Adult-onset idiopathic nephrotic syndrome associated with pure diffuse mesangial hypercellularity
Efstathios Alexopoulos,
Aikaterini Papagianni,
Maria Stangou,
Aphroditi Pantzaki1 and
Menelaos Papadimitriou
Departments of Nephrology and
1 Pathology, Hippokration General Hospital, Thessaloniki, Greece
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Abstract
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Background. Pure diffuse mesangial hypercellularity (DMH), in its primary form, is a relatively rare histological finding and few data exist in the literature regarding its clinical course and prognosis in nephrotic adults with this diagnosis.
Methods. We retrospectively analysed the clinical and histological data of 28 adult nephrotic patients (13 male) with this diagnosis with regard to response to the treatment, outcome and prognostic indicators.
Results. Of 25 patients treated with prednisolone (Pred), nine (36%) showed complete remission (CR) of proteinuria, eight (32%) partial remission (PR) and eight (32%) did not respond at all (NR). The combination of cyclosporin treatment with prednisolone of those with PR or NR produced one further complete and two partial remissions. At the end of follow-up (mean 64 months), 10 patients (40%) were in CR, nine (36%) in PR and six (24%) were NR and remained nephrotic. Renal function remained unchanged in patients with CR or PR. In contrast, the six non-responders progressed to end-stage renal disease (ESRD). Compared with non-responders, patients who responded to Pred were older and had normal renal function at presentation. This group also had less mesangial sclerosis and severe tubulointerstitial fibrosis and none showed synechiae with Bowman's capsule. IgM mesangial deposits were observed in 22% of patients with CR in response to Pred, in 37% of those with PR and in 100% of non-responders, who finally progressed to ESRD. A multivariate analysis of clinical and histological features at biopsy showed persistent nephrotic syndrome (P<0.001), the severity of DMH (P<0.03) and the presence of mesangial IgM (P<0.01) to have independent predictive value for ESRD. This analysis also demonstrated that only mesangial sclerosis (P<0.03) and the presence of mesangial IgM (P<0.002) independently predicted the response to therapy.
Conclusions. DMH associated with idiopathic nephrotic syndrome is a heterogeneous entity. Patients who respond to therapy (completely or partially) have a benign course similar to that of minimal change nephrotic syndrome. They are usually older and have normal renal function at presentation, whereas sclerotic lesions are less frequent findings in initial biopsies. Non-responders tend to be younger and progress to ESRD. Most of them have impaired renal function at first assessment and more prominent sclerotic lesions on initial biopsies. Mesangial IgM is an independent marker of poorer response to treatment and progression to ESRD but it lacks specificity.
Keywords: diffuse mesangial hypercellularity; IgM nephropathy; nephrotic syndrome; treatment; outcome; prognosis
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Introduction
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Diffuse mesangial hypercellularity (DMH) in idiopathic nephrotic syndrome (NS) was described originally by Churg et al. [1] and White et al. [2] in 1970. This histopathological pattern is relatively uncommon in Europe and North America where it is thought to account for 210% of all patients with NS [1,3,4]. DMH has been described in some patients with minimal change nephrotic syndrome (MCNS) who frequently are steroid resistant or steroid dependent [57]. DMH in idiopathic NS has also been seen in association with focal segmental glomerulosclerosis (FSGS) or the deposition of mesangial IgM [8,9]. The relationship between DMH, MCNS and FSGS remains unclear. Some authors suggested that DMH (with or without IgM deposits) is a distinct entity [10], while others classified the lesion with MCNS [11,12]. Others, however, believe that these three entities represent a continuum and that, over time, DMH may convert to normal, MCNS or FSGS [7].
Also, studies on the significance of mesangial IgM deposits fall into two groups, those that favour the distinction of an IgM mesangial nephropathy as a separate clinicopathological entity [13,18] and those that come to the conclusion that the presence of IgM is not of major significance [8,1922].
The relative paucity of information on the clinical course and pathological findings of adult patients with this rare condition prompted us to analyse retrospectively our data on 28 adult patients with idiopathic NS in whom the diagnosis of DMH was made. An attempt was also made to identify prognostic indicators of outcome or response to therapy of this lesion and its possible relationship to MCNS and FSGS.
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Subjects and methods
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From 1984 to 1996, clinical and histological data of all adult patients (>15 years of age) with NS and renal biopsies showing DMH were reviewed. The diagnosis of idiopathic DMH was based on the following criteria [23,24]: (i) the presence of three or more cells per mesangial region in a thin, 23 µm section away from the vascular pole; (ii) a lesion involving >80% of the glomeruli in the specimen; (iii) the absence of double contours or spikes of the glomerular capillary walls visible by silver impregnation; (iv) the absence of dense deposits in the basement membranes visible with the trichrome stain; and (v) no clinical or histological evidence of associated disease such as IgA nephropathy, HenochSchönlein purpura, systemic lupus erythematosus, vasculitis, HIV or streptococcal infection, or hepatic disease. All biopsies included in this study contained >10 glomeruli per biopsy (median 18 glomeruli per biopsy, range 1342) in order to exclude the possibility of missing FSGS due to sampling error [9]. The diagnosis of FSGS required the presence of scarring in a portion of some but not all glomeruli. Even the presence of a single glomerulus with segmental hyalinosis or scar of the glomerular tuft was sufficient to diagnose FSGS [9]. Patients showing classic FSGS in addition to DMH at the time of first diagnosis were also excluded from this analysis. Grading of the cellularity was done on the basis of the number of mesangial cells per peripheral mesangial area according to criteria adopted by the WHO Committee on Classification and Nomenclature of Renal Diseases [23]. One or two mesangial cells per area were accepted as normal, whereas three cells were indicative of mild mesangial hypercellularity, 45 cells represented moderate hypercellularity, and >5 cells were graded as severe hypercellularity. Based on these criteria, a total of 28 patients were identified. Clinical and laboratory information for each patient was available both at the time of biopsy and throughout their follow-up.
All biopsies were taken using a standard Trucut needle, before instituting treatment. In each case, four stains were available for review by light microscopy: haematoxylin and eosin, Masson trichrome, periodic acidSchiff and silver methenamine period acidSchiff (Jones). Immunofluorescence studies were done using labelled antisera against IgG, IgA, IgM, C3, C4 and fibrinogen. Lesions with sole or dominant IgM deposits in the mesangium were categorized in the IgM-positive group. Optical microscopy findings were analysed and classified by two independent observers (E.A. and A.P.) without knowledge of patient identity or outcome. In addition to establishing the diagnosis, the following features were recorded: the presence of mesangial sclerosis; the presence of epithelial cell proliferation; the presence of synechiae with Bowman's capsule; and the presence of diffuse mesangial deposits of IgM and C3. Furthermore, the severity of tubular atrophy and interstitial fibrosis, the extent of inflammatory tubulointerstitial (TIN) infiltrate and the presence of arteriosclerosis were also evaluated and graded on a scale from 0 to 3.
Definitions
NS was defined as proteinuria of >3 g/24 h together with a serum albumin of <3 g/dl. Haematuria was defined as >5 red blood cells per high power field. Normal renal function was defined as a plasma creatinine of
1.3 mg/dl. Renal insufficiency was defined as a persistent rise in plasma creatinine >1.3 mg/dl, and end-stage renal disease (ESRD) was the point at which dialysis treatment was started or plasma creatinine exceeded 10 mg/dl.
Patients with a diastolic blood pressure of >90 mmHg or a systolic pressure >140 mmHg were considered hypertensive. The outcome was defined as follows: complete remission was defined as when there was a stable reduction in urinary protein excretion to
0.25 g/24 h, and partial remission as when proteinuria ranged between 0.26 and <3 g/24 h in the presence of stable renal function.
Treatment
Twenty-five treated patients initially received prednisolone at a dose of 1 mg/kg/day for >1 month with progressive tapering. The average duration of treatment was 6 months (range 48 months). In patients with partial or no response to prednisolone, cyclosporin (CyA) or cyclophosphamide in combination with low dose oral prednisolone were given. CyA was given at a daily dose of 23 mg/kg (target whole-blood levels 200300 ng/ml) for an average period of 9 months (range 812 months) and cyclophosphamide at a daily dose of 12 mg/kg for 2 months.
Statistical analysis
Comparisons of clinical or histological data were performed using student's t-test for paired and unpaired data as well as
2 statistics. Multivariate analysis was used to detect independent effects on outcome of each clinical or histological parameter assessed. A similar approach was used to evaluate the impact of these same features on the response to therapy. A P-value of <0.05 was considered significant.
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Results
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A review of 751 renal biopsies performed between 1984 and 1996 revealed 28 patients (3.7%) with idiopathic DMH associated with NS. Clinical and demographic data of the patients are presented in Table 1
. All patients had NS at biopsy and 19 (68%) had microscopic haematuria. Nine patients (32%) had a plasma creatinine >1.5 mg/dl at presentation. Hypertension was found in 12 patients (43%). The mean period of follow-up was 64 months (range 8156 months).
Histological data of the patients are presented in Table 2
. DMH was found in all patients affecting most of the glomeruli (>80%) and, in each glomerulus, all mesangial areas were similarly affected (Figure 1
). Eighteen patients (64%) showed mesangial sclerosis usually of mild severity. Focal glomerular epithelial cell hyperplasia was observed in four patients (15%) and small glomerular adhesions of Bowman's capsule in three (11%). No true epithelial crescents were seen. Significant tubular atrophy and interstitial fibrosis were observed in 14 cases (50%). Nine patients (32%) had a prominent mononuclear cell infiltrate usually assembled around atrophic tubules. The immunofluorescent microscopic study showed a prominent positive reaction for IgM with or without C3 in 13 patients (46%) as a diffuse mesangial pattern. The deposition was usually moderately intense and observed in a granular pattern. In four of these patients, traces of mesangial IgG (three cases) and IgA (one case) were also identified. Complement components other than C3 were observed in five cases (C4 in one case, C1q in three, and C1q plus C4 in one).

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Fig. 1. Light photomicrography of a glomerulus with mesangial widening and severe diffuse mesangial hypercellularity (PASx400).
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Response to treatment and outcome
Twenty-five patients received oral prednisolone as initial therapy (Table 3
). Nine patients (36%) responded with complete remission of proteinuria, eight (32%) showed a partial remission and eight (32%) did not respond at all. The time of remission (complete or partial) ranged from 2 weeks to 4 months, with most patients responding within 3 months. During follow-up, two patients, with initial complete response to prednisolone, had two relapses of NS which always remitted after the reinstitution of prednisolone. In four steroid-resistant patients, cyclophosphamide was given. No response was observed in any of these cases. All patients with initial partial response to steroids or resistance to either prednisolone or cyclophosphamide subsequently received CyA in combination with low dose oral prednisolone. Of eight partial responders treated with CyA, a complete remission was achieved in one patient and a sustained partial remission in the remaining seven. Of the eight non-responsive patients, two went to a partial remission whereas six showed no response to CyA. At the end of follow-up, 10 patients (40%) had a complete remission of proteinuria, nine (36%) a partial remission and six (24%) did not respond to any form of treatment and remained nephrotics. Plasma creatinine remained stable in those with complete or partial response to the treatment (Table 3
). In contrast, all six non-responsive patients reached ESRD during the period of observation. Three CyA-treated patients developed hypertrichosis and one gum hyperplasia. Both complications reverted after CyA treatment was completed. In addition, mild hypertension occurred in two patients, which was treated with a calcium blocker.
Clinicopathological correlations and prognostic indicators
Based on a multivariate analysis of clinical characteristics, only the severity of proteinuria was found to be predictive of the degree of renal function impairment at the time of biopsy (P<0.01). When patients entering remission were excluded from the analysis, only proteinuria (P<0.001) was a significant independent risk factor for outcome (ESRD). None of the other clinical parameters including age and sex were predictive of renal survival. When this analysis was performed evaluating histological features only, the severity of mesangial hypercellularity (P<0.03) and the presence of diffuse mesangial IgM (P<0.01) had independent predictive value for ESRD.
Patients with complete or partial response to prednisolone did not differ with regard to age (58±14 vs 50±8 years, P=NS), plasma creatinine (1.0±0.7 vs 1.3±0.6 mg/dl, P=NS) and severity of proteinuria (4.1±0.3 vs 4.9±2.5 g/24 h, P=NS) at biopsy. However, when they were considered as a single group, they were significantly older and their plasma creatinine was significantly lower at first assessment in comparison with the non-responsive patients (Table 4
). In contrast, the severity of proteinuria was similar in both groups.
Mesangial sclerosis was a universal finding in non-responsive patients (100%) but it was found less frequently in the group of responders (58%, P<0.005) (Table 4
). In addition, synechiae with Bowman's capsule were not seen in any biopsy of the responders, whereas they were observed in all biopsies of non-responsive patients (100%). Also, significant tubulointerstitial fibrosis (
2+) was seen more rarely in responders (23%) than in non-responders (50%, P<0.03). Clinical characteristics of patients with or without mesangial IgM deposits are summarized in Table 5
. No significant differences between the two groups were observed. However, the presence of mesangial IgM was associated with a poorer response to therapy (Table 6
). With regard to the initial response to prednisolone, IgM deposition was seen in 22% of patients with a complete response, in 37% of those with a partial response and in all patients (100%) who did not respond at all (Figure 2
). When the data were analysed according to the final response to the treatment, IgM deposits were present in 20% of patients with a complete response, in 55% of those with a partial response and in 100% of patients who failed to respond to any form of therapy.

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Fig. 2. Schematic representation of the relationship between the presence of mesangial IgM deposits (percentage of treated patients) and the final response to the treatment.
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The multivariate analysis demonstrated that no clinical feature at the time of biopsy was predictive of a response to treatment. Of the histological findings that we measured at the time of biopsy, only the presence of mesangial sclerosis (P<0.03) and the presence of mesangial IgM (P<0.002) independently predicted the response to therapy.
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Discussion
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The results of the present study showed that adult patients with DMH and NS respond less well to prednisolone when compared with those with MCNS. Large clinical studies on adult patients with MCNS showed that corticosteroids induce a remission of NS in 8195% of all patients [25,26]. Contrary to these, only 68% of our patients with DMH responded to prednisolone with complete or partial remission of proteinuria. The poorer response obtained in this study is similar to that reported in children in the Southwest Pediatric Nephrology Study Group (SPNSG) [27] and the International Study of Kidney Disease in Children (ISKDC) [5]. Considering our patients as a single group, the response to steroids is comparable with the 64% response rate reported by us in patients with classic' FSGS and NS, after prolonged treatment (average 9 months) with prednisolone [28]. On this basis, DMH in adults with NS must be clearly differentiated from MCNS and should be regarded as a distinct entity. A closer look, however, reveals heterogeneous population with regard to response to steroids. Almost one-third of the patients respond completely to prednisolone in a way similar to that of patients with MCNS, and some have a relapsing course. Of the remaining, almost one-third remain steroid resistant throughout their course, and the remaining one-third show an intermediate response with persisting non-nephrotic proteinuria.
The use of cytotoxic drugs in the treatment of steroid-resistant cases is of little benefit. No response to cyclophosphamide therapy was observed in four patients with initial resistance to steroids. In agreement with the results of the SPNSG [27] and the ISKDG [5], our findings suggest that treatment with cytotoxic drugs is probably unwarranted in patients with DMH who are unresponsive to steroids. CyA has been used in a few patients with DMH and steroid-resistant NS, but, at present, no conclusion can be drawn regarding its efficacy because only a small number of patients have been treated so far [2931]. Of the eight patients who initially were resistant to prednisolone (including four patients non-responsive to cyclophosphamide), two (25%) went into complete remission after prolonged treatment with CyA. Of those with an initial partial response, CyA induced complete remission in one patient and sustained a partial response in the remaining seven. Overall, at the latest follow-up, 40% of our patients were in complete remission, 36% in partial remission while 24% did not respond to any form of treatment and remained nephrotic. We suggest, therefore, that CyA at a low dose for a prolonged period of time is safe and may be considered as an alternative treatment for patients with partial or no response to steroids.
The long-term prognosis of patients with DMH and NS is not as good as in those with MCNS, and ESRD occurs exceptionally in the latter group [25,26,32]. However, the response to the treatment is the most important clinical factor that determines the final outcome. Renal function remained stable in all patients who responded completely or partially to the treatment. In contrast, all six non-responsive patients (24%) had a protracted course and developed progressive loss of renal function culminating in ESRD. This is also true for children, where the reported incidence of azotaemia or ESRD among non-responders varies from 21 to 40% in different reports [7,12]. The above findings are supported further by the multivariate analysis which demonstrated that persistent NS was the only significant independent predictor of renal survival.
From this analysis, it was found that no clinical feature that we measured at the time of biopsy was predictive of response to treatment. However, a simple comparison between responders and non-responders showed that steroid-responsive patients were older and had normal renal function at biopsy. In contrast, non-responders were much younger and most of them had impaired renal function at first assessment. Otherwise, both groups did not differ with regard to the severity of DMH, the prevalence of haematuria or the degree of proteinuria. The reason why younger adult patients with this lesion are more often resistant to steroids is not clear. Waldherr and co-workers [7] reported an even lower rate of complete (12%) or partial (19%) responsiveness to steroids in nephrotic children with similar histological appearance. Perhaps different pathogenetic mechanisms may operate at different stages of life in producing the same lesion, some of which are steroid sensitive.
When a multivariate analysis was carried out to determine if any of the histological parameters had an influence on the response to treatment, only the presence of mesangial sclerosis had an independent predictive value. Mesangial sclerosis and significant TIN fibrosis were identified more frequently in non-responders. Also, synechiae with Bowman's capsule were seen in all biopsies of non-responsive patients and in none of the responders. Subsequent renal biopsies in two non-responders taken within 1 and 4 years after the initial diagnosis showed FSGS. Do these patients have undiagnosed FSGS from the beginning or a greater likelihood of developing FSGS? It is possible that an initial biopsy will show only unaffected glomeruli and miss the FSGS lesion, particularly early in the course of the disease. However, all cases in the present study had >10 glomeruli, making this possibility unlikely [9]. It seems, therefore, that steroid-resistant patients with DMH are prone to develop FSGS, and that DMH may represent an intermediate stage in such a transition [7].
To evaluate whether the presence of mesangial IgM deposits is really of clinical importance, we divided our cases into IgM-positive and IgM-negative subgroups and examined the influence of mesangial IgM on the response to therapy and outcome. IgM deposits were observed in only 29% of the patients who responded completely or partially to prednisolone and in all (100%) of those who did not respond at all. The same was also evident when the final response to therapy was evaluated according to the presence or absence of mesangial IgM deposits. Moreover, IgM deposits were present in all six cases who finally progressed to terminal renal failure. The multivariate analysis also demonstrated that the presence of mesangial IgM had an independent predictive value for response to therapy. These results indicate that the presence of mesangial IgM deposits in association with DMH increases the likelihood of resistance to therapy and reflects a more severe course of clinical disease. However, it lacks specificity since almost one-third of the responders showed similar deposits, but the absence of IgM deposition is always associated with a favourable response to treatment and excellent long-term outcome. Thus, despite different opinions [8,1322], our results support the view that DMH with IgM mesangial deposits is not a distinct clinicopathological entity, and the presence of mesangial IgM deposition correlates frequently, but not always, with a poorer response to treatment and worse outcome.
At present, we can conclude that adult patients with DMH and NS represent a heterogeneous group with different clinical courses despite similar morphological appearance in initial biopsies [33]. A considerable number of patients are responsive to therapy and do not progress to chronic renal failure. This group has many similarities with those with MCNS. Another group of patients is not responsive to therapy and progresses to ESRD. This group always shows IgM mesangial deposition and may represent an intermediate stage of transition to true FSGS. With the group of partial responders, it is difficult to come to any definite conclusion. These patients show an excellent clinical outcome but a poorer response to treatment. Whether they will lose their subnephrotic proteinuria spontaneously [77] or progress to frank FSGS at a later stage of their course is uncertain. Perhaps, serial biopsies taken at regular intervals in this group coupled with a longer follow-up can provide an answer to this question.
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Notes
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Correspondence and offprint requests to: E. Alexopoulos, MD, Department of Nephrology, Hippokration General Hospital, 50, Papanastasiou Str., 54642 Thessaloniki, Greece. 
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Received for publication: 21. 9.99
Revision received 4. 2.00.