Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network.

BACKGROUND: Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation. METHODS: In this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20). RESULTS: Eleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective. CONCLUSIONS: These data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.

Recurrent Membranoproliferative Glomerulonephritis After Kidney Transplantation: Risk Factors and Impact on Graft Survival.

BACKGROUND Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of end-stage renal disease (ESRD). Recurrence rates after transplantation range from 11.8% to 18.9% after 5 and 15 years, respectively. This study aimed to assess the risk factors of MPGN recurrence after kidney transplantation and its impact on graft survival. MATERIAL AND METHODS This was a single-center retrospective cohort, including renal transplant recipients older than 18 years, with a diagnosis of MPGN in native kidneys. Data were obtained from medical records during the first 5-year post-transplant follow-up. Primary endpoints were graft function and survival. Secondary endpoints were MPGN recurrence risk factors and these cases' clinical, laboratory, and histological features. RESULTS Twenty-eight patients were included; the majority male (60.7%), with a mean age of 24.0±9.4 years. At MPGN native diagnosis, all patients presented proteinuria, with C3 consumption in 42.9%. Histological analysis showed 13 (42.9%) MPGN type I and 5 (17.9%) type II, with no cases of type III. MPGN recurrence occurred in 7 (25.0%) patients; 85.7% were male, 57.1% were recipients from a living donor, all presenting nephrotic syndrome and hematuria, with C3 consumption in 71.4%. The graft function was similar between the groups. Two (28.6%) patients progressed to graft failure in the recurrence group, and 1 died with a functioning graft. CONCLUSIONS The MPGN recurrence rate was 25%, most of them recipients of kidneys from living donors. Nephrotic syndrome and C3 consumption were frequent at recurrence. The graft function was similar between the groups, and the 5-year graft survival rate in the recurrence group was higher than in other studies.

Recurrence of membranoproliferative glomerulonephritis post transplant - Is this mere recurrence of pattern or recurrence of disease?

Recurrence of membranoproliferative glomerulonephritis (MPGN) is seen in 1965% cases of postrenal transplant resulting in graft loss in up to 35-50% of cases. A 31-year-old female, after 1% years on maintenance hemodialysis, underwent ABO compatible deceased donor kidney transplantation with basiliximab induction. During the immediate posttransplant period, the patient had delayed graft function, but achieved nadir creatinine of 0.9 mg/dL by 10 days. Nine months posttransplant, the patient developed fever, anasarca, and decrease in urine output with albuminuria 3+, active sediments in urine, serum creatinine 3.5 mg/dL, 24-h urine protein 7.5 g, and low C3. The patient underwent graft biopsy. Subsequently, the patient received pulse steroid for three days and five sessions of plasmapheresis. Renal biopsy report was suggestive of MPGN with focal crescents and acute tubular necrosis. Immunofluorescence showed Ig G3+, C3 3+, к 3+, and negative for λ or other immunoglobulins or complements. As her native kidney disease was immune-complex-mediated MPGN with no light chain restriction, paraffin tissue of the native kidney was reexamined for light chain restrictions by immunoperoxidase method, but did not show light chain restriction. The patient underwent extensive workup for paraproteinemias, but results were negative. Subsequently, she received four doses of bortezomib. The patient's serum creatinine got reduced to 0.8 mg/dL and proteinuria reduced to 800 mg/day. Our case is unique as we were not able to demonstrate monoclonal deposits in native kidney sample although there was recurrence of MPGN with monoclonal light chain deposits post transplant. Our findings emphasize the need for thorough evaluation of paraproteinemias in patients with idiopathic MPGN even in the absence of light chain deposition in biopsy.

Kidney Transplantation in C3 Glomerulopathy: A Case Series.

RATIONALE & OBJECTIVE: C3 glomerulopathy (C3G), a form of glomerulonephritis associated with dysregulation of the alternative complement pathway, occurs either as dense deposit disease (DDD) or C3 glomerulonephritis (C3GN). Few studies have reported outcomes of patients with C3G after transplantation since its formal classification and the advent of complement-targeting therapies such as eculizumab. STUDY DESIGN: Case series of C3G. SETTING & PARTICIPANTS: We reviewed laboratory testing, native and allograft biopsy reports, and clinical charts of the 19 patients (12, C3GN; and 7, DDD) from our C3G registry who underwent transplantation between 1999 and 2016. RESULTS: During a median follow-up of 76 months, 16 patients had recurrent disease (10 of 12, C3GN; and 6 of 7, DDD), with median time to recurrence of 14 months in C3GN versus 15 months in DDD. Graft failure was more frequent in patients with DDD (6 of 7) than in patients with C3GN (3 of 12), occurred at a median time of 42 months posttransplantation, and was attributed to recurrent disease in half the failures. A rare genetic variant or autoantibody associated with alternative complement pathway abnormalities was detected in 9 of 10 screened patients. Treatment of 7 patients (8 allografts) with eculizumab was associated with variable clinical outcomes. LIMITATIONS: Incomplete testing for complement pathway abnormalities and genetic defects, incomplete records of HLA antigen matching, lack of centralized biopsy review, and limited sample size. CONCLUSIONS: In a case series of C3G transplant recipients, the proportion of disease recurrence was high in both C3GN and DDD, although graft loss appeared to occur more frequently in DDD. In a small subset of study patients, eculizumab therapy was not consistently followed by salutary outcomes.

A long history of dense deposit disease.

BACKGROUND: Dense Deposit Disease is a rare condition affecting the Bruch's membrane and the glomerular basement membrane. We report the progression of the ocular manifestations over a 30 year follow up period, longer than any previous report. CASE PRESENTATION: A 44 year old male presented with pigmentary changes at the macula noted by his optician. Best corrected visual acuity at presentation was good in both eyes. Fundoscopy showed pigmentary changes and drusen, and investigation using intravenous fundus fluorescein angiography did not demonstrate any choroidal neovascular membrane. The patient subsequently developed renal failure and received a dual renal transplant. The transplanted kidneys also failed over the coming year. The patient's vision gradually deteriorated and comparison between the images in 2010 and 1985 demonstrated a clear progression of the macula changes. Optical coherence tomography showed multiple subretinal hyper reflective drusenoid deposits. These deposits were also noted to be autofluorescent on blue auto-fluorescence. The young age at presentation of drusen, combined with the history of recurrent kidney failure and progression of subretinal deposits led to a diagnosis of dense deposit disease. CONCLUSIONS: Dense deposit disease is a rare condition affecting Bruch's membrane, but should be considered in the differential diagnosis of any patient under the age of 50 years presenting with drusen.

Clinicopathological analysis of proliferative glomerulonephritis with monoclonal IgG deposits in 5 renal allografts.

BACKGROUND: We present a case series of 5 patients with proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) of renal allografts to better define its natural history, presenting characteristics, pathological features and treatment outcome. RESULTS: These 5 patients presented 5 to 19 months post-kidney transplantation for complaints of serum creatinine (Scr) elevation, proteinuria or hematuria. Membranoproliferative glomerulonephritis (MPGN) pattern was the most frequently observed histological manifestation. Immunofluorescence showed monoclonal IgG3κin 3 patients and IgG3λ in the other 2 cases. Immunofluorescence staining helped to establish PGNMID in the absence of conspicuous microscopic changes in one case. Rituximab and bortezomib were effective in alleviating proteinuria in all 4 treated patients and decreasing Scr in 2 cases. Plasmapheresis treatment in another patient was not effective in preventing Scr elevation. At last-follow-up, 2 patients were in dialysis and 2 had improved kidney function with almost normal Scr and no proteinuria. The remaining one patient died of pulmonary infections. CONCLUSIONS: We conclude that PGNMID occurs early after kidney transplant. PGNMID should be included in the differential diagnoses of recurrent MPGN in renal allografts. Rituximab and bortezomib are helpful to decrease proteinuria and Scr in a subset of patients. Larger studies are needed to conclusively establish best treatment strategies for PGNMID in renal allografts.

A case of recurrent proliferative glomerulonephritis with monoclonal IgG deposits or de novo C3 glomerulonephritis after kidney transplantation.

Proliferative glomerulonephritis with monoclonal immunoglobulin (Ig)G deposits (PGNMID) is a rare disease with a treatment that is not well established. Several cases of recurrent PGNMID after kidney transplantation have been documented, but almost all cases reported symptoms such as elevated serum creatinine and/or urinary protein levels; subsequently, episode biopsies were performed and a diagnosis was made. This is the case of a 27-year-old man who underwent living-donor kidney transplantation. The aetiology of renal failure was membranoproliferative glomerulonephritis type III, which had been diagnosed at the age of 9 years. Protocol biopsy performed on postoperative day 62 revealed isolated granular C3 deposits in the glomerular capillaries and mesangium. We reviewed the native kidney biopsy and confirmed IgG3 deposition alone, with strong glomerular staining for lambda light chains and negative staining for kappa light chains. Accordingly, we re-diagnosed the aetiology of his renal failure as PGNMID and suspected recurrent PGNMID in the early stage; therefore, we administered plasma exchange therapy. Thereafter, protocol biopsies were performed twice, which revealed persistent isolated C3 deposition; therefore, we made a diagnosis of recurrent PGNMID or C3 glomerulonephritis. Currently, the patient has normal renal function, with negative urine findings for >1 year. Here, we present the histological findings of consecutive allograft biopsies performed in this patient.

Early recurrence of proliferative glomerulonephritis with monoclonal immunoglobulin deposits in a renal allograft.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMIDs) is a clinico-pathologic entity, the recurrence of which in the renal allograft has only recently been described. A 55-year-old male presented with rapid deterioration of renal function. Light microscopy showed membranoproliferative glomerulonephritis with kappa light chain restriction and only one sub-class of IgG. He subsequently underwent renal transplant. Two months later, he developed acute graft dysfunction. Renal biopsy showed a recurrence of the disease. Work up for multiple myeloma was positive. Membranoproliferative pattern of injury in the posttransplant setting has a wide range of differential diagnosis, PGNMID being one of them.

Membranoproliferative glomerulonephritis recurrence after kidney transplantation: using the new classification.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is an uncommon glomerular disorder that may lead to end stage renal disease (ESRD). With new understanding of the disease pathogenesis, the classical classification as MPGN types I, II, III has changed. Data on post-transplant MPGN, in particular with the newly refined classification, is limited. We present our center's experience of MPGN after kidney transplantation using the new classification. METHODS: This is a retrospective study of 34 patients with ESRD due to MPGN who received 40 kidney transplants between 1994 and 2014. We reviewed the available biopsies' data using the new classification. We assessed post transplantation recurrence rate, risk factors of recurrence, the response to therapy and allografts' survival. RESULTS: Median time of follow up was 5.3 years (range 0.5-14 years). Using the new classification, we found that pre-transplant MPGN disease was due to immune complex-mediated glomerulonephritis (ICGN) in 89 % of cases and complement-mediated glomerulonephritis (CGN) in 11 %. Recurrence was detected in 18 transplants (45 %). Living related allografts (P = 0.045), preemptive transplantations (P = 0.018), low complement level (P = 0.006), and the presence of monoclonal gammopathy (P = 0.010) were associated with higher recurrence rate in ICGN cases. Half of the patients with recurrence lost their allografts. The use of ACEi/ARB was associated with a trend toward less allograft loss. CONCLUSIONS: MPGN recurs at a high rate after kidney transplantation. The risk of MPGN recurrence increases with preemptive transplantation, living related donation, low complement level, and the presence of monoclonal gammopathy. Recurrence of MPGN leads to allograft failure in half of the cases.

Recurrent Glomerulonephritis in Renal Transplantation: Experience in Our Renal Transplantation Center.

BACKGROUND: Post-transplant recurrent glomerulonephritis (RGN) is the third cause of graft failure in the first year after renal transplantation (RT). The purpose of this study was to analyze the incidence of RGN, clinical presentation, and clinical evolution of transplanted renal graft in patients who underwent RT at our center. METHODS: We studied patients with glomerulonephritis (GN) who underwent RT (2007 to 2013).We analyzed sex, age, time in dialysis, type of GN, type of RT, time to post-transplant RGN, kidney function at the time of diagnosis of RGN, and renal graft evolution. Renal biopsy samples were processed in the anatomic pathology laboratory. RESULTS: Three hundred sixteen patients received kidney transplantation during this time period. In 83 cases, the reason for transplantation was primary GN. Of these 83 patients, 15 (18%) had RGN confirmed by renal biopsy. Data for these 15 patients include sex: 73.3% men, 26.7% women; mean age: 42.2 (29-73) years; type of RT: 80% cadaveric donor (CD) versus 20% living donor (LD); type of GN: 18.4% immunoglobulin (Ig)A nephropathy, 35.7% membranous GN, 10.53% type I membrano-proliferative GN (MPGN I), and 16.6% focal segmental glomerular sclerosis (FSGS). The mean time to post-transplant RGN was 2 years (1 month to 16 years). Patients who received an LD transplant had a shorter time to post-transplant RGN than those who had a CD transplant. One patient with FSGS and one with MPGN I had a time to post-transplant RGN of less than 1 year. In the evolution of renal function, 33.3% of patients had graft failure. CONCLUSIONS: The incidence of RGN was lower (18%) than that published in the literature. Membranous nephropathy was the most frequent cause of post-transplant RGN. Patients who underwent LD transplantation and those with IgA nephropathy had a shorter interval of time to post-transplant RGN than patients with FSGS and MPGN I.

Treatment-resistant recurrent membranoproliferative glomerulonephritis in renal allograft responding to rituximab: case report.

We report a case of idiopathic membranoproliferative glomerulonephritis (MPGN) recurring 2 years after a living-unrelated kidney transplantation. The disease was refractory to intravenous immunoglobulin and plasmapheresis. Treatment with 2 doses of rituximab resulted in remission of the disease. The disease relapsed 18 months later after an episode of cytomegalovirus pneumonitis. After treatment of the pneumonitis, a lung biopsy was performed owing to persistent chest symptoms, which revealed bronchiolitis obliterans with organizing pneumonia. Bone marrow examination and culture revealed presence of acid-fast bacilli, and culture grew Mycobacterium tuberculosis. A repeated course of rituximab was withheld because of infection with tuberculosis, the patient's chest symptoms, and rare reports of noninfectious lung disease after the use of rituximab. The patient continues to have proteinuria with impaired kidney function.

Recurrent Proliferative Glomerulonephritis With Monoclonal IgG Deposits After a Renal Transplant Which Was Insensitive to Pulse Therapy Remitted by Double Filtration Plasmapheresis.

Proliferative glomerulonephritis with monoclonal IgG deposits manifesting as a nephrotic syndrome recently has been described as a renal disease with the pathological features of mesangial and subendothelial deposits of monoclonal IgG. Eight cases of recurrent proliferative glomerulonephritis with monoclonal IgG deposits after a renal transplant have been reported. Almost all of these patients had a certain remission of proteinuria by steroids alone or with cyclophosphamide, and had further remission through other special treatments (ie, rituximab and plasmapheresis). We present a case of recurrent proliferative glomerulonephritis with monoclonal IgG deposits of the IgG3? subtype after a renal transplant, which was insensitive to pulse intravenous methyl-prednisolone and cyclophosphamide remitted by double filtration plasmapheresis. This case report reveals that recurrent proliferative glomerulo-nephritis with monoclonal IgG deposits may be insensitive to intravenous pulse therapy of methylprednisolone and cyclophosphamide. We advocate double filtration plasmapheresis as an effective treatment of proliferative glomerulo-nephritis with monoclonal IgG deposits on remission of proteinuria.

Clinical findings, pathology, and outcomes of C3GN after kidney transplantation.

C3 glomerulonephritis (C3GN) results from abnormalities in the alternative pathway of complement, and it is characterized by deposition of C3 with absent or scant Ig deposition. In many patients, C3GN progresses to ESRD. The clinical features, pathology, and outcomes of patients with C3GN receiving kidney transplantation are unknown. Between 1996 and 2010, we identified 21 patients at our institution who received a kidney transplant because of ESRD from C3GN. The median age at the time of initial diagnosis of C3GN at kidney biopsy was 20.8 years. The median time from native kidney biopsy to dialysis or transplantation was 42.3 months. Of 21 patients, 14 (66.7%) patients developed recurrent C3GN in the allograft. The median time to recurrence of disease was 28 months. Graft failure occurred in 50% of patients with recurrent C3GN, with a median time of 77 months to graft failure post-transplantation. The remaining 50% of patients had functioning grafts, with a median follow-up of 73.9 months. The majority of patients had hematuria and proteinuria at time of recurrence. Three (21%) patients were positive for monoclonal gammopathy and had a faster rate of recurrence and graft loss. Kidney biopsy at the time of recurrence showed mesangial proliferative GN in eight patients and membranoproliferative GN in six patients. All allograft kidney biopsies showed bright C3 staining (2-3+), with six biopsies also showing trace/1+ staining for IgM and/or IgG. To summarize, C3GN recurs in 66.7% of patients, and one half of the patients experience graft failure caused by recurrence.

Recurrent membranoproliferative glomerulonephritis after second renal graft treated with plasmapheresis and rituximab.

We present a case of a 45-year-old man who suffered from idiopatic membranoproliferative glomerulonephritis (MPGN) in the native kidney that relapsed after his first and second renal grafts. The patient was diagnosed in 1990 with lobular MPGN type I, receiving his first renal graft in 1996. In 2001, a biopsy showed recurrence of MPGN type I (rMPGN). He underwent a second renal graft in 2008. In January 2010, he experienced increased proteinuria and creatinine. Upon electron microscopy of a renal graft biopsy we diagnosed a new rMPGN. At the time of the biopsy, complement levels were normal, although C3 and C4 decreased further. We administered 12 plasmapheresis (PP) sessions and four doses of rituximab. Due to persistent renal impairment, we performed a new biopsy 3 months later, showing less severity of the acute lessions. He received a new cycle of treatment (PP+rituximab). One year later, his renal function was stable with a creatinine ranging between 2 and 2.5 mg/dL and a protein/creatinine ratio less than 1 mg/mg. We concluded that the treatment stopped the disease progression.

Allograft failure in kidney transplant recipients with membranoproliferative glomerulonephritis.

BACKGROUND: Membranoproliferative glomerulonephritis types I (MPGN-I) and II (MPGN-II) are rare diseases that in limited case series have been reported to recur frequently in kidney transplants and have a negative impact on allograft survival. STUDY DESIGN: Retrospective database review. SETTING & PARTICIPANTS: 189,211 primary kidney transplants in the United Network for Organ Sharing (UNOS) database from September 1987 to May 2007. PREDICTOR OR FACTOR: MPGN-I (811 patients; 0.4%), MPGN-II (179 patients; 0.1%), other GN (58,129 patients; 30.7%), and all other diagnoses (130,092 patients; 68.7%). OUTCOMES: Death-censored and non-death-censored allograft survival. RESULTS: Compared with controls, patients with MPGN-I and MPGN-II were significantly younger at the time of transplant, with a median age of 36 and 27 years compared with 44 years in the GN group and 46 years in all other disease groups, respectively (all P < 0.001). Mortality in patients with MPGN-I (8.8%) was significantly lower compared with the GN (11.3%; P = 0.02) and other disease (16.6%; P < 0.001) populations and lower in those with MPGN-II (9.5%) compared with the other disease (16.6%; P = 0.01) population. Graft failure rates were significantly higher in the MPGN-I (44.5%) cohort, but not in the MPGN-II (45.3%) cohort compared with the GN (38.0%) population (P < 0.001 and P = 0.05, respectively); neither MPGN cohort differed from the other disease (43.0%) population (P = 0.4 and P = 0.5). Overall, 10-year death-censored graft survival was similar for MPGN-I (56.2%) and MPGN-II (57.5%); both were significantly worse than for GN (65.2%; P < 0.001 and P = 0.003, respectively), and only MPGN-I was significantly worse than the other disease (60.0%) population (P = 0.004). Of allograft failures with a reported cause, disease recurrence was the primary cause in 36 (14.5%) MPGN-I and 18 (29.5%) MPGN-II transplant recipients and was significantly higher compared with 879 (6.6%) GN and 1,319 (4.4%) all-other-disease recurrence failures (P < 0.001). LIMITATIONS: Limited pretransplant clinical and biopsy data. CONCLUSIONS: A diagnosis of MPGN-I or MPGN-II has a significant negative impact on overall primary allograft survival compared with other forms of glomerulonephritis, whereas only MPGN-I has a significant, but modest, negative effect compared with other causes of end-stage renal disease.

Recurrent membranoproliferative glomerulonephritis after kidney transplantation.

On examination of the records of 1321 patients following kidney transplant over an 11-year period, we found that 29 patients had recurrent membranoproliferative glomerulonephritis (MPGN). We excluded from this analysis patients who had MPGN type II, those with clear evidence of secondary MPGN, and those lacking post-transplant biopsies. During an average of 53 months of follow-up, we found using protocol biopsies that 12 of these patients had recurrent MPGN diagnosed 1 week to 14 months post-transplant. In 4 of the 12 patients this presented clinically, whereas the remaining had subclinical disease. The risk of recurrence was significantly increased in patients with low complement levels. Serum monoclonal proteins were found in a total of six patients; appeared to be associated with earlier, more aggressive disease; and were more common in recurrent than non-recurrent disease. The recurrence of MPGN was marginally higher in recipients of living-donor kidneys. Some patients developed characteristic lesions within 2 months post-transplant, whereas others presented with minimal, atypical histological changes that progressed to MPGN. Of 29 patients, 5 lost their allograft and 2 patients remain on chronic plasmapheresis. Our study shows the risk of MPGN recurrence and progression depends on identifiable pretransplant characteristics, has variable clinical impact, and can result in graft failure.