 ± 2.27, and by 2.5 years all except one patient were enrolled in dialysis program and were enlisted for transplantation. P value between MePGN without hypertension and MePGN + hypertension were 0.002 for first year, <0.001 for second year, and 0.001 for third year, whereas these values when compared with FSGS group and MePGN + hypertension were not significant.
Figure 2: Creatinine (in mg%) compared to mesangial proliferative glomerulonephritis (MePGN) with hypertension and focal and segmental glomerulosclerosis (FSGS).

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When comparing 24-h urinary protein leak in the three groups, FSGS could not be studied since almost all patients were enrolled in maintenance dialysis. When comparing MePGN without hypertension group with MePGN + hypertension group, 1 year, 2 years, 3 years, and 4 years 24-h urinary protein leak were 0.92 ± 1.92, 0.13 ± 0.33, 0.08 ± 1.15, and 0.14 ± 0.18, respectively, in MePGN group and for the group with hypertension, it were 1.83 ± 1.53, 2.73 ± 1.49, and 4.48 ± 1.07, respectively, for the first 3 years of follow-up. Since the patients had already developed chronic renal failure after 3 years, proteinuria was irrelevant at that point onward. The p values at 1 year and 2 years were 0.04 and <0.001, respectively. Almost all the patients were on prednisone, with varying doses of 5-60 mg/day.

Regarding histological markers, FSGS lesions had the worst prognosis in terms of rapidity of rise in proteinuria, SCr, and immunosuppressive requirement like Cyclosporin A. Also once there was downhill course with falling renal function profile, there was no effective immunosuppressive agent.


   Discussion Top


IgMN is an ill-understood glomerulonephritis (GN) found to affect all ages and both genders. The incidence has been recorded to be around 4.8-7.8% with some studies showing male predilection and others showed female predilection. [4],[5],[6],[7] Our observation falls in same pattern and showed an incidence of 4.3% among all renal biopsies with no gender predilection. The incidence is lower than primary IgA nephropathy, which was noted in 16.5% of our patients although both the immunoglobulins have predilection to glomerular mesangial regions and both the diseases have fairly similar natural history except that primary IgA nephropathy is known to be preceded by upper respiratory tract infections and that its malignant form can manifest histologically as crescentic GN unlike IgMN. [8] Several studies were carried out to understand the pathogenic role of IgM deposits in mesangium, whether they were steroid dependent/resistant, and whether there was any role of IgM deposits or complement fixation in therapeutic management. [9],[10],[11],[12] However, no consensus has been reached so far. It was only observed that patients with IgMN had very high levels of circulating complement fixing IgM immune complexes, which were significantly heavier than IgM molecule as compared to controls and patients with NS who did not qualify for IgMN. Regarding long-term prognosis, it has been observed that hypertension and proteinuria were the clinical bad prognosticators, and interstitial fibrosis and tubular atrophy along with FSGS were bad pathological prognosticators. [13] The same has been observed in our study.


   Conclusion Top


This is the first Indian study to our knowledge of IgMN in adults and adolescents carried out over a period of 5.8 years, which has shown that hypertension, proteinuria, and interstitial fibrosis at presentation have bad prognosis. Histologically MePGN is the commonest presentation with two-third being steroid-dependent.

 
   References Top

1.Cohen AH, Border WA, Glassock RJ. Nephrotic syndrome with glomerular mesangial IgM deposits. Lab Invest 1978;38:610-9.  Back to cited text no. 1
    
2.Little MA, Dorman A, Gill D, Walshe JJ. Mesangioproliferative glomerulonephritis with IgM deposition: Clinical characteristics and outcome. Ren Fail 2000;22:445-57.  Back to cited text no. 2
    
3.A report of the ISKDC. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. J Pediatr 1981;98:561-4.  Back to cited text no. 3
    
4.Sawsan M. Jalalah. Patterns of primary glomerular diseases among adults in the Western region of Saudi Arabia. Saudi J Kid Dis Transpl 2009;20:295-9.  Back to cited text no. 4
    
5.Myllymäki J, Saha H, Mustonen J, Helin H, Pasternack A. IgM nephropathy: Clinical picture and long-term prognosis. Am J Kidney Dis 2003;41:343-50.  Back to cited text no. 5
    
6.Bhasin HK, Abuelo JG, Nayak R, Esparza AR. Mesangioproliferative Glomerulonephritis. Lab Invest 1978;39:21-9.  Back to cited text no. 6
    
7.Saha H, Mustonen J, Pasternack A, Helin H. Clinical follow-up of 54 patients with IgM Nephropathy. Am J Nephrol 1989;9:124-8.  Back to cited text no. 7
    
8.Vanikar A, Trivedi H, Kanodia K, Patel R, Shah P. Pathological Spectrum of Primary immunoglobulin A Nephropathy in Western India., Gazzetta Medica Italiana Arch Sci Med 2005;164:465-72.  Back to cited text no. 8
    
9.Disciullo SO, Abuello JG, Moalli K, Pezzullo JC. Circulating heavy IgM in IgM nephropathy. Clin Exp Immunol 1988;73:395-400.   Back to cited text no. 9
    
10.Tejani A, Nicastri AD. Mesangial IgM nephropathy. Nephron 1983;35:1-5.   Back to cited text no. 10
    
11.Vilches AR, Turner DR, Cameron JS, Ogg CS, Chantler C, Williams DG. Significance of mesangial IgM deposition in 'minimal change' nephrotic syndrome. Lab Invest 1982;46:10-5.  Back to cited text no. 11
    
12.Pardo V, Riesgo I, Zeillerueol G, Strauss J. The clinical significance of mesangial IgM deposits and mesangial hypercellularity in minimal change nephrotic syndrome. Am J Kidney Dis 1984;3:264-9.  Back to cited text no. 12
    
13.Sumethkul V, Sakulsaengprapha A, Chalermsanyakorn P, Indraprasit S. Su Survival analysis of Thai patients with IgM nephropathy, focal segmental glomerulosclerosis and membranous nephrotic syndrome. J Med Assoc Thai 2000;83:S123-9.  Back to cited text no. 13
    

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Correspondence Address:
A V Vanikar
Department of Pathology, Laboratory Medicine and Transfusion Services and Immunohematology, Institute of Kidney Diseases and Research Centre and Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.77315

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