Recurrence of Membranoproliferative Glomerulonephritis Type II in Renal Allografts: The North American Pediatric Renal Transplant Cooperative Study Experience
Michael C. Braun*,
Don M. Stablein,
Lorraine A. Hamiwka,
Lorraine Bell,
Sharon M. Bartosh|| and
C. Frederic Strife¶
* The Brown Foundation Institute of Molecular Medicine and the Department of Pediatrics, Division of Pediatric Nephrology and Hypertension, University of Texas Health Science Center at Houston, Houston, Texas; The EMMES Corporation, Rockville, Maryland; Division of Pediatric Nephrology, Alberta Children’s Hospital University of Calgary, Calgary, Alberta, Canada; Montreal Children’s Hospital, McGill University Heath Centre, Department of Pediatrics, Division of Pediatric Nephrology, Montreal, Quebec, Canada; || Department of Pediatrics, University of Wisconsin, University of Wisconsin Children’s Hospital, Madison, Wisconsin; and ¶ Department of Pediatrics, Division of Nephrology and Hypertension, University of Cincinnati College of Medicine, and The Children’s Hospital Research Foundation, Cincinnati, Ohio
Address correspondence to: Dr. Michael C. Braun, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 2121 W. Holcombe Boulevard, Houston, TX 77030. Phone: 713-500-2438; Fax: 713-500-2424; E-mail: michael.c.braun{at}uth.tmc.edu
Received for publication February 16, 2005.
Accepted for publication March 28, 2005.
Membranoproliferative glomerulonephritis type II (MPGN II) isan uncommon form of complement-dependent acquired renal disease.Although it has been recognized since the 1970s that MPGN IIrecurs almost universally in renal transplants, data regardingthe long-term consequences of disease recurrence are limited.Therefore, a retrospective comparative analysis of 75 patientswith MPGN II contained in the North American Pediatric RenalTransplant Cooperative Study transplantation database was performed.Five-year graft survival for patients with MPGN II was significantlyworse (50.0 ± 7.5%) compared with the database as a whole(74.3 ± 0.6%; P < 0.001). Living related donor organshad a significantly better 5-yr survival (65.9 ± 10.7%)compared with cadaveric donor organs (34.1 ± 9.8%; P= 0.004). The primary cause of graft failure in 11 (14.7%) patientswas recurrent disease. Supplemental surveys were obtained on29 (38%) of 75 patients. Analysis of these data indicated thatrecurrent disease occurred in 12 (67%) of the 18 patients withposttransplantation biopsies. Although there was no correlationbetween pretransplantation presentation, pre- or posttransplantationC3 levels, and either disease recurrence or graft failure, therewas a strong association between heavy proteinuria and diseaserecurrence. The presence of glomerular crescents in allograftbiopsies had a significant negative correlation with graft survival.At last follow-up, patients with recurrent disease had significantlyhigher serum creatinine and qualitatively more proteinuria thanpatients without biopsy-proven disease. These data indicatethat recurrent MPGN II has a significant negative impact onrenal allograft function and survival.
Membranoproliferative glomerulonephritis type II (MPGN II) isan uncommon form of chronic renal disease characterized by persistentsystemic hypocomplementemia, glomerular C3 deposition, and abundantdense deposits within the lamina densa of the glomerular basementmembrane (GBM) (1). Since the original characterization of thisdisease by Habib in 1975, little progress has been achievedwith respect to the pathogenesis and the treatment of this disorder(2). Results of therapeutic trials using corticosteroids, immunosuppressiveagents, or antiplatelet therapy have been disappointing (1,3).Despite major advances in our ability to slow the progressionof many forms of chronic renal injury, the clinical course ofMPGN II remains one of slow deterioration, with 50% of patientsdeveloping ESRD within 10 yr of diagnosis (1,4). Renal transplantationremains the final therapeutic option for the majority of patientswith MPGN II. However, MPGN II has been reported to recur in18 to 100% of renal allografts, depending on the criteria usedto define recurrence, and rates of graft failure as a resultof disease recurrence have ranged from 0 to 100% (5,6). Currently,there are fewer than 170 reported cases of renal transplantsin adults and children with MPGN II (2,4–27). Most reportsare limited in terms of samples size, with the most recent caseseries in 1999 containing fewer than one dozen patients (26).Detailed information is available on fewer than half of thereported patients, and long-term follow-up data are surprisinglysparse. Although the almost invariable recurrence of dense depositsin renal allografts is not disputed, the impact of the recurrenceof these deposits on graft survival is uncertain. To investigatethe impact of disease recurrence in a large population of pediatricrenal transplant patients, we analyzed the North American PediatricRenal Transplant Cooperative Study (NAPRTCS) database with respectto overall graft survival and obtained supplemental data surveysto identify potential predictors of disease recurrence.
The NAPRTCS database (1985 to 2002) was queried for individualswho had biopsy-proven MPGN II. Data including age, gender, ethnicity,age at transplantation, cadaveric (CAD) versus living-relateddonor (LRD) source, type of immunosuppression, graft survival,duration of dialysis, and cause of graft failure were analyzedin comparison with the NAPRTCS database as a whole.
Supplemental questionnaires were sent to all centers that wereidentified as having a patient with MPGN II contained withinthe NAPRTCS database. The centers were asked to provide additionalinformation regarding (1) original presentation, (2) immediatepretransplantation features, (3) posttransplantation course,(4) and status at most recent follow-up. The information requestedincluded age, height, weight, serum albumin, creatinine, C3concentrations, nephritic factor, degree of hematuria and proteinuria,clinical features (asymptomatic hematuria or proteinuria, acuteglomerulonephritis, nephrotic syndrome, or rapidly progressiveglomerulonephritis), the presence of hypertension, treatmentand/or immunosuppression, and biopsy findings. For the purposesof this study, disease recurrence was defined solely on thebasis of electron dense deposits within the GBM. In addition,a comprehensive search of electronic databases as well as manualreviews of references from published manuscripts, review articles,and textbooks were performed to identify reports of individualswho had MPGN II and underwent renal transplantation. Data regardinggraft survival and length of follow-up were abstracted and collated.
Statistical Analyses
Data were analyzed using SAS and SPSS software. Survival analysiswas performed using log-rank analysis. Distribution and frequencyof variables was analyzed by either 2 analysis or Fisher exacttest when appropriate. Comparisons between groups were performedusing the t test, Pearson correlation statistics, and the log-ranktest. P < 0.05 was assumed to be statistically significant.The studies contained in this report were approved by the Children’sHospital Medical Center Institutional Review Board.
Seventy-five primary renal allografts in patients with MPGNII were identified within the NAPRTCS database. Demographicdata are presented in Table 1. As a group, MPGN II patientsdid not differ from the database as a whole with respect togender, ethnicity, or donor source. They were, as expected,older, with 58% being older than 12 yr compared with 45% ofthe database (P = 0.03). There was no significant differencein donor source. Supplemental surveys were received on 29 patients(response rate of 39%). There were no significant differencesin terms of demographic data comparing the responding groupwith the entire MPGN II population contained in the database(Table 1). That a significant number of patients had been transferredto adult transplant centers for care, and medical records datingback several decades were no longer accessible had a negativeimpact on the overall response rate.
Table 1. Demographic data for primary renal allografts from the NAPRTCS database, MPGN II patients contained within the database, and MPGN II patients with supplemental survey informationa
Initial Presentation and Management (Survey Population)
The clinical features of the survey population at the initialpretransplantation diagnosis of MPGN II are presented in Table 2.Mean age at initial presentation was 10.4 ± 0.6 yr.Most patients had a significant reduction in renal functionwith a mean serum creatinine of 2.7 ± 0.5 mg/dl and anestimated GFR of 62.4 ± 10.7 ml/min uncorrected. Serumalbumin concentrations were also reduced, with a mean of 2.6± 0.2 g/dl. Hypocomplementemia was present at the timeof diagnosis in 95% of patients with a mean serum C3 level of50.4 ± 9.0 mg/dl. Severe depression of C3 levels (<20mg/dl) was present in 20% of patients. Renal biopsies at thetime of initial diagnosis were indicative of severe renal injury.Glomerular injury was particularly pronounced. Moderate to severemesangial proliferation was noted in 65% of biopsies. Some degreeof global sclerosis was present in half of the biopsies, with20% having >20% global sclerosis. Most prominent, however,was the severity of crescentic disease, which was noted in 70%of biopsies, with >50% of patients having >50% glomerularcrescents. Interstitial fibrosis was unusual, with <15% havingmore than moderate fibrosis; however, 45% had moderate to severeinterstitial infiltrates.
Table 2. Clinical features at initial pretransplantation presentation of MPGN II patients in the survey group (data available on 25 of 29 patients)
The disease in these patients’ native kidneys was treatedby a variety of therapeutic regimens. Steroids were given to92% of patients in a number of different modalities: 62.5% receivedpulse methylprednisolone (mean number of pulses 3.9 ±07; range 2 to 10) in combination with either daily or alternate-dayoral prednisone, cyclophosphamide was given to 17% of patients,two patients were treated with alternate-day prednisone alone,two patients were treated with antihypertensive therapy alone,and a single patient was treated with daily prednisone. Choiceof therapy had little impact on renal survival, with a meantime from diagnosis to transplantation of 3.4 ± 0.6 yr.
Graft Survival
On the basis of the NAPRTCS database, the number of primarytransplants for MPGN II was evenly distributed during the 16-yrstudy period, with an average of 2.7 patients per year. Theproportion of CAD or LRD renal transplants did not vary significantlywithin 5-yr cohorts during the study period (Figure 1). Themean follow-up times for the 5-yr cohorts 1987 to 1992, 1993to 1997, and 1998 to 2003 were 56, 42, and 23 mo, respectively.There were no statistically significant intracohort differencesfor duration of follow-up between LRD and CAD organ recipients.With regard to graft survival, differences in 10-yr survivalwere difficult to analyze given the limited number of patientsavailable for analysis; only one patient had follow-up >9yr. However, there was a significant difference in graft survivalat 5 yr (Figure 2A). In comparison with the database as a whole,renal allografts in patients with MPGN II had significantlyworse survival at 5 yr: 74.3 ± 0.6% compared with 50.0± 7.5%, respectively (P < 0.001). Allograft survivalof patients with MPGN II was significantly worse than that ofother patients with a primary diagnosis of glomerulonephritiscontained in the NAPRTCS database (Figure 2B). The 5-yr survivalof non–MPGN II glomerulonephritis transplants (n = 852)was 80.8% for LRD and 71.1% for CAD donors (P = 0.003). Of the165 renal transplants performed in individuals with MPGN IIreported in the literature, data on graft survival and lengthof follow-up were available on 78 (4,5,8,9,11–15,17–26).The 45 ± 2.0% 5-yr graft survival in this populationwas not significantly different from that seen in the MPGN IIpatients contained in the NAPRTCS database (Figure 3).
Figure 1. The distribution of cadaveric (CAD) and living-related donor (LRD) renal transplants for membranoproliferative glomerulonephritis type II (MPGN II) contained in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database (n = 75). Data are stratified by 5-yr cohorts for the period 1987 to 2003.
Figure 2. Allograft survival in MPGN II recipients. Overall graft survival was significantly worse for MPGN II patients. Five-year allograft survival (A) was 50.0 ± 7.5% for MPGN II recipients compared with 74.3 ± 0.6% for the NAPRTCS registry as a whole (P = 0.001, log rank). In comparison with MPGN II patients, as a group, registry patients with a primary diagnosis of glomerulonephritis had a significantly better 5-yr survival (B): 72.1 ± 0.8% (n = 852, P = 0.003).
Figure 3. NAPRTCS MPGN II graft survival in comparison with the reported literature. The 5-yr graft survival of 45 ± 2.0%, derived from previously published MPGN II cases (n = 78), did not differ significantly from the 50 ± 7.5% 5-yr survival seen in the NAPRTCS MPGN II group (P > 0.05, log rank).
When graft survival of the NAPRTCS database was analyzed bydonor source, there was a clear difference in survival (Figure 4).Patients who had MPGN II and received CAD allografts hada 5-yr graft survival of 34.1 ± 9.8% compared with 65.9± 10.7% graft survival of LRD allografts (P = 0.004).Comparison of LRD graft survival in MPGN II patients and thedatabase as a whole indicates that that there was little differencein LRD survival (65.9 ± 10.7% versus 81.0 ± 0.7%,respectively; P > 0.05).
Figure 4. Comparison of MPGN II allograft survival by donor source. In patients with a primary diagnosis of MPGN II, 5-yr allograft survival for CAD organs, 34.1 ± 9.8%, was significantly worse than the 65.9 ± 10.7% survival seen for LRD organs (P < 0.005, log rank).
During the study period, 29 of the 75 primary MPGN II allograftscontained in the database failed (Table 3). In comparison withthe database as a whole, there were no significant differencesin causes of graft loss with the exception of disease recurrence(P < 0.05). Disease recurrences exceeded chronic allograftnephropathy by three-fold as a cause of graft failure. Of the75 primary transplants, 11 (14.7%) were lost as a result ofdisease recurrence, with a mean time to graft failure of 823± 188 d (range 6 to 2170 d). When analyzed by donor source,82% (9 of 11) of the failures caused by recurrence occurredin CAD allografts compared with 18% (2 of 11) in the LRD group(P < 0.01). There was no difference in frequency of recurrencewith respect to ethnicity, gender, or age. Although the meanduration of pretransplantation dialysis was shorter in the LRDpopulation than the CAD recipients, 14 and 24 mo, respectively,this difference was not statistically significant. Durationof pretransplantation dialysis did not correlate with graftsurvival (P = 0.6).
Table 3. Comparison of causes of primary graft failures between NAPRTCS database as a whole and the MPGN II patients within the database
One living unrelated donor transplant was performed and wasstill functioning 21 mo later at the time of last follow-up.Seven preemptive transplants were performed; three have failedas a result of posttransplant lymphoproliferative disorder,chronic rejection, and unknown reasons. The four remaining graftswere functioning at the time of last follow-up, 11, 11, 85,and 108 mo posttransplantation.
Five repeat renal transplants were identified in five individuals.The causes of initial graft failure were primary nonfunction,graft thrombosis, hemolytic uremic syndrome, recurrent disease,and recurrent urinary tract infections. Three of the five graftswere functioning at last follow-up. The recipients of the tworemaining grafts had died; one individual with hemolytic uremicsyndrome–related initial graft failure had significantgraft dysfunction from recurrent MPGN II in the second graftat the time of his death, and the other individual died witha functional graft.
Analysis of MPGN II Recurrence in the Survey Population
Recurrence data for the survey population are presented in Table 4.Graft loss was attributed directly to disease recurrencein four patients—30.7% of the patients with biopsy-provenrecurrence, or slightly less than 14% of the survey population.Although the presence of biopsy-proven recurrence had a negativeimpact on graft survival, with a median graft survival in therecurrence group of 5.4 yr compared with 9.7 yr in patientswithout biopsy-proven disease, this did not reach the levelof statistical significance (P = 0.09).
Table 4. MPGN II disease recurrence within the survey population (n = 29)
Reported indications for biopsy at the time of recurrence werepossible acute rejection in 55% of patients, suspected recurrencein 22%, and scheduled surveillance biopsies in 11%. The remainderhad no indication reported. Biopsy findings at the time of recurrencedid not correlate with biopsy findings at the time of initialpretransplantation diagnosis. The severity of mesangial proliferationwas typically less than that seen at pretransplantation diagnosisin all patients with disease recurrence. Only three patientswere noted to have moderate to severe mesangial proliferation.One patient had marked glomerular sclerosis (60%), and one patienthad severe crescentic disease (40% glomerular crescents). Nopatient had significant evidence of tubulointerstitial disease.Concurrent pathology was noted in three patients: two had evidenceof acute rejection, and one patient had evidence of chronicrejection. Multiple biopsies were available on five patientswith recurrent disease ranging from 3 mo to 4 yr after the initialbiopsy. Glomerular sclerosis was found in four of the five patientswith serial biopsies with from 10 to 50% of the glomeruli affected.This did not differ significantly from the severity of glomerularsclerosis noted in biopsies of patients without evidence ofdisease recurrence (data not shown). Serial biopsies from threepatients were found to have crescentic glomerular lesions, twowith >40% affected glomeruli. The presence of glomerularcrescents in the allograft biopsy had a negative correlationwith graft survival and were never seen in biopsies of patientswithout evidence of MPGN II recurrence (R = –0.541, P= 0.03).
At the time of biopsy, patients with biopsy-proven disease recurrencehad evidence of significant renal dysfunction: mean serum creatinineconcentration 2.8 ± 0.7 mg/dl and heavy proteinuria witha median value of 3+ by urine dipstick. Whereas microscopichematuria was equally common in those with or without biopsy-provenrecurrent disease, heavy proteinuria was exceedingly uncommonin patients without biopsy-proven recurrence. Worsening of hypertensionwas reported in <30% of patients with recurrence, and serumalbumin levels were almost universally normal (mean serum albumin3.5 ± 0.2 g/dl). Serum C3 levels were reported as normalin 37.5% of patients at the time of biopsy-proven disease recurrence.There was no correlation between the severity of hypocomplementemiaeither at initial presentation or at the time of transplantationand disease recurrence (Table 5). Nephritic factor assays werenot routinely performed either pre or posttransplantation, exceptin two instances in which they were reported as negative.
Table 5. Relative frequencies of clinical parameters in the survey population for patients with biopsy-proven recurrence compared with those without evidence of disease recurrence
Treatment for disease recurrence varied substantially. At thetime of recurrence, all patients were on calcineurin inhibitorsas part of their immunosuppression regimen. Cyclosporine wasstopped in one patient, three patients were switched from cyclosporineto tacrolimus, and two patients had tacrolimus discontinued.The remainder had the dose of calcineurin inhibitor reduced.Oral prednisone was increased in six patients, two were changedto alternate-day prednisone, and four patients were treatedwith pulse methylprednisolone. Two of the four patients whowere treated with pulse methylprednisolone experienced graftfailure as a result of disease recurrence. Two patients weretreated with plasmapheresis; in both cases, the grafts eventuallyfailed as a result of disease recurrence. Overall, patientswith biopsy-proven MPGN II recurrence had significantly worserenal function at the time of last follow-up than patients withoutevidence of disease recurrence; they had heavier proteinuria,with 75% having 3+ compared with 92% of those without recurrencewith trace or less (P < 0.001). Patients with biopsy-provenrecurrence also had more severe renal insufficiency, with amean serum creatinine of 4.8 ± 1.3 mg/dl compared with1.9 ± 0.4 mg/dl in those without recurrence (P = 0.025).
This study represents the largest single case series of renaltransplantation in patients with MPGN II and serves to highlightthe difficulties that the transplant physician who cares forthese patients faces. Although the data provided by the surveypopulation represents the largest and most detailed analysisavailable to date on renal transplantation in MPGN II, becauseof the small sample size and the possibility of confoundingeffects from unmeasured variables, these data must be viewedwith caution. Findings contained in this report indicate thatthe overall allograft survival in patients with MPGN II is significantlyworse compared with a well-defined contemporaneous control groupof pediatric renal transplant recipients, with a 5-yr allograftsurvival rate of only 50% compared with nearly 75% in the controlpopulation. There has been considerable debate over the useof LRD as an organ source for transplantation in MPGN II, andit has been suggested that cadaveric sources be used preferentially.However, in this study, fewer than 40% of cadaveric organs werefunctioning 5 yr posttransplantation compared with 65% in thedatabase as a whole, whereas there was no statistical differencein graft survival for LRD organs. These data strongly suggestthat LRD organs have a significant long-term survival advantagecompared with CAD organs. The basis for this is uncertain; however,it is possible that abnormalities in the recipient’s complementsystem, which initiate the primary disease, are acceleratedby the increased immunoreactivity of a cadaveric renal allograft.Activation of the complement system has been well describedin both acute and chronic allograft rejection, and recent studieslinking low levels of chronic complement activation to the developmentof chronic allograft nephropathy support this hypothesis, althoughthis remains speculative at best (28–30). It is importantto recognize that this study does not address the impact ofgenetic deficiencies in complement proteins on disease recurrence.This is particularly relevant with respect to Factor H deficiencyand MPGN II. The use of LRD in this subset of MPGN II patientsis still of major concern, and further studies are requiredto address this critical question (31–33).
Supplemental survey data indicate that patients who had MPGNII and underwent renal transplantation as children had a muchmore rapid progression to ESRD than that typically cited inthe literature (1). Historically, 50% of patients with MPGNII will progress to ESRD within 10 yr of diagnosis (4). However,within the current study population, the mean interval fromdiagnosis to transplantation was <4 yr. The biopsy findingsat the time of initial pretransplant presentation suggest thatmost, if not all, of the patients contained in this study hadevidence of severe renal injury, with >70% of the patientshaving crescentic lesions at the time of initial diagnosis.Given that the mean age at presentation was slightly less than11 yr, patients who presented with milder disease likely progressedto ESRD in early adulthood and thus are not contained in theNAPRTCS database. Although it could be argued that this representsan inherent selection bias toward patients who are at increasedrisk for graft loss as a result of recurrence, several linesof evidence suggest that this is not true. First, there wasno correlation between biopsy findings at the time of initialdiagnosis and either graft loss as a result of disease recurrenceor graft survival. Second, the graft survival data derived fromprevious published reports of MPGN II allografts, which representa largely adult population, are almost identical to those seenin the pediatric population contained in this study. This suggeststhat the poor outcome seen in the NAPRTCS population is representativeof the MPGN II population as a whole and not limited to pediatrictransplantation alone. In distinction to these data is the reportby Briganti et al. (27). In a comprehensive analysis of recurrentglomerulonephritis in the ANZDATA transplantation database,they reported no graft losses as a result of recurrent MPGNII in a cohort of 18 patients. However, because of the smallsample size, details regarding donor source and length of follow-upwere not described. Overall, in this report, recurrent diseasewas the third most common cause of graft failure after chronicrejection and death, with a 10-yr incidence of failure as aresult of recurrent disease of 8.4%.
In this study, the frequency of graft failure directly attributableto disease recurrence was 15% at 5 yr. This indicates that graftfailure as a result of recurrent disease is a much greater problemin the MPGN II population than in other forms of glomerulonephritis.The higher failure rate is in agreement with previous reportsby Andresdottir and others (24,26). Consistent with previousreports, the histologic findings at the time of biopsy-provenrecurrence were variable, ranging from isolated dense depositswithin the GBM to marked mesangial proliferation to crescenticglomerular lesions. There was no clear correlation between biopsyfindings and graft survival with the exception of glomerularcrescents, which had a significant negative correlation withgraft survival. The data obtained from serial biopsies indicatethat there is progression from isolated GBM deposits to severeglomerular injury in some patients. The lack of correlationbetween isolated recurrence of the defining lesion of MPGN II,dense deposits, and graft survival is one of the critical findingscontained in this study. This suggests that there is a subsetof patients with MPGN II in whom the finding of isolated recurrenceof dense deposits does not herald impending graft failure.
Analysis of clinical variables failed to identify clinicallyuseful predictors of disease recurrence or graft loss. It hadbeen suggested that patients who presented initially with rapidlyprogressive glomerulonephritis or nephrotic syndrome were atan increased risk for graft failure as a result of disease recurrence.However, analysis of these clinical features at initial presentationas well as the severity of renal insufficiency and degree ofhypocomplementemia failed to predict graft failure as a resultof disease recurrence or graft survival. In fact, patients whopresented with asymptomatic disease were more likely to havebiopsy-proven recurrence than those whose initial presentationincluded rapidly progressive glomerulonephritis or nephroticsyndrome. The utility of serum complement levels to predictor reflect disease recurrence has been much debated. Early reportssuggested that persistence of hypocomplementemia was associatedwith disease recurrence; however, later reports by Droz andMuller failed to confirm this association (25,34,35). In thisstudy, there was no correlation between C3 levels pre or posttransplantationand either graft survival or the presence of disease recurrence.More than one third of patients with biopsy-proven disease recurrencehad normal C3 levels at the time of biopsy. These data confirmthat hypocomplementemia in and of itself is of little utilityin predicting disease recurrence. One surprising finding fromthe survey data was the lack of nephritic factor data. Althoughthere is strong evidence linking the development of MPGN IIto the presence of circulating nephritic factor, only two patientshad nephritic factor levels reported (both negative). This maybe due to the difficulty in obtaining nephritic factor levelsoutside the research laboratory, and thus its ability to predictrecurrence remains largely untested. The only clinical variablethat was present consistently in patients with biopsy-provenrecurrence was heavy proteinuria.
Data from the supplemental surveys also highlight the heterogeneityof therapeutic interventions for recurrent disease. Given thelack of data regarding the efficacy of any therapy for MPGNII pretransplantation, it is not surprising that the treatmentof recurrent MPGN II in allografts was so individualized. Therehave been very few published reports on the treatment of recurrentMPGN II. Successful plasmapheresis has been reported for thetreatment of MPGN II recurrence; however, there are no long-termdata on graft survival after plasmapheresis, and thus is itdifficult to evaluate the impact of this intervention (36,37).Plasmapheresis was used in two patients in this study, bothof whom ultimately lost their grafts. Although there is evidencethat patients with Factor H deficiency may benefit from plasmapheresis,there currently are few data regarding its use in patients posttransplantation(33,38–40). Given the heterogeneous nature of the choiceof therapies and that only four of 13 patients who had biopsy-provenrecurrence in the survey group experienced graft loss as a resultof their primary disease, it was impossible to determine whetherany of these interventions had any impact on graft survival.
Taken together, the data contained in this report indicate thatrenal transplantation in patients with MPGN II should be undertakenwith caution. Patients and families should be counseled regardingthe poor overall graft survival, regardless of whether diseaserecurs, and that there seems to be an advantage with respectto graft survival for LRD allografts compared with CAD organs.At present, there do not seem to be any clear predictors ofdisease recurrence or prognostic markers for graft survival,save for the presence of persistent heavy proteinuria. Finally,should MPGN II recur in the allograft, there are few data tosuggest that any therapeutic interventions will have a positiveimpact on graft survival save for isolated reports of plasmapheresis,for which there are few long-term outcome data.
Acknowledgments
This study was supported by a grant from the KIDNEEDS Foundation(Iowa City, Iowa).
We thank the NAPRTCS centers that provided the supplementaldata for this study, NAPRTCS, and Dr. Clark West for adviceand critical review of the manuscript.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
West CD: Idiopathic membranoproliferative glomerulonephritis in childhood.
Pediatr Nephrol 6
: 96
–103, 1992[CrossRef][Medline]
Habib R, Gubler MC, Loirat C, Ben Maiz H, Levy M: Dense deposit disease. A variant of membranoproliferative glomerulonephritis.
Kidney Int 7
: 204
, 1975[Medline]
Donadio JV Jr, Offord KP: Reassessment of treatment results in membranoproliferative glomerulonephritis, with emphasis on life-table analysis.
Am J Kidney Dis 14
: 445
–451, 1989[Medline]
Cameron JS, Turner DR, Heaton J, Williams DG, Ogg CS, Chantler C, Haycock GB, Hicks J: Idiopathic mesangiocapillary glomerulonephritis: Comparison of types I and II in children and adults and long-term prognosis.
Am J Med 74
: 175
–192, 1983[CrossRef][Medline]
Droz D, Nabarra B, Noel LH, Leibowitch J, Crosnier J: Recurrence of dense deposits in transplanted kidneys: I. Sequential lesions.
Kidney Int 15
: 386
–395, 1979[Medline]
Briner J: Glomerular lesions in renal allografts.
Adv Intern Med Pediatr 49
: 1
–76, 1982
Galle P, Mahieu P: Electron dense alteration of the kidney basement membranes.
Am J Med 58
: 749
–764, 1975[CrossRef][Medline]
Mathew TH, Mathews DC, Hobbs JB, Kincaid-Smith P: Glomerular lesions after renal transplantation.
Am J Med 59
: 177
–190, 1975[CrossRef][Medline]
Berthoux F, Ducret F, Colon S, Blanc-Brunat N, Zech PY, Traeger J: Renal transplantation in mesangioproliferative glomerulonephritis (MPGN): Relationship between the high frequency of recurrent glomerulonephritis and hypocomplementemia.
Kidney Int Suppl 7
: 323
–327, 1975
Turner DR, Cameron JS, Bewick M, Sharpstone P, Melcher D, Ogg CS, Evans DJ, Trafford AJ, Leibowitz: Transplantation in mesangiocapillary glomerulonephritis with intramembranous dense "deposits": Recurrence of disease.
Kidney Int 9
: 439
–448, 1976[Medline]
Beaufils H, Gubler MC, Karam J, Gluckman JC, Legrain M, Kuss R: Dense deposit disease: Long term follow-up of three cases of recurrence after transplantation.
Clin Nephrol 7
: 31
–37, 1977[Medline]
Hamburger J, Crosnier J, Noel LH: Recurrent glomerulonephritis after renal transplantation.
Annu Rev Med 29
: 67
–72, 1978[CrossRef][Medline]
Davis AE, Schneeberger EE, Grupe WE, McCluskey RT: Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children.
Clin Nephrol 9
: 184
–193, 1978[Medline]
Jukkola AF, Mantaring T, Roy S, Murphy WM: Recurrent dense deposit disease in renal allograft.
Urology 11
: 395
–397, 1978[CrossRef][Medline]
Curtis JJ, Wyatt RJ, Bhathena D, Lucas BA, Holland NH, Luke RG: Renal transplantation for patients with type I and type II membranoproliferative glomerulonephritis.
Am J Med 66
: 216
–225, 1979[CrossRef][Medline]
Morzycka M, Croker BP, Seigler HF, Tisher CC: Evaluation of recurrent glomerulonephritis in kidney allografts.
Am J Med 72
: 588
–598, 1982[CrossRef][Medline]
Eddy A, Sibley R, Mauer SM, Kim Y: Renal allograft failure due to recurrent dense intramembranous deposit disease.
Clin Nephrol 21
: 305
–313, 1984[Medline]
Habib R, Antignac C, Hinglais N, Gagnadoux MF, Broyer M: Glomerular lesions in the transplanted kidney.
Am J Kidney Dis 10
: 198
–207, 1987[Medline]
Moritz MJ, Burke JF, Jarrell BE, Carabasi RA: The incidence of membranoproliferative glomerulonephritis in renal allografts.
Transplant Proc 19
: 2206
–2207, 1987[Medline]
O’Meara Y, Green A, Carmody M, Donohoe J, Campbell E, Browne O, Walshe J: Recurrent glomerulonephritis in renal transplants: Fourteen years’ experience.
Nephrol Dial Transplant 4
: 730
–734, 1989[Abstract/Free Full Text]
Bennett WM, Fassett RG, Walker RG, Fairley KF, d’Apice AJ, Kincaid-Smith P: Mesangiocapillary glomerulonephritis type II (dense-deposit disease): Clinical features of progressive disease.
Am J Kidney Dis 13
: 469
–476, 1989[Medline]
Vangelista A, Frasca GM, Martella D, Bonomini V: Glomerulonephritis in renal transplantation.
Nephrol Dial Transplant 1
: 42
–46, 1990
Broyer M, Selwood N, Brunner F: Recurrence of primary renal disease on kidney graft: A European pediatric experience.
J Am Soc Nephrol 2[Suppl]
: S255
–S257, 1992
Muller T, Sikora P, Offner G, Hoyer PF, Brodehl J: Recurrence of renal disease after kidney transplantation in children: 24 years of experience in a single center.
Clin Nephrol 49
: 82
–90, 1998[Medline]
Andresdottir MB, Assmann KJ, Hoitsma AJ, Koene RA, Wetzels JF: Renal transplantation in patients with dense deposit disease: Morphological characteristics of recurrent disease and clinical outcome.
Nephrol Dial Transplant 14
: 1723
–1731, 1999[Abstract/Free Full Text]
Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ: Risk of renal allograft loss from recurrent glomerulonephritis.
N Engl J Med 347
: 103
–109, 2002[Abstract/Free Full Text]
Fearon DT, Daha TB, Weiler JM, Carpenter CB, Austen KF: Pathways of complement activation in membranoproliferative glomerulonephritis and allograft rejection.
Transplant Proc 9
: 729
–739, 1977[Medline]
Sijpkens YW, Joosten SA, Wong MC, Dekker FW, Benediktsson H, Bajema IM, Bruijn JA, Paul LC: Immunologic risk factors and glomerular C4d deposits in chronic transplant glomerulopathy.
Kidney Int 65
: 2409
–2418, 2004[CrossRef][Medline]
Mauiyyedi S, Pelle PD, Saidman S, Collins AB, Pascual M, Tolkoff-Rubin NE, Williams WW, Cosimi AA, Schneeberger EE, Colvin RB: Chronic humoral rejection: Identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries.
J Am Soc Nephrol 12
: 574
–582, 2001[Abstract/Free Full Text]
Loirat C, Niaudet P: The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children.
Pediatr Nephrol 18
: 1095
–1101, 2003[CrossRef][Medline]
Donne RL, Abbs I, Barany P, Elinder CG, Little M, Conlon P, Goodship TH: Recurrence of hemolytic uremic syndrome after live related renal transplantation associated with subsequent de novo disease in the donor.
Am J Kidney Dis 40
: E22
, 2002[CrossRef][Medline]
. Watanabe S, Yamaguchi Y, Suzuki T, Ikezoe M, Matsumoto N, Chikamoto H, Nagafuchi H, Horita S, Hattori M, Shiraga H, Tokumoto T, Tanabe K, Toma H, Ito K: Inherited factor H dysfunction and complement-associated glomerulonephritis in renal grafts of first and second transplantations.
Clin Transplant 15[Suppl 5]
: 45
–50, 2001
Mclean RH, Geiger H, Burke B, Simmons R, Najarian J, Vernier RL, Michael AF: Recurrence of membranoproliferative glomerulonephritis following kidney transplantation: Serum complement component studies.
Am J Med 60
: 60
–72, 1976[CrossRef][Medline]
Leibowitch J, Halbwachs L, Wattel S, Gaillard MH, Droz D: Recurrence of dense deposits in transplanted kidney: II. serum complement and nephritic factor profiles.
Kidney Int 15
: 396
–403, 1979[Medline]
Fremeaux-Bacchi V, Weiss L, Brun P, Kazatchkine MD: Selective disappearance of C3NeF IgG autoantibody in the plasma of a patient with membranoproliferative glomerulonephritis following renal transplantation.
Nephrol Dial Transplant 9
: 811
–814, 1994[Abstract/Free Full Text]
Kurtz KA, Schlueter AJ: Management of membranoproliferative glomerulonephritis type II with plasmapheresis.
J Clin Apheresis 17
: 135
–137, 2002[CrossRef][Medline]
Gerber A, Kirchhoff-Moradpour AH, Obieglo S, Brandis M, Kirschfink M, Zipfel PF, Goodship JA, Zimmerhackl LB: Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality.
Pediatr Nephrol 18
: 952
–955, 2003[CrossRef][Medline]
Taylor CM: Hemolytic-uremic syndrome and complement factor H deficiency: Clinical aspects.
Semin Thromb Haemost 27
: 185
–190, 2001[CrossRef][Medline]
Received for publication February 16, 2005.
Accepted for publication March 28, 2005.
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Top
Abstract
Introduction
2 analysis or Fisher exact test when appropriate. Comparisons between groups were performed using the t test, Pearson correlation statistics, and the log-rank test. P < 0.05 was assumed to be statistically significant. The studies contained in this report were approved by the Children’s Hospital Medical Center Institutional Review Board. 
