Abstract
Background: The prognostic factors, the outcome and the most favorable treatment regimen are not entirely known for children with membranoproliferative glomerulonephritis (MPGN). MPGN is a rarely observed disease more prevalent in adolescents, so we aimed to review the clinical and histological properties, treatments and the outcome of our patients who were diagnosed as MPGN. Methods: Fifty-one children – diagnosed with MPGN – were selected from biopsy records in Dr. Sami Ulus Maternity and Children's Hospital Pediatric Nephrology Department from January 1999 to January 2011. A retrospective analysis was made of 33 regularly followed children. Results: Thirty-three patients were identified, 13 female and 20 male. Their age groups at presentation ranged from 4 to 15 years. The following duration was 26–144 months (mean 74). Following the initial treatment, 20 (60%) patients achieved complete remission. Six patients with nephrotic syndrome and one with non-nephrotic proteinuria showed partial remission. The condition of one patient with nephrotic syndrome was unchanged with the persisting symptoms. The one patient with nephrotic syndrome and four others with non-nephrotic proteinuria did not respond to initial treatment as their renal functions decreased gradually. Conclusion: We concluded that only degree of tubulointerstitial damage on the initial biopsy is determinative for prognosis of childhood MPGN. If the patient receives high doses of steroid therapy in the early stages, their treatment is more likely to be successful. The effect of immunosuppressive treatment on MPGN is not clear.
Introduction
Membranoproliferative glomerulonephritis (MPGN) is a rare disease in childhood. The term MPGN is often use to indicate a general pattern of glomerular injury, seen in a variety of disease processes that share a common pathogenetic mechanism, rather than to describe a single disease entity.Citation1 MPGN may appear as a primary disorder, at the same time, accompany to other chronic diseases including malignancy, systemic lupus erythematosus, mixed essential cryoglobulinemia and infections such as hepatitis B and C.
Morphologically, MPGN is characterized by diffuse mesangial cell proliferation and the thickening of capillary walls due to subendothelial extension of the mesangium.Citation2 Complement activation is often observed. Usually, there is a reduction in circulating complement C3 and evidence of alternate pathway activation. Immunohistochemistry usually reveals complement deposition in glomeruli.
Idiopathic MPGN is one of the least common types of primary renal causes of nephritic syndrome in children. Nephrotic syndrome (NS), nephritic syndrome, asymptomatic proteinuria with hematuria and recurrent episodes of gross hematuria are the clinical features observed at initial presentation.Citation3 MPGN mainly affects teenagers and adolescents. The incidence for MPGN in patients with nephrotic syndrome is approximately 4–8% in children and 7% in adult.Citation4–6
The prognostic factors, the outcome and the most favorable treatment regimen are incompletely known in children. Because, MPGN is a rare disease and more commonly observed in adolescents. Thus, following periods by pediatric nephrologists are commonly more limited compared to adults. We aimed to review the clinical and histopathological properties, treatment regimens, outcome and prognostic factors of our patients with primary MPGN.
Subjects and methods
A total of 51 children were diagnosed as MPGN in Dr Sami Ulus Maternity and Children's Hospital Pediatric Nephrology Department from January 1999 to January 2011. Eight patients with secondary forms of MPGN (four of them were secondary to hepatitis B, two were hepatitis C and two were SLE) and 10 patients, who had shorter follow-up period (<24 months) were removed from the study. A retrospective analysis of 33 children with primary MPGN was carried out. The diagnosis of MPGN was based on clinical and laboratory findings, and was confirmed by renal biopsy on light and immunofluorescence (IF) microscopy. Electron microscopic examination could be performed in only eight patients. Chronic renal index was defined as the presence of globally sclerosed glomeruli, tubular atrophy and interstitial fibrosis. The patients were determined as with severe or mild tubulointerstitial damage (TD).
Definitions
Proteinuria was evaluated by a 24-hour quantitative measurement. Non-nephrotic range proteinuria (NNP) was defined as proteinuria 4–40 mg/m2/h and serum albumin >3.0 g/dL. Nephrotic syndrome (NS) was defined as the presence of proteinuria >40 mg/m2/h, serum albumin <3.0 g/dL and edema.
Hematuria was defined as macroscopic if visible to the naked eye and microscopic if five or more red blood cells were seen per high power field on the microscopic examination of urine.
Hypertension was defined a blood pressure documented as >95th percentile for height, based on Task Force recommendations.Citation6
Hypocomplementemia was defined as serum C3 level <0.8 mg/l or/and C4 level <0.12 mg/l.
Tubulointerstitial damage (TD) was defined as mild and severe. Mild was evaluated <25% and severe was >25% tubulointerstitial damage in biopsy specimen.
Renal failure (RF) was defined as estimated glomerular filtration rate <90 mL/min/1.73 m2. Estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) was calculated from the Schwartz formula.Citation7
Chronic kidney disease (CKD) was defined as eGFR <90 mL/min/1.73 m2 for more than 3 months.Citation8
End-stage renal disease (ESRD) was defined as eGFR <15 mL/min/1.73 m2 or commencement of renal replacement therapy.
Complete remission (CR) was accepted as proteinuria <4 mg/m2/h, serum albumin level >3 g/dL and normal serum creatinine level (Screa).
Partial remission (PR) was defined as proteinuria reduction of 50% or greater from the presenting value and absolute proteinuria 4–40 mg/m2/h.
Statistical analysis
We analyzed the data with SPSS for Windows 11.5 software package program (Chicago, IL) and expressed data as mean ± standard deviation. In comparison of two independent groups, Fisher's Exact test was chosen. We preferred Spearman's correlation coefficient test to evaluate the relation between two variable results and considered a “p” value <0.05 as statistically significant.
Results
Thirty-three patients were identified (13 female and 20 male) in this study. Their ages at presentation ranged from 4 to 15 years (10.53 ± 3.08). They were followed for 26 to 144 months (mean 74 months). Electron microscopy was performed to just eight patients; one of the patients was found Tip 3 and others were Tip 1 MPGN. Thirteen patients (39%) had consanguinity of their parents, and three patients (9%) had a similar renal disease history in other family members.
Presentation features
shows features of the patients at presentation. Initially, hematuria (100%) was observed in all of the patients. Thirteen patients (39.4%) had macroscopic hematuria. The second most common presentation finding was nephrotic syndrome; which was determined in 23 (69.7%) patients. Non-nephrotic range proteinuria was found in seven (21.2%) patients. Of the 19 (57.5%) children with hypocomplementemia, 14 had isolated low serum concentration of C3, five had low serum C3 and C4 together. Eighteen (54.5%) cases were hypertensive and nine (27.2%) had RF at presentation.
Table 1. The features of the patients at presentation.
Renal biopsy findings
The diagnosis in all patients was proven by renal biopsy. On light microscopy, diffuse mesangial hypercellularity, increase of mesangial matrix, thickening of the peripheral GBM and lobular appearance were detected in all patients. Seven patients (21%) had globally sclerosed glomeruli. Tubulointerstitial damage was determined in 14 patients (42.4%) (mild damage in eight and severe in six). Ten patients (30.3%) had crescents (crescent ratio >50% in two patients and <50% in eight patients). On IF microscopy; C3 deposits in 27, IgG deposits in 21 and IgM deposits in eight patients were detected. Both C3 and IgG deposits were observed in 19 patients. Seven patients in whom electron microscopic examination could be performed were determined as MPGN Type 1 and one was Type 2.
Treatment regimens
The details of all patients including demographic and presentation features, treatment regimens and prognosis are illustrated in . At presentation, 23 patients had NS and 10 patients had NNP. Eight of the 23 patients with NS and one of the 10 patients with NNP had RF at presentation. All the patients with NS and one patient with NNP and RF were given pulse methyl-prednisolone (PMP) (30 mg/kg for three days, monthly) at presentation and continued 1–6 months due to their outcome. All patients were treated with oral prednisolone (P) (initial dose 2 mg/kg/day, max. 60 mg/day, later in tapering doses every other day for a lengthy period) after the pulse therapy. All patients were given angiotensin converting enzyme inhibitor (ACEI).
Table 2. The demographic features, presentation findings, treatment regimens and prognosis of the patients.
Nine patients with NNP were given only ACEI at presentation, while only one patient with NNP could achieve complete remission. Five patients developed NS, therefore treated by oral P. Three patients developed NS and RF during the follow-up period and they were given PMP and oral P.
The five patients who developed RF during the follow-up period and one patient who persisted as NS were also given other immunosuppressive treatments – cyclophosphamide (n = 4) (2 mg/kg/day, for 2–3 months), cyclosporine (n = 1) (3–5 mg/kg/day) and mycophenolate mofetil (n = 1) (1200 mg/m2/day) (). However, there was no change in their outcome.
In the following period, 12 cases relapsed (nine patients one relapse, two patients two relapses, one patient three relapses) under the low-dose alternate day oral P treatment. All relapses were treated with PMP and tapering doses of alternate day oral P for a lengthy period; and all patients achieved complete or partial remission.
Prognosis
Of the 15 patients who had only NS at admission, 13 developed complete (n = 8) or partial (n = 5) remission, one patient persisted as NS and one patient reached CKD. The eight patients who had NS and RF at admission developed complete (n = 7) or partial (n = 1) remission; none ongoing to CKD. In contrast, of the 10 patients who had NNP (one had also RF) at admission, six developed remission (five CR, one PR) and four went to CKD. At the end of the follow-up period, 20 patients (60.6%) achieved CR, seven patients (21.2%) achieved PR, one patient (3%) persisted as NS and five patients (15.2%) went to CKD (). When the patients with CKD were classified according to their GFR, three patients were in Stage 3, one in Stage 4 and one in Stage 5 (ESRD); and the latest patient underwent renal transplantation.
Table 3. The prognosis of the patients.
Age and sex
There were no statistical differences in renal survival when analyzed by age. However, CKD was determined more frequently in girls than boys. In the group of patients with CKD, four cases were girl and one case was boy (p = 0.05).
Hypertension
In 15 (74%) of the patients who had hypertension at presentation, remission was achieved while three (16%) of them was CKD (p=0.85). There were no statistical differences between two groups. We did not specify any effect of hypertension at presentation on the renal survival.
Hypocomplementemia
We realized that four out of the five patients with CKD had low complement. However, 14 (52%) patients with good prognosis had low complement C3. There was no statistically significant difference in renal survival between those with normal serum complement concentration at presentation compared with those with low complement concentration (p=0.25).
Renal failure
The four patients out of five progressed to CKD who had not renal failure findings at presentation. There was no significant difference in renal survival between those with initial renal failure and those with normal renal function (p=0.65).
Tubulointerstitial damage
The 12 patients had TD at the initial biopsy specimen. Eight (66%) of the cases achieved complete remission, while four (33%) progressed to CKD. On the other hand, one of 13 patients progressed to CKD (7%) who had not TD at initial biopsy. Four (80%) of five patients with CKD had TD at the presentation. There were significant differences between the remission and the CKD group about TD in the initial biopsy (p = 0.038).
The cases were determined as group with severe or mild TD according to first biopsy. Three (75%) out of four patients progressed to CKD had severe TD. Only one (25%) patient with CKD did not have severe. We had just five patients who progressed to CKD; therefore, we did not use statistical analysis. The percent values were evaluated for the prognosis of patients with TD.
Immunosuppressive treatment
Total of six cases was used to immunosuppressive treatment on the side of the steroid. All of them could not inhibit progressing to CKD. In this study, there were five patients who progressed to CKD. All of these patients were used to immunosuppressive treatment (cyclophosphamide was used in four patients, cyclosporine was used for one and mycophenolate mofetil was used for one), because these cases relapsed or did not respond to steroid therapy.
Discussion
MPGN is specifically characterized by functional impairment of the glomerular basement membrane causing progressive loss of renal function, which eventually results in end-stage kidney disease.Citation9 MPGN mainly affects teenagers and adolescents. Children with MPGN have an unfavorable prognosis and typically develop ESRD during late childhood or early adolescence.Citation10,Citation11 The frequency of primary MPGN in childhood is 5–8% among causes of primary nephrotic syndrome.Citation5,Citation6,Citation12 In the past decade, understanding of the role of complement system in the pathogenesis of MPGN has illuminated the field and led to a paradigm shift in classification.Citation13 According to this classification, a glomerulonephritis with C3 staining alone with intra-membranous highly electron-dense deposits on electron microscopy suggests Tip 2 MPGN (dense deposit disease – DDD).Citation13,Citation14 Glomerular deposits of C3 alone, without immunoglobulin, are the hallmark of alternative complement pathway dysregulation through inherited or acquired defects. These forms are called as C3 glomerulopathy.Citation13
Primary MPGN is a rare disease and affects patients in late childhood. Therefore, the follow-up time of these patients in pediatric clinics is limited. At present, there have been few studies about treatment of childhood MPGN and most of them were uncontrolled. The place of immunosuppressive therapy in the childhood MPGN treatment is not exactly known. In this paper, our experiences about childhood primary MPGN were reported.
In our study, mainly one feature predicted an adverse outcome: severe chronic tubulointerstitial damage on the initial biopsy. We found that neither the severity of proteinuria nor the renal failure at presentation have a significant effect on the prognosis.
Thirteen girls and 20 boys were recruited in our study. There were more boys than girls; however, four of five patients who were progressing to CKD at the end were female. Although the member numbers of the two groups were scarce, the difference was found statistically significant.
According to this study, we found that chronic renal TD is a useful indicator for the prediction of the outcome. Except the one, all of the patients who had severe TD reached CKD (n = 4). This finding was similar to the previous reports.Citation15,Citation16
In the literature, Cansick et al.Citation16 reported that nephrotic syndrome at presentation is associated with a poor prognosis; this relation was previously published by Schwertz et al.Citation11 and Somers et al.,Citation17 as well. However, according to Cansick et al., the degree of proteinuria of patients without nephrotic syndrome did not predict the outcome. In our study, non-nephrotic proteinuria group consisted of seven patients, three of them developed CKD, although only one of 23 patients with nephrotic syndrome progressed into CKD. Therefore, we could not correlate between severity of proteinuria and patients who had diminished eGFR at the end.
It is reported that renal dysfunction and hypertension at onset were associated with poor prognosis.Citation18 In the present study, we observed that renal dysfunction and hypertension at the presentation have no effect on prognosis. According to a more currently published study by Cansick et al.,Citation16 impaired eGFR at the onset may or may not indicate structural disease and was not a prognostic indicator.
In childhood MPGN treatment strategy, the place of the steroid therapy is not controversial. Evidence-based controlled trials recommend the use of high-dose steroid regimes for children presenting with nephrotic proteinuria and/or renal dysfunction.Citation19 On the other hand, the length of the steroid therapy, preference of pulse or oral steroids, when to add a second immunosuppressive drug are not yet clear. We prefer the recurrent doses of pulse steroid therapy for children presented with severe proteinuria and/or renal impairment. In our case series, 15% of the patients progressed to CKD and 3% to ESRD, respectively. In the literature, approximately 40% of patients progress to ESRD within 10 years of diagnosis.Citation20 Our follow-up duration was 26–144 months (mean 74 months). Therefore, we conclude that if this period was longer, then the proportion of our patients ongoing to CKD might increase.
We usually prefer recurrent doses of pulse steroid therapy as an initial treatment of childhood MPGN. If a relapse occurred in a patient who was known as good-responsive to steroids, we repeated pulse steroids. We believe that using early and high-dose steroid therapies might have positive effect on our low CKD percentages. On the other hand, we used to apply immunosuppressive treatments (cyclophosphamide, cyclosporine, mycophenolate mofetil) if patient did not respond to or relapsed while using high dose steroids. None of the five patients benefitted from immunosuppressant treatments. These cases were unresponsive to treatment and then progressed to CKD. During the course of the study, we assessed the records of the patients, most of which belonged to previous periods. Hence, we did not have the chance to re-evaluate. Therefore, we speculate that the underlying pathology of these five cases might be with MPGN Type II of C3 nephropathy. Undoubtedly, if we had electron microscopic definition for all of the patients, our study would be more informative.
We concluded that neither the severity of proteinuria nor the renal failure at presentation had a significant effect on the prognosis. According to our study, the only parameter determinative for prognosis of childhood MPGN is the presence of tubulointerstitial damage on the initial biopsy. We suggest that if steroid therapy would be used earlier at high dosages, it can be more successful. However, we could not demonstrate any additional effect of immunosuppressant drugs on MPGN. We believe that, there is need for more extensive and controlled studies that would include both adult and children patients. On the light of these studies, patients with MPGN might be sufficiently treated and considering side-effects of immunosuppressant drugs, unnecessary usage would be avoided.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Kher V, Gulati S. Mesangiocapillary glomerulonephritis. Oxford Textbook of Clinical Nephrology. 3rd ed. Oxford: Oxford University Press; 2005
- Alchi B, Jayne D. Membranoproliferative glomerulonephritis. Pediatr Nephrol. 2010;25:1409–1418
- Nakopoulou L. Membranoproliferative glomerulonephritis. Nephrol Dial Transplant. 2001;16(Suppl 6):71–73
- Orth SR, Ritz E. The nephrotic syndrome. N Engl J Med. 1998;338:1202–1211
- Iitaka K, Nakamura S, Moriya S, et al. Hypocomplementemia and membranoproliferative glomerulonephritis in children. Clin Exp Nephrol. 2005;9:31–33
- Safaei A, Maleknejad S. Spectrum of childhood nephrotic syndrome in Iran: A single center study. Indian J Nephrol. 2009;19:87–90
- National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114:555–576
- Schwartz GJ, Haycock GB, Edelmann Jr CM, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976;58(2):259–263
- West CD, McAdams AJ, McConville JM, Davis NC, Holland NH. Hypocomplementemic and normocomplementemic persistent (chronic) glomerulonephritis: Clinical and pathologic characteristics. J Pediatr. 1965;67:1089–1112
- Wei C-C, Wang W, Smoyer WE, Licht C. Trends in pediatric primary membranoproliferative glomerulonephritis costs and complications. Pediatr Nephrol. 2012;27:2243–2250
- Schwertz R, De Jong R, Gretz N, Kirschfink M, Anders D, Scharer K. Outcome of idiopathic membranoproliferative glomerulonephritis in children. Acta Pediatr. 1996;85:308–312
- Asinobi AO, Gbadegesin RA, Adeyemo AA, et al. The predominance of membranoproliferative glomerulonephritis in childhood nephrotic syndrome in Ibadan, Nigeria. West Afr J Med. 1999;18:203–206
- D'Agati VD, Bomback AS. C3 glomerulopathy: What's in a name? Kidney Int. 2012;82(4):379–381
- Bomback AS, Appel GB. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol. 2012;8(11):634–642
- Schmitt H, Bohle A, Reineke T, Mayer-Eichberger D, Vogl W. Long-term prognosis of membranoproliferative glomerulonephritis type 1. Nephron. 1990;55:242–250
- Cansick JC, Lennon R, Cummins CL, et al. Prognosis, treatment and outcome of childhood mesangiocapillary (membranoproliferative) glomerulonephritis. Nephrol Dial Transplant. 2004;19(11):2769–2777
- Somers M, Kertesz S, Rosen S, et al. Non-nephrotic children with membranoproliferative glomerulonephritis: Are steroids indicated? Pediatr Nephrol. 1995;9(2):140–144
- Donadio JV, Holley KE. Membranoproliferative glomerulonephritis. Semin Nephrol. 1982;2:204–209
- Levin A. Management of membranoproliferative glomerulonephritis: Evidence-based recommendations. Kidney Int. 1999;55(Suppl 70):41–46
- Alchi B, Jayne D. Membranoproliferative glomerulonephritis. Pediatr Nephrol. 2010;25:1409–1418