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Clinicopathologic Correlation and Outcome of C1q Nephropathy

Satoshi Hisano^*, Yuko Fukuma, Yoshie Segawa, Kazuhiko Niimi, Yoshitsugu Kaku, Ken Hatae, Takao Saitoh, Morishige Takeshita^*, and Hiroshi Iwasaki^*

Department of ^* Pathology and Pediatrics, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Division of Nephrology and Rheumatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; and Department of Nephrology, Fukuoka Municipal Children's Hospital, Fukuoka, Japan

Correspondence: Dr. Satoshi Hisano, Department of Pathology, Faculty of Medicine, Fukuoka University, 7–45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Phone: 092-801-1011; Fax: 092-863-8383; E-mail: hisanos1{at}cis.fukuoka-u.ac.jp

	Abstract

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Background and objectives: The number of patients with C1q nephropathy (C1qN) in previous reports is small and the duration of follow-up is short. Our study describes the clinicopathologic correlation and clinical outcome through the mean follow-up period of 7.2 yr in 61 patients.

Design, settings, participants, & measurements: Sixty-one patients, 1 to 67 yr of age, with C1qN were enrolled in this study.

Results: According to presentation at onset, patients were divided into two groups: asymptomatic urinary abnormalities (asymptomatic) (n = 36) and nephrotic syndrome (NS) (n = 25). Light microscopy showed minimal change disease (MCD) in 46 patients (75%), mesangial proliferative glomerulonephritis in 7 (12%), and focal segmental glomerulosclerosis (FSGS) in 8 (13%). The prevalence of MCD was higher in the NS group than in the asymptomatic group. Nine patients in the asymptomatic group and all patients in the NS group were treated with prednisolone and/or cyclosporine. Normal urinalysis was found in 10 patients in asymptomatic group and 8 in NS group during the follow-up. Thirteen patients in the NS group were frequent relapsers at the latest follow-up. Three patients with FSGS developed chronic renal failure 8 to 15 yr after the diagnosis. C1q deposits disappeared in 3 of 8 patients receiving repeat biopsy, and 2 of these 3 showed FSGS.

Conclusions: The prognosis of C1qN is good, associated with MCD in a large number. In some patients, C1q deposits disappear through the follow-up period. FSGS may develop in some patients on repeat biopsies. Further investigation is critically needed to settle this issue.

	Introduction

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C1q nephropathy (C1qN) is a controversial diagnostic entity (1–11). The term was first used by Jennette and Hipp (1,2) in 1985, describing 15 patients with dominant or co-dominant mesangial deposition of C1q on immunofluorescence (IF). Most patients with C1qN were children and young adults. The average age of patients was 10.2 to 24.2 yr (1–12). Previous reports described that the urinary findings in patients with C1qN were heavy proteinuria or nephrotic range proteinuria with or without hematuria (1,3–5,9–11). Iskandar et al. (4) reported that the histologic findings were minimal change disease (MCD) in 8 and focal segmental glomerulosclerosis (FSGS) in 7. During the mean follow-up period of 30 mo, clinical outcome was poor in patients with FSGS despite prednisone treatment, and patients with MCD kept normal renal function.

Markowitz et al. (9) reported 19 patients with C1qN, 3 to 42 yr of age (mean age, 24.2 yr), presenting nephrotic range proteinuria or nephrotic syndrome. Light microscopy showed FSGS in 17 and MCD in 2. During a mean follow-up period of 27.1 mo, one patient had complete remission of proteinuria and six had partial remission. Four patients with FSGS had progressive renal insufficiency despite steroid and/or immunosuppressive agents. They suggested that C1qN falls within the clinicopathologic spectrum of idiopathic FSGS/MCD.

In our recent report of C1qN in 30 (1.4%) of 2221 children, 1 to 15 yr of age, undergoing renal biopsy, childhood C1qN was found in a wide clinical spectrum showing asymptomatic urinary abnormalities to nephrotic syndrome (NS) (12). A large number of C1qN showed MCD in 73%. The prevalence of FSGS was only 7%. However, FSGS developed in some children on repeat biopsies. There were some children showing the disappearance of C1q deposits through the follow-up period.

The number of patients with C1qN in previous reports is small and the duration of follow-up is short (1–11). A larger number of patients and a longer follow-up study are needed to clarify the clinicopathologic correlation in C1qN. The subjective patients of our previous report were only children (12). The present study here describes the clinicopathologic correlation and clinical outcome through the mean follow-up period of 7.2 yr (3 to 18 yr) in 61 patients, 1 to 67 yr of age, with C1qN, including children and adult patients.

	Materials and Methods

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Between 1975 and 2004, renal pathology from 16,860 patients, 1 to 76 yr of age, who received percutaneous renal biopsy, was examined at our laboratory. Sixty-one (0.4%), 1 to 67 yr of age, were diagnosed as C1qN. C1qN was based on the criteria described by Jennette and Falk (3): 1) presence of 2+ or greater of C1q in the mesangium on IF, 2) corresponding mesangial or paramesangial electron dense deposits (EDD) by electron microscopy (EM), and 3) lack of the clinical and pathologic evidence of systemic lupus erythematosus.

Informed consents were obtained from patients or their parents before renal biopsies. After approval was obtained from the Human Ethics Review Committee of Fukuoka University, this study protocol was implemented.

Light microscopy was evaluated on sections stained with periodic acid-Schiff and periodic acid-methenamine silver. Fluorescein isothiocyanate-labeled rabbit anti-human IgG, IgA, IgM, C1q, C3, and fibrinogen polyclonal antibodies (Dako, Copenhagen, Denmark) were used on IF. EM was observed by a JEM 100CX (JEOL, Tokyo, Japan). The degree of interstitial fibrosis was semiquantitatively evaluated on a scale of 0 to 3: 0, no interstitial fibrosis; 1+, 10% to 25% of fibrosis in the interstitium of the cortex; 2+, 26% to 50% of fibrosis in the interstitium of the cortex; 3+, more than 50% of fibrosis in the interstitium of the cortex. The intensity of immunohistologic deposits on IF was semiquantitatively evaluated on a scale of 0 to 4+: 0, negativity of the glomerular area; 1+, almost 25% positivity of the glomerular area; 2+, 26% to 50% positivity of the glomerular area; 3+, 51% to 75% or more positivity of the glomerular area, and 4+, 76% or more positivity of the glomerular area. The intensity of EDD on EM was semiquantitatively scored on a scale of 0 to 3+: 0, no EDD in the glomerular area; 1+, presence of EDD in one part of mesangial, subepithelial, and subendothelial areas; 2+, presence of EDD in two parts of mesangial, subepithelial, and subendothelial areas; 3+, presence of EDD in three or more parts of mesangial, subepithelial, and subendothelial areas. The histology and the grading of IF and EDD were reviewed by 2 observers (S.H. and Y.S.) without prior knowledge of clinical information.

These 61 patients were followed up at affiliated hospitals. The clinical and laboratory parameters examined at the time of the biopsy and at the latest follow-up were blood pressure (BP), urinalysis, serum protein, serum creatinine, serum C3 and C4, antinuclear antibody, anti-DNA, and lupus erythematosus cell preparation. Hematuria and proteinuria were determined as previously reported (13,14). Hematuria was expressed as red blood cells per high-power field in sedimentation and proteinuria was expressed semiquantitatively as milligrams per deciliter. Hypertension in children was defined as BP higher than the 95 percentile for age as indicated by the Task Force on Blood Pressure Control in Children (15). Hypertension in adults was defined according to the National High Blood Pressure Education Program Coordinating Committee (16). NS was defined according to the definition of International Study of Kidney Disease in Children (17) and proteinuria of more than 3.5 g per day plus hypoalbuminemia in adult patients (18). Postural proteinuria was completely excluded in this study.

Prednisolone was administered initially at a dose of 2 mg/kg per day for children or 40 mg per day for adults on each day for 4 wk, followed by a dose of 2 mg/kg per day or 40 mg per day on alternate days for 4 wk, and then tapered off for 4 to 12 mo. The same dose of prednisolone to the initial dose was started at the time of relapse of NS. Cyclosporine was administered at a dose of 2 to 4 mg/kg per day on each day for 6 to 24 mo combined with prednisolone.

Statistical Analysis
Data were expressed as mean ± SD. Association of categorical variables was examined with the ² test. Differences in mean values between groups were examined for statistical significance by using the Mann-Whitney U test.

	Results

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Profiles of Patients with C1qN
Clinical and pathologic findings at the time of biopsy are listed in Table 1. The mean age was 19.6 ± 15.4 yr. Two groups were classified according to the mode of patients at the time of renal biopsy, as shown in Table 1. Thirty-six patients (59%) were detected as asymptomatic hematuria and/or proteinuria (asymptomatic), and the remaining 25 (41%) were found as NS. In the asymptomatic group, 17 patients (patients 1, 2, 4, 6, 8 to 19, and 21) were detected at the urine screening test for school children and five patients (patients 25, 28, 29, 34, and 35) were detected at the urine screening test in senior high school or university. The remaining 14 patients were by chance found by the urine screening test at a visit to the hospital. None of patients had hypertension at the time of biopsy except for two patients (patients 27 and 30). None of our patients showed the clinical and serologic manifestations associated with systemic lupus erythematosus.

Mesangial EDD alone, mesangial EDD + subepithelial EDD, mesangial EDD + subendothelial EDD, and mesangial EDD + subepithelial EDD + subendothelial EDD were found in 28 (78%), 5 (14%), 3 (8%), and 1 (3%), respectively, in the asymptomatic group, whereas mesangial EDD alone and mesangial EDD + subendothelial EDD were found in 24 (96%) and 1 (4%), respectively, in the nephrotic group.

Clinical Outcome
Comparison in the clinical findings between the biopsy and the latest follow-up is summarized in Table 2. The mean age at the time of biopsy was not different between the two groups. In renal pathology, the number of MCD was greater in the nephrotic group than in the asymptomatic group. The mean duration of follow-up was 7.2 ± 4.4 yr (range, 3 to 18 yr). The mean duration between the biopsy and the latest follow-up was not different between the two groups. BP was not different at both the biopsy and the latest follow-up between the two groups. The degree of proteinuria was greater at both the biopsy and the latest follow-up in the nephrotic group compared with that in asymptomatic group, but the degree of hematuria was greater in the asymptomatic group at both the biopsy and the latest follow-up compared with that in the nephrotic group. The degree of proteinuria decreased significantly in both groups between at the biopsy and at the latest follow-up. The degree of creatinine clearance was lower in the asympatomatic group at the biopsy than in the nephrotic group, but that was not different at the latest follow-up between two groups.

One patient (patient 21) in the asymptomatic group received the second biopsy 2 yr after the biopsy because of nephrotic range-heavy proteinuria. Seven patients (patients 38, 42, 44, 48, and 50 to 52) in the nephrotic group received the second biopsy 2 to 4 yr after the first biopsy because of frequent relapsing NS. Mesangial C1q deposition disappeared in 3 patients (patients 21, 42, and 52) at the second biopsy, and two patients (patients 21 and 42) showed FSGS at the second biopsy. The remaining patients showed MCD at the second biopsy. Normal urinalysis was found in one patient (patient 48) with prednisolone and cyclosporine at the latest follow-up, and persistent proteinuria was evident in one patient (patient 44). The remaining 4 patients showed frequent relapsing NS at the latest follow-up. Four patients (patients 9, 36, 41, and 59) were retrospectively found to have received biopsy 2 to 6 yr before the enrolling of the present study. At that time, IF study revealed no deposition of immunoglobulins and complement components in these 4 patients.

	Discussion

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In the present study, the number of patients is more and the duration of follow-up is longer compared with those in previous reports (1–11). A large number of C1qN revealed MCD on light microscopy in both asymptomatic and nephrotic patients in the present study as well as our previous report (12). There were 3 patients showing the disappearance of C1q deposits through the follow-up period. FSGS developed in 2 of these 3 patients on repeat biopsies. There were 4 patients who showed no mesangial C1q deposition in the biopsy performed before the enrolling of the present study. In our relative long-term follow-up, the prognosis of C1qN is good in both asymptomatic and nephrotic patients.

Previous reports described that urinary findings in patients with C1qN were heavy proteinuria or nephrotic range proteinuria with or without hematuria (1,3–5,9–11). In our current study as well as our previous report (12), patients with C1qN were detected as having mild to nephrotic range proteinuria. In contrast to our results, MCD was in 8 cases and FSGS in 7 in pediatric 15 cases of Iskandar et al. (4). Markowitz et al. (9) reported that FSGS was in 17 patients and MCD in 2. In our study, the prevalence of FSGS was smaller in number as compared with the results of Iskandar et al. (4) and Markowitz et al. (9). The difference between our and their results may be due to the difference of the number of examined subjects and race. In Japan, patients with asymptomatic urinary abnormalities have been detected by annual urine screening of schoolchildren. We performed renal biopsy widely in those with mild proteinuria to nephrotic range proteinuria, whereas most patients reported by Iskandar et al. (4) and Markowitz et al. (9) had nephrotic range proteinuria with hypertension or renal insufficiency. Therefore, the selection of patients with C1qN may be biased in their studies. Our patients may be detected in the early stage of C1qN.

The degree of proteinuria and hematuria improved in both asymptomatic and nephrotic groups with prednisolone and/or cyclosporine treatment through the follow-up. Normal urinalysis was evident in 10 patients in the asymptomatic group and in 8 in the nephrotic group through the follow-up. However, 13 patients in the nephrotic group were still frequent relapsers at the latest follow-up. Three patients with FSGS (2 in the asymptomatic group and one in the nephrotic group) showed chronic renal failure despite prednisolone treatment. In our study, only 3 of 61 (5%) showed chronic renal failure 8 to 15 yr after the diagnosis. The remaining patients had normal urinalysis or persistent urinary abnormalities with normal renal function at the latest follow-up. In our relative long-term follow-up (a mean follow-up period of 7.2 yr), the prognosis of C1qN appears to be good. The reason of a better prognosis in our patients is considered to be associated with MCD in a larger number of patients compared with those of Iskandar et al. (4) and Markowitz et al. (9).

There are some unresolved issues concerning C1qN. The first question is that the prevalence of this disease is lower compared with the prevalence of IgA glomerulonephritis in 18% to 40% of all primary glomerular diseases (19). The prevalence of C1qN is 0.21% to 4% (1–12). In our patients, the prevalence of C1qN was 0.4% in renal biopsies, including primary and secondary glomerular diseases. The prevalence of C1qN is about 0.8%, even in primary glomerular diseases (our laboratory's unpublished data between 1975 and 2004). The second question is that a large number of histologic findings show MCD in our patients. C1q is the first component of the classical complement pathway by binding to the Fc region of IgG and IgM after their union with antigen. It is not surprising that IgG is deposited in approximately 60% of C1qN patients. However, no remarkable mesangial proliferation is found in a large number of our patients. IgA glomerulonephritis shows a wide spectrum of morphologic findings from MCD to diffuse mesangial proliferation with or without sclerotic glomeruli (19). There are some patients with IgA glomerulonephritis in whom mesangial IgA deposits disappeared through the follow-up. Urinalysis improved in these patients with the disappearance of mesangial IgA deposits (19). Some patients with IgA glomerulonephritis were reported to have lipoid nephrosis with dominant mesangial IgA deposition on IF and mesangial EDD on EM (20,21). This group is considered to be a variant of IgA glomerulonephritis with overlapping syndrome of lipoid nephrosis (20,21). In 3 of 8 patients receiving repeat biopsy, C1q deposits disappeared at the time of the second biopsy. However, histologic findings and urinalysis were worsened in these 3 patients despite disappearance of C1q deposits. The pathogenesis of C1qN is likely to be different from IgA glomerulonephritis in view of the disappearance of mesangial deposits. Furthermore, in our current study, 4 patients were retrospectively found to have showed no mesangial deposits of C1q in the biopsy performed before the enrolling of the present study. These results suggest that C1qN may be overlapping or superimposing with MCD, mesangial proliferative glomerulonephritis, or FSGS. C1q immune complex may by chance deposited in the mesangial area in underlining diseases of MCD, mesangial proliferative glomerulonephritis, or FSGS. However, from the results of our current study, we could not completely clarify whether C1qN was a distinct clinical entity or C1qN was overlapping with the other glomerulonephritides.

	Conclusion

Top Abstract Introduction Materials and Methods Results Discussion Conclusion Disclosures References

 
C1qN is found in patients with a wide clinical and a wide histologic spectrum. A large number of C1qN show MCD in asymptomatic and symptomatic patients. In our relative long-term follow-up, the prognosis of C1qN is good. There are some patients showing the disappearance of C1q deposits through the follow-up period. FSGS may develop in some patients with time. Further investigation is critically needed to settle this issue.

	Disclosures

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None.

	Footnotes

 
Published online ahead of print. Publication date available at www.cjasn.org.

Received February 19, 2008. Accepted June 20, 2008.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: CJN.00830208v1 3/6/1637    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hisano, S. Articles by Iwasaki, H. Search for Related Content PubMed PubMed Citation Articles by Hisano, S. Articles by Iwasaki, H.