Clin Exp Nephrol (2013) 17:92–98 DOI 10.1007/s10157-012-0667-6
ORIGINAL ARTICLE
Positive C1q staining associated with poor renal outcome in membranoproliferative glomerulonephritis Takashi Takei • Mitsuyo Itabashi • Takahito Moriyama • Ari Shimizu Yuki Tsuruta • Ayami Ochi • Kayu Nakayama • Chihiro Iwasaki • Keiko Uchida • Kosaku Nitta
•
Received: 1 March 2012 / Accepted: 27 June 2012 / Published online: 21 July 2012 Ó Japanese Society of Nephrology 2012
Abstract Background Pathogenesis and clinical prognosis of membranoproliferative glomerulonephritis (MPGN) has not yet been established. Methods We conducted a retrospective study of 41 patients with MPGN (type I and III) and examined the renal survival. In addition, factors contributing to survival time were analyzed. Results Fourteen patients (34 %) were classified into the renal death group. Patients with nephrotic syndrome and positive C1q staining of glomerular deposits showed a particularly poor prognosis. Significantly higher frequency of nephrotic syndrome and higher urinary protein excretion were observed in the renal death group (p = 0.0002, p = 0.0002) than in the renal survival group. The intensity of C1q staining was positively correlated with the severity of the proteinuria (p = 0.004). Factors that influenced the survival time were positive C1q staining of glomerular deposits (p = 0.003), presence of nephrotic syndrome (p = 0.004), serum albumin (p = 0.02), and proteinuria (p = 0.04). Conclusions C1q staining in glomerular deposits and nephrotic syndrome were important factors influencing the prognosis and outcome in MPGN patients. C1q deposition may play a key role in the pathogenesis of MPGN, as evidenced by numerous observations, such as induction of proteinuria.
T. Takei (&) M. Itabashi T. Moriyama A. Shimizu Y. Tsuruta A. Ochi K. Nakayama C. Iwasaki K. Uchida K. Nitta Department of Medicine, Kidney Center, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan e-mail:
[email protected]
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Keywords Membranoproliferative glomerulonephritis (MPGN) Nephrotic syndrome C1q staining Renal prognosis
Introduction The term membranoproliferative glomerulonephritis (MPGN) is usually used to denote a general pattern of glomerular injury seen in a variety of disease processes sharing a common pathogenetic mechanism rather than to describe a single disease entity [1]. Etiologically, the condition may be of unknown cause (idiopathic) or may be associated with systemic and infectious disorders (secondary). Renal outcome in patients with MPGN is poor, with a reported 10-year renal survival rate of approximately 40 % [2]. Indicators of poor renal prognosis in patients with MPGN are hypertension, impaired renal function, low hemoglobin, nephrotic syndrome, urinary polymers of albumin, and sodium-dodecyl-sulphate polyacrylamide gel electrophoresis protein (SDS-PAGE) pattern [3]. Morphologically, MPGN is characterized by diffuse mesangial cell proliferation and thickening of the capillary walls due to subendothelial extension of the mesangium. Morphologic indicators of poor prognosis are crescents, sclerosis, mesangial proliferation, tubulointerstitial disease, and glomerular and interstitial a-smooth muscle actin expression [3]. There are at least two (possibly three) distinct morphological types of MPGN, both (all) of which are related to complement activation. MPGN type I (classical MPGN), the most common variant, is characterized by the presence of subendothelial deposits of immune complexes associated with activation of the classical complement pathway. MPGN type III, which some pathologists consider a
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morphologic variant of type I, is characterized by the same findings as those in type I, with additional presence of subepithelial deposits [4]. MPGN type II (dense-deposit disease: DDD) is a unique variant characterized by the presence of additional intramembranous dense deposits. This type is known to be associated with the presence in serum of an immunoglobulin (Ig), namely, C3 nephritic factor (C3NeF), which stabilizes C3 convertase (C3bBb), thereby causing persistent activation of the alternate complement pathway. Recently, glomerular pathologies characterized by the isolated deposition of C3 could usefully be classified by the term C3 glomerulopathy. DDD should be considered a form of C3 glomerulopathy [5]. MPGN type II is less common than MPGN type I or type III, and accounts for 5–33 % of all cases of MPGN [6]. It is also associated with a worse prognosis [7]. Therefore, in this study, we examined the pathology, clinical presentations, and outcomes of idiopathic MPGN type I and type III but not MPGN type II. Some authors included MPGN type I in the category of C1q nephropathy, although other authors recommend that this form of glomerulonephritis should be an exclusion criterion for C1q nephropathy [8–10]. Recent studies suggested that C1q nephropathy falls within the clinicopathologic spectrum of idiopathic minimal-change nephropathy and focal segmental glomerulonephritis (FSGS) [8, 11, 12]. We also compared the frequency of C1q staining of glomerular immune deposits and prognosis between patients with MPGN types I and III.
Methods Patients Among patients seen at the Department of Medicine of the Kidney Center at Tokyo Women’s Medical University between 1977 and 2005, data of 41 patients diagnosed with idiopathic membranoproliferative glomerulonephritis (IMPGN) types I or III based on the renal biopsy findings were reviewed. All patients were Japanese. The diagnosis of IMPGN types I or III was based on: (1) presence of a kidney disorder characterized by mesangial cell proliferation and structural changes in glomerular capillary walls; types I and III were defined based on the pathological features; (2) a: no known associated systemic disease; b: negative serology for hepatitis B and C, human immunodeficiency virus, and antinuclear antibodies, and c: no positive family history at the time of biopsy; (3) distinction between idiopathic and secondary MPGN was not established by histology alone but by a combination of morphological findings and available clinical data. Data were collected from medical records, electronic patient
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databases, and electronic pathology resources. Clinical data were evaluated in relation to age at the time of diagnosis. Blood pressure was measured, and the following laboratory tests were performed according to standard hospital procedures: measurement of urinary protein excretion (UP g/day); urinary red blood cell count per high-powered field (U-RBC/HPF),; measurement of serum creatinine (sCr, mg/dl); estimated glomerular filtration rate (eGFR, ml/min); serum albumin (Alb, g/dl); serum immunoglobulin G (IgG mg/dl); C3 (mg/dl); C4 (mg/dl); and CH50 (U/ml). Histological findings All renal biopsy specimens were obtained by the percutaneous needle biopsy method. Specimens were fixed with 10 % phosphate-buffered formalin (pH 7.2), embedded in paraffin, and cut into 2-lm sections. Hematoxylin and eosin (H&E), periodic acid-Schiff, silver methenamine, and Masson trichrome staining were performed for light microscopy. Each specimen was evaluated for glomerular, interstitial, and vascular changes. Two independent observers with no knowledge of clinical data scored changes semiquantitatively. Percentages of glomeruli exhibiting glomerular obsolescence, crescent formation, and glomerular tuft adhesion to Bowman’s capsule were estimated. Mesangial cell proliferation in each patient was semiquantitatively estimated as follows: grade 0, no abnormality; grade 1, mild proliferation; grade 2, moderate proliferation; grade 3, severe proliferation. The extent of interstitial fibrosis was graded into four categories according to the percent area of fibrotic lesions relative to the total cortical area: grade 0, \5 %; grade 1, 5–20 %; grade 2, 20–40 %; grade 3, [40 %. Arteriolosclerotic changes were also evaluated using a similar grading scale: grade 0, no abnormality; grade 1, mild abnormality; grade 2, moderate abnormality; grade 3, severe abnormality. For immunofluorescence microscopy, kidney samples were frozen in liquid nitrogen, and cryostat sections were stained with fluorescein-isothiocyanate-labeled antisera to human IgG, IgM, IgA, C3, and C1q (Dakopatts, Copenhagen, Denmark). The intensity of glomerular mesngial and capillary-wall staining was graded: 0, no abnormality; 1mild; 2, moderate; 3, severe. Tissue for electron microscopy (EM) was fixed in buffered 1 % osmium tetroxide and embedded in Epon. Ultrathin sections were stained with uranyl acetate and lead citrate. Treatment Patients with [0.5 g/day proteinuria were initially treated with prednisolone orally at 0.8 mg/kg a day for the first 4 weeks; daily dose was tapered thereafter by 5 mg every 4 weeks until the dose was reduced to 0.4 mg/kg.
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Treatment was maintained at the daily dose of 0.4 mg/kg for 18 months and thereafter tapered even further. All patients received steroid therapy for about 2 years. Patients showing steroid-resistance were given additional intravenous pulse methylprednisolone therapy, and if there was still no response, cyclosporin or cyclophosphamide therapy was initiated. For patients with hypertension, one or more antihypertensive drugs, i.e., calcium-channel blockers, angiotensin-converting enzyme inhibitors, or angiotensinreceptor blockers were administered. Definitions Nephrotic syndrome was defined as proteinuria C3.5 g/day, serum albumin \3.0 g/dl, edema, and hyperlipidemia. Complete remission was defined as clinical improvement supported by a daily UP excretion of \0.3 g, as represented by the result of a urinary dipstick test for albumin of trace, or a negative urinary dipstick test result for albumin. Statistical analysis Data are expressed as means ± standard deviation (SD). Significance of differences between groups was examined by Student’s t test for nonpaired samples. Clinical parameters in were analyzed by repeated-measures analysis of variance (ANOVA). Categorical variables were compared with the v2 test, Kruskal–Wallis test, Pearson test, or Fisher’s test, as appropriate. Survival was assessed by the Kaplan–Meier method. A stepwise multiple regression analysis was performed to identify independent risk factors for renal death among parameters selected by univariate analyses. All statistical analyses were performed using JUMP 8 software (SAS Institute Cary, NC, USA).
Results Clinical manifestations at the time of renal biopsy are shown in Table 1. The mean Cr level was 1.07 ± 0.32 mg/dl, eGFR 80.5 ± 29.2 ml/min, and daily UP excretion 4.56 ± 3.14 g. Sixteen patients (39 %) had nephrotic syndrome. Histological findings are shown in Table 1. Percentages of cases with MPGN types I (44 %) and III (56 %) were similar. The renal outcomes are shown in Fig. 1. Fourteen of the 41 patients (34 %) showed renal death, and the average interval from diagnosis until dialysis initiation was 8.7 ± 5.5 years. We divided patients according to renal outcome into two groups: renal survival group and renal death group. We then compared clinical data, therapy, prognosis, and outcome between groups. Comparative clinical characteristics are shown in Table 1. Significantly
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higher frequency of nephrotic syndrome and higher daily UP excretion were observed in the renal death group (p = 0.0002, p = 0.0002). Renal function at diagnosis was more impaired in the renal death group (Cr p = 0.03, eGFR p = 0.01). A significantly lower serum albumin and frequency of complete remission were observed in the renal death group (p = 0.01, p = 0.02). There was no significant difference in the therapy administered between groups. As to prognosis, renal survival time was significantly shorter (p = 0.0004) in the nephrotic syndrome group than in the nonnephrotic syndrome group (Fig. 1a). Histological data of the two groups at the time of diagnosis are shown in Table 1. Findings on immunofluorescence study were strongly positive staining for C3 (87.8 %) and, less frequently, for IgG (63.4 %), C1q (58.5 %), IgM (51.2 %), and IgA (43.9 %). There was no significant difference in C3, IgG, IgM, and IgA deposits, including deposits localized to glomerular capillary wall or mesangium between renal survival and renal death groups. However, comparison revealed significant differences in the number of patients showing positive staining for C1q and the intensity of C1q staining in glomerular deposits [number frequency, intensity: renal survival group vs. renal death group 12 (46 %) vs. 12 (80 %); p = 0.02, 0.7 ± 0.9 vs. 1.5 ± 0.9; p = 0.04)] between the renal survival and renal death groups. C1q deposits localized to glomerular capillary wall and mesangium were evident in 20 patients and to the mesangium alone were evident in four patients; however, there was no significant difference in deposit localization between the two groups. In addition, prognosis of patients with and without C1q staining in glomerular deposits was examined. Renal survival time was significantly shorter (p = 0.03) in patients showing positive staining for C1q than in those showing negative staining for C1q regarding glomerular deposits (Fig. 1b). We also found a correlation between the intensity of C1q staining in glomerular deposits and daily UP excretion (p = 0.004) and serum Alb (p = 0.007) (data not shown). Next, we analyzed factors that influenced survival times: multiple regression analysis identified six factors, including the presence/absence of C1q staining (p = 0.003), presence/absence of nephrotic syndrome (p = 0.004), serum Alb (p = 0.02), daily UP excretion (p = 0.04), and severity of mesangial cell proliferation (p = 0.02) and interstitial fibrosis (p = 0.03) (Table 2).
Discussion IMPGN is an uncommon renal disease that accounts for only 6.4–7.3 % of all primary glomerulopathies [13, 14]. The renal outcome in patients with IMPGN is poor, with a
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Table 1 Clinicopathological data at baseline in renal death and renal survival group in membranoproliferative glomerulonephritis (MPGN) Total (n = 41)
Renal survival (n = 26)
Renal death (n = 14)
p value
Age (year)
36.4 ± 19.5
33.5 ± 18.5
45.3 ± 19.6
NS
Female/male
18/23
14/13
4/10
NS
Systolic BP (mmHg)
131.7 ± 20.4
128.3 ± 18.1
141.8 ± 25.1
NS
Diastolic BP (mmHg)
77.9 ± 11.4
77.4 ± 10.0
79.3 ± 16.1
NS
UP (g/day)
4.56 ± 3.14
3.65 ± 2.86
6.41 ± 2.96
0.0002
Sediment RBC (/HPF)
27.1 ± 29.4
28.0 ± 30.1
25.0 ± 29.3
NS
Serum creatinine (mg/dl)
1.07 ± 0.32
1.00 ± 0.30
1.25 ± 0.26
0.03
eGFR (ml/min)
80.5 ± 29.2
87.4 ± 30.4
62.6 ± 17.8
0.01
Albumin (g/dl)
2.8 ± 0.6
3.1 ± 0.6
2.5 ± 0.2
0.01
C3 (mg/dl)
68.3 ± 34.1
63.6 ± 33.3
79.8 ± 35.8
NS
C4 (mg/dl) CH50 (U/ml)
24.7 ± 14.1 32.8 ± 10.4
23.8 ± 15.3 32.8 ± 11.9
26.7 ± 12.0 32.8 ± 6.2
NS NS
IgG (mg/dl)
768.4 ± 268.7
795.1 ± 248.3
715.0 ± 319.4
NS
Nephrotic syndrome (n)
16
5
11
0.0002
PSL (n)
37/41
23/27
14/14
NS
Average clinical course (years)
12.8 ± 7.7
13.6 ± 8.6
10.6 ± 5.5
NS
Complete remission
17/41
15/27
2/14
0.02
2.2 ± 0.8
2.0 ± 0.8
2.4 ± 0.8
NS
Pathology Mesangial cell proliferation (grade 0–3) Glomerular obsolescence (%)
12.3 ± 12.8
9.3 ± 12.8
16.9 ± 18.2
NS
Crescent formation (%)
5.3 ± 9.00
3.3 ± 9.0
9.2 ± 12.6
NS
Glomerular tuft adhesion to Bowman’s capsule (%)
6.85 ± 12.0
6.9 ± 11.3
12.2 ± 18.4
NS
Interstitial fibrosis (grade 0–3)
1.4 ± 0.9
1.2 ± 0.8
1.5 ± 0.9
NS
Arterio-arteriolosclerotic changes (grade 0–3)
0.6 ± 0.8
0.4 ± 0.8
0.6 ± 0.9
NS
IgG (n, Intensity:mean)
26, 10, 1.2 ± 0.9
16, 1.1 ± 1.0
10, 1.2 ± 0.9
NS
IgM
21, 0.8 ± 0.8
14, 0.8 ± 0.8
7, 0.8 ± 0.9
NS
IgA C3
18, 0.5 ± 0.6 36, 1.4 ± 0.7
12, 0.5 ± 0.6 23, 1.4 ± 0.7
6, 0.6 ± 0.8 13, 1.6 ± 0.7
NS NS
C1q
24, 0.7 ± 0.9
12, 0.7 ± 0.9
12, 1.5 ± 0.9
0.02, 0.04
Type I/ III (%)
44
46
43
NS
Values are expressed as mean ± SD.; p value: significantly different between the renal death group and the renal survival group BP blood pressure, UP urinary protein excretion, RBC red blood cells, HPF high-power field, eGFR estimated glomerular filtration rate, IgG immunoglobulin G, NS not significant, PSL prednisolone
reported 10-year renal survival rate of 32–40 %, and complete remission is achieved with treatment in only 5–7.6 % of patients [15, 16]. Droz et al. [15] reported that the 10-year renal survival rate in adult patients with MPGN type I was 60 %. Bohle et al. [16] reported a 5-year renal survival rate of 51 % and a 10-year survival rate of 32 % in patients with MPGN type I. In the large series of 220 patients with MPGN type I from Germany, 23 % of patients died during follow-up, 26 % showed progression to end-stage renal disease (ESRD), 24 % developed chronic renal failure, and only 27 % stabilized in terms of renal function (average follow-up duration, 5 years) [17]. The clinical and laboratory findings and prognosis of patients with MPGN type III are generally similar to those of patients with MPGN type I. However, several reports
have suggested a more guarded prognosis in relation to long-term renal survival for patients with MPGN type III than for those with MPGN type I. Braun et al. [18] compared the course and long-term outcomes of 21 patients with MPGN type I and 25 patients with MPGN type III. They reported that MPGN type III patients had longerlasting hypocomplementemia, hematuria and proteinuria and a higher rate of disease relapse compared with patients with MPGN type I. In our study, there were no significant differences in the severity of hypocomplementemia, hematuria, and proteinuria, or in the prognosis between patients with MPGN types I and III. The presence of nephrotic syndrome at clinical onset has been reported by some researchers to be indicative of poor prognosis [19]. Other features predictive of poor prognosis
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Fig. 1 a Kaplan–Meier renal analysis of survival in relation to the presence/absence of nephrotic syndrome. Comparison of renal survival rate between the nephrotic syndrome group (n = 16) and the nonnephrotic syndrome group (n = 25). X-axis indicates followup period (years); Y-axis indicates survival rate (%). p = 0.0004 between the nephrotic and nonnephrotic syndrome groups as assessed
Table 2 Multiple regression analysis for risk factors of renal death Parameter
F value
P value
Age
1.1
0.3
Female/male
3.8
0.06
UP
4.4
0.04
Sediment RBC
0.001
1
eGFR
3.6
0.07
Albumin
6.2
0.02
10.3
0.004
Nephrotic syndrome Glomerular obsolescence
0.004
0.9
Crescent formation
0.03
0.9
Glomerular tuft adhesion to Bowman’s capsule
0.02
0.9
Mesangial cell proliferation Interstitial fibrosis
6.2 5.4
0.02 0.03
Arterio-arteriolosclerotic changes
1
0.3
IgG (IF)
0.02
0.9
IgM (IF)
1
0.3
IgA (IF)
0.2
0.6
C3 (IF)
2.4
0.1
C1q (IF)
10.4
Type III
0.01
0.003 0.9
UP urinary protein excretion, RBC red blood cells, eGFR estimated glomerular filtration rate, Ig Immunoglobulin, IF immunofluorescence
are the absence of clinical remission during disease course, initial impairment of renal function, and persistent hypertension [16]. We analyzed the factors that might influence renal survival times; multiple regression analysis identified the presence of C1q staining in renal glomerular deposits as the most significant factor influencing renal survival. The pathogenesis of MPGN is not yet clearly understood. It is believed that MPGN type I results from chronic
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by the log-rank test. b Kaplan–Meier renal survival analysis in relation to presence/absence of C1q staining of glomerular deposits. Comparison of renal survival rate between C1q-positive (n = 24) and C1q-negative (n = 17) groups. X-axis indicates the follow-up period (years); Y-axis indicates survival rate (%). p = 0.03 between the C1qpositive and C1q-negative groups as assessed by log-rank test
antigenemia and generation of nephritogenic immune complexes that preferentially localize in the subendothelial spaces. The precise nature of the putative antigen(s) in most patients with MPGN type I is unknown. Recent studies demonstrate the contribution of innate immunity to both generation of antibodies deposited as immune complexes and to local inflammatory responses directed against glomerular immune deposits [20, 21]. Immune complexes activate the complement system via the classical pathway, leading to generation of chemotactic factors (C3a, C5a) that mediate accumulation of platelets and leukocytes and of terminal complement components (C5b-9) that directly induce cell injury. Leukocytes release oxidants and proteases that mediate capillary-wall damage and cause proteinuria and a fall of GFR. Cytokines and growth factors released by both exogenous and endogenous glomerular cells lead to mesangial cell proliferation and matrix expansion [22]. Complement perturbation in MPGN type III is thought to be related to a slow-acting nephritic factor that stabilizes a properdin-dependent C5-convertase, (Cb3) 2BbP, thus activating the terminal pathway. Hence, the use of the term nephritic factor of the terminal pathway (NeFt) [2]. Unlike C3NeF, this nephritic factor has not been reported in healthy individuals. Although we did not investigate it in this study, deposits observed in renal biopsies of patients with MPGN type III are reported to be closely associated with circulating nephritic-factor-stabilized convertase and hypocomplementemia, suggesting that NeFt is fundamental to the pathogenesis of MPGN type III [23]. The most common finding on immunofluorescence study is a strongly positive staining for C3 and, less frequently, for IgG and IgM, in a fine-to-course granular pattern along glomerular capillaries in patients with MPGN types I and III [2]. Early complement components (C1q or
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C4) and properdin are also frequently recognized. Nasr et al. [24, 25] recently described an entity of proliferative glomerulonephritis associated with monoclonal IgG deposits with MPGN features. Although IgG was the only immunoglobulin deposited in four patients in our study, there were no patients with monoclonal IgG positivity for kappa or lambda. Markowitz et al. [12] suggested that C1q nephropathy was within the spectrum of minimal-change nephropathy and FSGS. They assumed that C1q could bind to immunoglobulins that become trapped nonspecifically in the mesangium as a result of increased mesangial trafficking in the setting of glomerular proteinuria. Presence/ absence of C1q staining of glomerular deposits in MPGN types I and III may strongly influence disease course and patient prognosis. Vikse et al. [26] analyzed prognostic factors in 273 patients with MPGN. They stated that glomerular immunodeposits of C1q did not affect progression to ESRD. However, their series showed lower proteinuria (0.65 g/day) and mean follow-up period (34.8 months) than those in our series (proteinuria 4.56 g/day, mean follow-up 12.8 years). The intensity of C1q staining was correlation with daily UP excretion, serum albumin, and presence/absence of nephrotic syndrome in our study; however, the relationship between pathogenesis of C1q nephropathy and podocyte injury remains uncertain [27, 28]. Trouw et al. investigated how anti-C1q autoantibodies contribute to the development of nephritis in mouse models. They show that administration of anti-C1q mAb to naive mice results in glomerular deposition of C1q and anti-C1q autoantibodies but not in overt renal disease. In addition, they show that administration of anti-C1q autoantibodies to mice pretreated with C1q-fixing antiglomerular basement membrane (anti-GBM) antibodies, as a model for glomerular immune complex disease, resulted in strong synergistic enhancement of renal disease. Therefore, anti-C1q autoantibodies can be pathogenic to the kidney but only in the context of C1q-containing glomerular immune complexes [29, 30]. Therefore, it might be necessary to examine anti-Ciq autoantibodies in the future. C1q deposition could play a key role in the pathogenesis of MPGN, as evidenced by numerous observations—such as induction of proteinuria—and may induce the development of nephrotic syndrome. In summary, one third of patients in our study showed progression to ESRD in a mean of 8.7 years of follow-up. In particular, patients with nephrotic syndrome and C1q staining in glomerular deposits showed a particularly poor prognosis. The intensity of C1q staining was positively correlated with daily UP excretion. Factors found to influence renal survival time—namely, the presence/ absence of C1q staining in glomerular deposits, presence/ absence of nephrotic syndrome, serum Alb, daily UP excretion, and severity of mesangial cell proliferation and
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interstitial fibrosis—may also be applicable to treatment decisions. Improvement in renal outcomes in patients with MPGN largely relies on measures to reduce proteinuria and the evaluation of C1q staining in glomerular deposits and may be keystone. Conflict of interest
None.
References 1. Kher V, Gulati S. Mesangiocapillary glomerulonephritis. In: Davidson AM, editor. Oxford textbook of clinical nephrology. 3rd ed. Oxford: Oxford University Press; 2005. p. 523–45. 2. Alchi B, Jayne D. Membranoproliferative glomerulonephritis. Pediatr Nephrol. 2010;25:1409–18. 3. Zhou XJ, Silva FG. Membranoproliferative glomerulonephritis. In: Jennette JC, Olson JL, Schwartz MM, Silva FG editors. Heptinstall’s pathology of the kidney, 6th edn. Philadelphia: Lippincott Williams and Wilkins; 2009, vol 1, pp 253–319. 4. Jackson EC, McAdams AJ, Strife CF, Forristal J, Welch TR, West CD. Differences between membranoproliferative glomerulonephritis types I and III in clinical presentation, glomerular morphology, and complement perturbation. Am J Kidney Dis. 1987;9:115–20. 5. Fakhouri F, Fre´meaux-Bacchi V, Noe¨l LH, Cook HT, Pickering MC. C3 glomerulopathy: a new classification. Nat Rev Nephrol. 2010;6:494–9. 6. Habib R, Gubler MC, Loirat C, Ma¨iz HB, Levy M. Dense deposit disease: a variant of membranoproliferative glomerulonephritis. Kidney Int. 1975;7:204–15. 7. Cansick JC, Lennon R, Cummins CL, Howie AJ, McGraw ME, Saleem MA, et al. Prognosis, treatment and outcome of childhood mesangiocapillary (membranoproliferative) glomerulonephritis. Nephrol Dial Transplant. 2004;19:2769–77. 8. Vizjak A, Ferluga D, Rozic M, Hvala A, Lindic J, Levart TK, et al. Clinical presentations, and outcomes of C1q nephropathy. J Am Soc Nephrol. 2008;19:2237–44. 9. Nishida M, Kawakatsu H, Komatsu H, Ishiwari K, Tamai M, Sawada T. Spontaneous improvement in a case of C1q nephropathy. Am J Kidney Dis. 2000;35:E22. 10. Davenport A, Maciver AG, Mackenzie JC. C1q nephropathy: do C1q deposits have any prognostic significance in the nephrotic syndrome? Nephrol Dial Transplant. 1992;7:391–6. 11. Hisano S, Fukuma Y, Segawa Y, Niimi K, Kaku Y, Hatae K, et al. Clinicopathologic correlation and outcome of C1q nephropathy. Clin J Am Soc Nephrol. 2008;3:1637–43. 12. Markowitz GS, Schwimmer JA, Stokes MB, Nasr S, Seigle RL, Valeri AM, et al. C1q nephropathy: a variant of focal segmental glomerulosclerosis. Kidney Int. 2003;64:1232–40. 13. Stratta P, Segoloni GP, Canavese C, Sandri L, Mazzucco G, Roccatello D, et al. Incidence of biopsy proven primary glomerulonephritis in an Italian province. Am J Kidney Dis. 1996;27:631–9. 14. Faedda R, Satta A, Tanda F, Pirisi M, Bartoli E. Immunosuppressive treatment of membranoproliferative glomerulonephritis. Nephron. 1994;67:59–65. 15. Droz D, Noel LH, Barbanel C, Gru¨nfeld JP. Long-term evolution of membranoproliferative glomerulonephritis in adults: spontaneous clinical remission in 13 cases with proven regression of glomerular lesions in 5 cases. Nephrologie. 1982;3:6–11. 16. Bohle A, Wehrmann M, Bogenschu¨tz O, Bogenschu¨tz O, Batz C, Vogl W, et al. The long-term prognosis of the primary
123
98
17.
18.
19.
20. 21.
22. 23.
Clin Exp Nephrol (2013) 17:92–98 glomerulonephritides. A morphological and clinical analysis of 1747 cases. Pathol Res Pract. 1992;188:908–24. Schmitt H, Bohle A, Reineke T, Mayer-Eichberger D, Vogl W. Long-term prognosis of membranoproliferative glomerulonephritis type I. Significance of clinical and morphological parameters: an investigation of 220 cases. Nephron. 1990;55: 242–50. Braun MC, West CD, Strife CF. Differences between membranoproliferative glomerulonephritis types I and III in long-term response to an alternate-day prednisone regimen. Am J Kidney Dis. 1999;34:1022–32. Little MA, Dupont P, Campbell E, Dorman A, Walshe JJ. Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk. Kidney Int. 2006;69:504–11. Walker PD. Dense deposit disease: new insights. Curr Opin Nephrol Hypertens. 2007;16:204–12. Smith KD, Alpers CE. Pathogenic mechanisms in membranoproliferative glomerulonephritis. Curr Opin Nephrol Hypertens. 2005;14:396–403. Nakopoulou L. Membranoproliferative glomerulonephritis. Nephrol Dial Transplant. 2001;16:71–3. West CD, McAdams AJ. Membranoproliferative glomerulonephritis type III: association of glomerular deposits with circulating nephritic factor-stabilized convertase. Am J Kidney Dis. 1998;32:56–63.
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24. Nasr SH, Satoskar A, Markowitz GS, Valeri AM, Appel GB, Stokes MB, et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol. 2009;20:2055–64. 25. Nasr SH, Markowitz GS, Stokes MB, Seshan SV, Valderrama E, Appel GB, et al. Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int. 2004;65:85–96. 26. Vikse BE, Bostad L, Aasarød K, Lysebo DE, Iversen BM. Prognostic factors in mesangioproliferative glomerulonephritis. Nephrol Dial Transplant. 2002;17:1603–13. 27. Shappell SB, Myrthil G, Fogo A. An adolescent with relapsing nephrotic syndrome: minimal-change disease versus focal-segmental glomerulosclerosis versus C1q nephropathy. Am J Kidney Dis. 1997;29:966–70. 28. Barisoni L, Schnaper HW, Kopp JB. A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol. 2007;2:529–42. 29. Trouw LA, Groeneveld TW, Seelen MA, Duijs JM, Bajema IM, Prins FA, et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest. 2004;114:679–88. 30. Trouw LA, Seelen MA, Visseren R, Duijs JM, Benediktsson H, de Heer E, et al. Anti-C1q autoantibodies in murine lupus nephritis. Clin Exp Immunol. 2004;135:41–8.
