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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 5  |  Page : 969-975
IgM nephropathy: Clinical picture and pathological findings in 36 patients


Pathology Department, King Abdul-Aziz University, Jeddah, Saudi Arabia

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Date of Web Publication6-Sep-2011
 

   Abstract 

Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by a variable degree of mesangial hyper- cellularity and diffuse IgM deposits. This study describes the clinical presentation and the morphological findings in 36 patients, five adults and 31 children, with IgMN. The initial manifestations of the disease were the nephrotic syndrome in 32 patients, proteinuria in two, hematuria associated with proteinuria in 16 and isolated recurrent gross hematuria in two patients. The nephrotic syndrome was steroid responsive in 9% of the cases, steroid dependent in 25% and steroid resistant in 66%. Five patients were hypertensive at the onset of the disease. The mean follow- up period was 3.4 years (range, 1-7 years). One patient developed end- stage kidney disease five years after the diagnosis. On light microscopy, 24 specimens showed mild focal and segmental mesangial hyper- cellularity, 10 cases were normal in cellularity and two cases showed diffuse global mesangial hyper- cellularity. Four cases showed focal and segmental glomerulosclerosis. Mild interstitial inflammation and fibrosis were observed in 11 cases and focal tubular atrophy and hypertensive hyaline arteriosclerosis were noted in three cases. In addition to IgM, the immunofluorescence study showed C3 deposits in 12 cases, IgG in nine cases and IgA in one case. Electron dense- deposits in the mesangium and para- mesangial areas were demonstrated on electron microscopy in 22 cases. In view of its different clinical presentations and the constant findings of diffuse mesangial IgM deposition in all the cases, it is concluded that this form of nephropathy constitutes a distinct entity separate from minimal change disease or focal and segmental glomerulosclerosis. Patients with IgMN had a higher prevalence of steroid resistance and dependence in the proteinuric group.

How to cite this article:
Mokhtar GA. IgM nephropathy: Clinical picture and pathological findings in 36 patients. Saudi J Kidney Dis Transpl 2011;22:969-75

How to cite this URL:
Mokhtar GA. IgM nephropathy: Clinical picture and pathological findings in 36 patients. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2019 Aug 19];22:969-75. Available from: http://www.sjkdt.org/text.asp?2011/22/5/969/84429

   Introduction Top


Immunoglobulin M nephropathy (IgMN) was first reported in 1978 by two independent groups of investigators. [1],[2] In both the series, the initial native renal biopsy showed mesangial hyper- cellularity on light microscopy (LM) and diffuse granular mesangial IgM deposits on immunofluorescence (IF) examination; in all cases, other forms of glomerulonephritis and systemic diseases were excluded. The majority of their patients presented with heavy proteinuria that did not respond well to steroids. Progression to end- stage kidney disease (ESKD) was noted in a small proportion of their patients, in whom repeat kidney biopsy demonstrated focal and segmental glomerulosclerosis (FSGS). This was followed by several other series that described similar pathological findings in the kidney biopsy of patients who presented with the nephrotic syndrome, asymptomatic proteinuria and/or hematuria. [3],[4],[5],[6],[7],[8],[9] Since its first description, IgMN created a major controversy as to whether it is a distinct clinico- pathological entity or not. Some investigators consider this entity as a transitional form between minimal change disease (MCD) and FSGS. [10],[11] However, many reports have demonstrated increased steroid resistance and less- favorable outcome in IgMN compared with MCD and, thus, consider it as a distinct clinico- pathological entity. [1],[3],[4],[5],[7],[12],[13],[14],[15] The present study describes the clinical and pathological features of cases of IgMN seen at the King Abdulaziz University Hospital, Jeddah, Saudi Arabia, between 2000 and 2008.


   Materials and Methods Top


A computer data- based search was performed for all the kidney biopsies with the diagnosis of IgMN between January 2000 and December 2008. Of 200 renal biopsies received at the pathology department during that period, 40 cases had been diagnosed as IgMN. The slides and the pathology reports were retrieved from the surgical pathology archives and reviewed by the author.

All the cases were divided into three portions; for histology, direct IF and electron microscopy (EM), and processed as previously described. [16]

The histological slides were re- assessed for the presence and the degree of mesangial hypercellularity and matrix expansion, presence or absence of FSGS, tubular atrophy, interstitial inflammation and fibrosis and vascular intimal change.

For IF studies, the glomerular findings were graded as negative, trace, 1+, 2+ and 3+. Four cases were excluded from the study because they showed only trace focal and segmental IgM positivity on the IF study.

The patients' charts were also retrieved from the medical records and the following clinical parameters were recorded: age at onset, gender, clinical presentation at onset of the disease, presence or absence of hematuria, blood pressure, 24- hour urine protein level at presentation, blood urea nitrogen and creatinine levels and the duration of follow- up post- renal biopsy. The patients were treated with steroids and/or immunosuppressive therapy.

Clinical definitions

Nephrotic syndrome is defined as proteinuria of 3.5 g/24 hours or greater. Nephrotic patients were classified according to their response to steroids as follows:

  1. Steroid responsive; those who had complete remission of proteinuria during the treatment and the remission persisted for at least two months after stopping the treatment.
  2. Steroid dependent, where complete remission was obtained during the treatment but recurrence occurred when the dose was reduced below a critical level or relapse was noted on two successive occasions.
  3. Steroid resistant is defined as no remission over a period of at least eight consecutive weeks of steroid therapy.
  4. Remission is defined as a reduction in urinary protein concentration to less than 0.15 g/24 hours and reduction of erythrocytes to less than three cells per high- power field (HPF).
  5. Relapse is the reappearance of proteinuria on at least three consecutive examinations within seven days.
  6. Hematuria is defined as presence of three or more erythrocytes per HPF in the urinary sediment. The patient was regarded as hypertensive if resting blood pressure was >90 th percentile for age.

   Results Top


Clinical findings

Of the 36 patients who fulfilled the inclusion criteria, 31 (86%) were children and five (14%) were adults, with a mean age of 7.2 years (range 1-39 years). Twenty- two patients (61%) were male and 14 (39%) were female, with a male: female ratio of 1.6:1. The initial manifestation was the nephrotic syndrome in 32 patients (89%), of whom 21 (66%) were steroid resistant, eight (25%) were steroid dependent and three patients (9%) were steroid responsive. Two patients (6%) presented with mild asymptomatic proteinuria. Microscopic hematuria was detected in 16 patients (44%) and recurrent gross hematuria was the only manifestation in two patients (6%). The blood pressure was elevated at presentation in five patients (14%). The mean 24- hour urine protein was 8.22 grams and none of the patients had impaired renal function at the onset of symptoms. The follow- up period following renal biopsy ranged from 1 to 7 years (mean 3.4). Follow- up was available for 23 patients. Only one patient out of the 23 developed ESKD five years after the diagnosis. One patient died one year after the renal biopsy secondary to sepsis. Sixteen out of the 23 patients (70%) had frequent relapses while on steroids and immunosuppressive therapy and the remaining seven patients were responsive to the therapy.

[Table 1] summarizes the clinical findings of the 36 patients with IgMN.
Table 1: Summary of the clinical findings in 36 patients with IgMN.

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Kidney biopsy findings

The dominant LM finding was mild to moderate mesangial matrix expansion, which was observed in all the 36 biopsies [Figure 1]. The mesangial hyper- cellularity was variable. Twenty- four cases (67%) showed mild focal segmental mesangial hyper- cellularity and two cases (6%) showed diffuse moderate hypercellularity [Figure 2]a-c. In ten cases (28%), the cellularity was normal. Four cases (11%) showed evidence of FSGS on LM [Figure 2]d. Eleven cases (31%) had mild focal interstitial fibrosis and inflammation, and three of these cases also showed mild tubular atrophy. Hyaline arteriolosclerosis was noted in three cases; all these patients had elevated blood pressure at the onset of the disease.
Figure 1: The glomeruli showing mild segmental mesangial matrix expansion (JMS 200×).

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Figure 2:

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In addition to IgM, the other glomerular IF findings included C3 staining in 12 cases, IgG in nine cases and IgA in one case. In all the cases, the IgM staining was diffuse mesangial with an intensity of 2+ and 3+ [Figure 3]. Electron- dense deposits in the mesangial and para-mesangial areas were seen on EM examination in 22 cases (61%) [Figure 4]. Six cases showed ill- defined densities in the mesangium and in eight cases, the only findings were mesangial matrix expansion, with or without mesangial hyper- cellularity.
Figure 3: Immunofluorescence staining for IgM showing diffuse, granular staining (3+) mainly in the mesangium and few rare capillary loops (IF, 600×).

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Figure 4: Electron microscopic image showing mesangial matrix expansion and few small electron-dense deposits (TEM × 5752).

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[Table 2] summarizes the pathological findings in 36 cases of IgMN.
Table 2: Renal biopsy findings in 36 patients with diffuse IgM mesangial deposits.

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   Discussion Top


This present study describes the clinical and morphological findings of 36 adults and children with a biopsy- proven diagnosis of IgMN. Several studies have been published regarding the significance of IgM- associated mesangio- proliferative glomerulonephritis. The issue of whether IgMN is a distinct entity is controversial. Many investigators favor its distinction as a separate clinico- pathological entity, while some still consider it as a variant of MCD. Prasad et al have studied 31 patients with glomerular IgM deposition and found no statistically significant difference in the steroid responsive rate of these patients from patients with MCD who do not have IgM on IF examination. [17] Also, a recent study by Al- Eisa et al who compared 27 children with IgMN with a group of 63 children with MCD found no significant differences in relapse rate between the two groups. [18] On the other hand, Myllymaki et al who studied 110 patients with IgMN, adults and children, reported that 23% of the patients had progressed to ESRD. Zeis et al studied 64 children with IgMN and reported that 30% progressed to FSGS. [19],[20]

The steroid response rates in patients with IgMN varies considerably between the studies, with a mean percentage of steroid resistance of 28%. [21] In the current study, 66% of the patients with diffuse mesangial IgM deposits and the nephrotic syndrome were steroid resistant and 33% were steroid dependent. This is considerably higher than what was reported previously. In a recent report by Kari et al of the morphological pattern of steroid- resistant NS in 36 children living in Saudi Arabia, IgMN was the second most common cause of steroid- resistant NS, constituting 28% of the cases. [22]

Myllymaki et al had a wide range of age distribution, with the adult patients being more in number than children. [19] In contrast, the present study shows a predominance of children by 86%, with a median age of 7.2 years. Some studies of IgMN have reported a male predominance, [2],[10],[16],[18],[23] whereas others have reported a larger female population. [1],[4],[5],[7],[13],[24] A higher number of males than females was observed in this study. In some studies, the disease manifesting only as hematuria was seen predominantly in female patients. [5],[19] In the current study, more male patients than female patients had hematuria in addition to proteinuria.

The reported incidence of ESKD in patients with IgMN ranges from six to 23%. [5],[16],[20] Only one patient out of 23 (4%), in whom follow- up was available, developed ESKD five years after the initial diagnosis. However, the follow- up period for the patients in this study is relatively short.

Many studies had found that IgMN progresses to FSGS with time. [1],[3],[9],[12],[19] In the present study, four out of 36 cases (11%) had histological evidence of FSGS on biopsy, and primary FSGS was excluded because of the diffuse IgM positivity. Only one of these four patients progressed to ESKD.

The morphological findings on renal biopsy of patients with IgMN range from normal to mild mesangial hyper- cellularity, but a constant finding is mesangial matrix expansion in all the cases, including those that were normal in cellularity. EM examination demonstrated electron- dense immune- type deposits in 61% of the cases and, in addition, 22% showed ill- defined densities in the mesangium. Matrix expansion was observed on EM in all the cases.

The pathogenesis of IgMN remains unclear. Some have suggested abnormal T- cell function or a disturbance in immune- aggregate clearance by mesangial cells. [13],[15] In support of these theories, many studies have reported increased serum IgM or IgM immune- complex concentrations in patients with IgMN. [4],[25]

In conclusion, this study showed distinctive clinical features and pathological findings of IgMN in the study patients, suggesting that IgMN represents a distinct clinico- pathological entity that is more common among children. Also, there was a higher prevalence of steroid dependence and resistance with frequent relapses and increased risk of progression to FSGS.

 
   References Top

1.Cohen AH, Border WA, Glassock RJ. Nephrotic syndrome with glomerular mesangial IgM deposit. Lab Invest 1978;38:610- 9.  Back to cited text no. 1
    
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3.Lawler W, William G, Tarpey P, Mallick NP. IgM associated primary diffuse mesangial proliferative glomerulonephritis. J Clin Pathol 1980; 33:1029- 38.  Back to cited text no. 3
    
4.Helin H, Mustonen J, Pastermack A, Antonen J. IgM- associated glomerulonephritis. Nephron 1982;31:11- 6.  Back to cited text no. 4
    
5.Saha H, Mustonen J, Pastermack A, Helin H. Clinical follow- up of 54 patients with IgM nephropathy. Am J Nephrol 1989;9:124- 8.  Back to cited text no. 5
    
6.Tejani A, Nicastri AD. Mesangial IgM nephropathy. Nephron 1983;35:1- 5.  Back to cited text no. 6
    
7.Kopolovic J, Shvil Y, Pomeranz A, Ron N, Rubinger D, Oren R. IgM nephropathy: morphological study related to clinical findings. Am J Nephrol 1987;7:275- 80.  Back to cited text no. 7
    
8.Hsu HC, Chen WY, Lin GJ, et al. Clinical and immunopathologic study of mesangial IgM nephropathy: Report of 41 cases. Histopathology 1984;8:435- 46.  Back to cited text no. 8
    
9.Cohen AH, Border WA. Mesangial proliferative glomerulonephritis. Semin Nephrol 1982:2:228- 40.  Back to cited text no. 9
    
10.Vilches AR, Turner DR, Cameron JS, Ogg CS, Clantler C, Williams DG. Significance of mesangial IgM deposition in minimal change nephrotic syndrome. Lab Invest 1982;46:10- 5.  Back to cited text no. 10
    
11.Ji- Yun Y, Melvin T, Sibley R, Michael AP. No evidence for a specific role of IgM in mesangial proliferation of idiopathic nephrotic syndrome. Kidney Int 1984;25:100- 6.  Back to cited text no. 11
    
12.Hsu HC, Chen WY, Lin GJ, et al. Clinical and immunopathologic study of mesangial IgM nephropathy: Report of 41 cases. Histopathology 1984;8:435- 46.  Back to cited text no. 12
    
13.Cavalo T, Johnson MP. Immunopathologic study of minimal change glomerular disease with mesangial IgM deposits. Nephron 1981;27:281- 4.  Back to cited text no. 13
    
14.Trachtman H, Carroll F, Phadke K, et al. Paucity of minimal change lesion in children with early frequency relapsing steroid responsive nephrotic syndrome. Am J Nephrol 1987;7:13- 7.  Back to cited text no. 14
    
15.Lin CY, Chu CM. Studies of circulating immune complexes and lymphocyte subpopulations in childhood IgM mesangial nephropathy. Nephron 1986;44:198- 203.  Back to cited text no. 15
    
16.Lawer W, Trapey P, Williams G, Acheson EJ, Mallick NP. Diseases and histological normality of the renal glomerulus: a clinicopathological study. J Clin Pathol 1976;29:380- 97.  Back to cited text no. 16
    
17.Prasad DR, Zimmerman SW, Barkholder PM. Immunohistologic features of minimal changes neprhotic syndrome. Arch Pathol Lab Med 1977;101:345- 9.  Back to cited text no. 17
    
18.Al- Eisa A, Carter JE, Lirenman DS, Magil AB. Childhood IgM nephropathy: Comparison with minimal change disease. Nephron 1996;72:37- 43.  Back to cited text no. 18
    
19.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. 19
    
20.Zeis PM, Kavazarakis E, Nakopoulou L, et al. Glomerulopathy with mesangial IgM deposits: long- term follow up of 64 children. Pediatr Int 2001;43:287- 92.  Back to cited text no. 20
    
21.Border WA. Distinguishing minimal- change disease from mesangial disorders. Kidney Int 1988;34:419- 34.  Back to cited text no. 21
    
22.Kari JA, Halawani M, Mokhtar G, Jalalah SM, Anshasi W. Histopathology of steroid- resistant nephrotic syndrome in children living in the Kingdom of Saudi Arabia. Pediatr Nephrol 2009;24(7):1429- 30.  Back to cited text no. 22
    
23.Vangelista A, Frasca G, Biagini G, Bonomini V. Long term study of mesangial proliferative glomerulonephritis with IgM deposits. Proc Eur Dial Transplant Assoc 1981;18:503- 7.  Back to cited text no. 23
    
24.Gonzalo A, Mampaso F, Gallego N, Quereda C, Fierro C, Ortuno J. Clinical significance of IgM mesangial deposits in the nephrotic syndrome. Nephron 1985;41:246- 9.  Back to cited text no. 24
    
25.Disciullo SO, Abuelo JG, Moalli K, Pezzullo JC. Circulating heavy IgM in IgM nephropathy. Clin Exp Immunol 1988;73:395- 400.  Back to cited text no. 25
    

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Correspondence Address:
Ghadeer A Mokhtar
Consultant Pathologist and Nephropathologist, Pathology Laboratory, King Abdul-Aziz University Hospital, P.O. Box 80215, Jeddah
Saudi Arabia
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PMID: 21912027

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    Figures

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    Tables

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