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Mycophenolate Mofetil in Combination with Steroids for Treatment of C3 Glomerulopathy: A Case Series
Abstract
Background and objectives:
C3 glomerulopathy is a form of complement-mediated GN. Immunosuppressive therapy may be beneficial in the treatment of C3 glomerulopathy. Mycophenolate mofetil is an attractive treatment option given its role in the treatment of other complement-mediated diseases and the results of the Spanish Group for the Study of Glomerular Diseases C3 Study. Here, we study the outcomes of patients with C3 glomerulopathy treated with steroids and mycophenolate mofetil.
Design, setting, participants, & measurements:
We conducted a retrospective chart review of patients in the C3 glomerulopathy registry at Columbia University and identified patients treated with mycophenolate mofetil for at least 3 months and follow-up for at least 1 year. We studied clinical, histologic, and genetic data for the whole group and compared data for those who achieved complete or partial remission (responders) with those who did not achieve remission (nonresponders). We compared remission with mycophenolate mofetil with remission with other immunosuppressive regimens.
Results:
We identified 30 patients who met inclusion criteria. Median age was 25 years old (interquartile range, 18-36), median creatinine was 1.07 mg/dl (interquartile range, 0.79-1.69), and median proteinuria was 3200 mg/g creatinine (interquartile range, 1720-6759). The median follow-up time was 32 months (interquartile range, 21-68). Twenty (67%) patients were classified as responders. There were no significant differences in baseline characteristics between responders and nonresponders, although initial proteinuria was lower (median 2468 mg/g creatinine) in responders compared with nonresponders (median 5000 mg/g creatinine) and soluble membrane attack complex levels were higher in responders compared with nonresponders. For those tapered off mycophenolate mofetil, relapse rate was 50%. Genome-wide analysis on complement genes was done, and in 12 patients, we found 18 variants predicted to be damaging. None of these variants were previously reported to be pathogenic. Mycophenolate mofetil with steroids outperformed other immunosuppressive regimens.
Conclusions:
Among patients who tolerated mycophenolate mofetil, combination therapy with steroids induced remission in 67% of this cohort. Heavier proteinuria at the start of therapy and lower soluble membrane attack complex levels were associated with treatment resistance.
... Die Therapie hängt in der Regel von der zugrundeliegenden Pathogenese ab (siehe unten). Neben einer ursachenspezifischen Therapie ist in manchen Fällen eine immunsuppressive Therapie indiziert [3][4][5][6], jedoch ist aufgrund der niedrigen Inzidenz, kleiner Patient:innenzahlen in wenigen prospektiven Studien und der Heterogenität dieser Patient:innenkohorten eine solide Therapieempfehlung nur schwer möglich. Aus diesen Gründen ist eine immunsuppressive Therapie immer individualisiert durchzuführen. ...
... Möglicherweise profitieren jedoch v. a. Patient:innen mit einer C3G auch bei niedrigerer Proteinurie (> 1 g/Tag) und einer Hämaturie von einer immunsuppressiven Therapie [17]. Diese Empfehlung basiert auf retrospektiven Kohorten und der Extrapolation von Daten von anderen proliferativen Glomerulonephritiden [5,6,18]. Kontrollierte Daten zur MPGN gibt es nicht. ...
... 2). Diese Empfehlungen basieren auf den Ergebnissen von 2 retrospektiven Studien zur C3G bei Erwachsenen, können jedoch auch für eine IK-GN angewandt werden [5,6]. In der Arbeit In 67-86 % der Fälle kommt es zu einer partiellen oder kompletten Remission, allerdings ist die Relapsrate nach Reduktion oder Absetzen von MMF relativ hoch (38-50 %). ...
Zusammenfassung
Die membranoproliferative Glomerulonephritis (MPGN) repräsentiert eine heterogene Gruppe von Erkrankungen. Das gemeinsame Merkmal eines membranoproliferativen Läsionsmusters in der Histologie der Nierenbiopsie kann sowohl idiopathisch/primär auftreten, als auch – wesentlich häufiger – eine sekundäre Ursache haben. Die historische licht- und elektronenmikroskopische Einteilung in MPGN Typ I bis III wurde weitgehend verlassen und in den letzten Jahren durch eine Pathogenese-orientierte Einteilung ersetzt. Von einer Immunkomplex-GN (IK-GN) spricht man beim Vorliegen einer MPGN mit C1q, C3 und/oder C4 Ablagerungen, während eine MPGN mit dominanten C3-Ablagerungen als C3-Glomerulopathie (C3G) bezeichnet wird. Diese wird wiederum in eine C3-Glomerulonephritis (C3GN) und eine dense-deposit disease (DDD) eingeteilt. Diese Diagnosen können nur durch eine Nierenbiopsie gestellt werden. Mögliche Ursachen für eine MPGN sind chronische Infektionen (v. a. Hepatitis B und C, bakterielle Infektionen, Infektionen mit Protozoen). Autoimmunerkrankungen (v. a. Lupus, rheumatoide Arthritis) oder Malignome (v. a. hämatologische maligne Erkrankungen). Insbesondere im Falle einer C3G wird auch eine umfassende Abklärung des Komplementystems empfohlen. Therapeutische Entscheidungen sind aufgrund der niedrigen Inzidenz und des heterogenen klinischen Erscheinungsbildes einer MPGN individuell zu treffen, eine optimale generelle Therapie ist unbekannt. Im Falle einer identifizierten Ursache einer MPGN wird prinzipiell empfohlen diese zu behandeln, ebenso sollte die supportive Therapie, wie auch bei anderen Glomerulonephritiden optimiert werden. Bei anhaltender signifikanter Proteinurie und einer eGFR > 30 ml/min/1,73 m ² wird eine Therapie mit systemischen Steroiden und Mycophenolat Mofetil empfohlen. Weitere Therapieoptionen sind Rituximab und Eculizumab. Eine rapid-progressive MPGN sollte wie eine ANCA-assoziierte Vaskulitis therapiert werden. Die Rekurrenzraten nach einer Nierentransplantation sind sehr hoch und therapeutisch herausfordernd.
... For instance, it is unclear the precise pathogenic mechanisms which lead to particular clinical phenotypes of the disease, nor is it clear why in some patients the disease develops earlier and with a more aggressive presentation (9). While several case series have described the potential benefit of corticosteroids plus mycophenolate mofetil (MMF) in C3 glomerulopathy (10,11), the underlying mechanisms of action of this immunosuppressive regimen and the reasons why some patients do not respond, whereas others do, are not completely understood (12). Thus, the scientific community awaits with great expectations the results of several ongoing trials, and the advances in the development of newer complement inhibitors targeting early components of the complement cascade (7,13). ...
... Proteinuria at the time of clinical diagnosis is a well-known determinant of kidney outcomes in C3 glomerulopathy (11,12,18,19). However, the longitudinal change in proteinuria during the follow-up and their impact in kidney prognosis has not extensively been analyzed. ...
... The amount of proteinuria at the time of clinical diagnosis has been shown to be an independent predictor of kidney failure in several previous cohorts of C3 glomerulopathy (11,12,18,19). In the study by Avasare et al, patients who did not respond to MMF exhibited higher baseline proteinuria and an increment in proteinuria was observed at last follow-up (11). ...
Introduction
The association between a change in proteinuria over time and its impact in kidney prognosis has not been analyzed in C3 glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure.
Methods
Retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modeling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure.
Results
The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13–41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥ 50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (HR: 0.79; 95% CI : 0.56–0.97; p < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up.
Conclusion
The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.
... For patients with proteinuria 1-2 g/day (children > 0.5 g/day) despite receiving optimized supportive therapy, treatment with mycophenolate mofetil (MMF) or mycophenolic acid analogs (combined with corticosteroids) is considered reasonable, especially with albuminuria increases over time and severe activity lesions in kidney biopsy. [177][178][179][180][181][182][183][184][185] While the mechanism of action is not known, MMF likely decreases glomerular inflammation rather than inhibiting C3NeF activity. As baseline proteinuria increases, the probability of an effect with MMF decreases. ...
... Some benefit from the use of calcineurin inhibitors has also been reported. [179][180][181][182][183][184][185] Currently, oral immunosuppressive agents are the mainstay of treatment for more severe forms of C3G and IC-MPGN for lack of proven alternatives. ...
... Treatment options include supportive therapy, immunosuppressives, and anti-complement treatments. The combination of corticosteroid and mycophenolate mofetil (MMF) is the most preferred treatment regimen and the e cacy of this regimen has been demonstrated in several studies [10,11]. Although there are limited data, some studies have suggested that individuals with pathogenic variants in complement genes have a less favorable response to treatment [7,12]. ...
... Although there are studies on the e cacy of MMF exposure in the treatment of C3 glomerulopathy [11,24,27], the number of studies investigating the e cacy of MMF in C3 glomerulopathy developed on genetic basis is very few [12]. Fontan et al [12] investigated whether corticosteroids plus MMF combination positively affect outcomes and disease progression in patients with genetically diagnosed or having complement regulatory factors. ...
Background
C3 glomerulopathy(C3G) is a complement-mediated disease caused by abnormalities in the alternative complement pathway. Although genetic studies are not required for diagnosis, they are valuable for treatment planning and prognosis prediction. The aim of this study is to investigate the clinical phenotypes, kidney survival, and response to MMF treatment in pediatric C3G patients with and without mutations in complement related genes.
Methods
Sixty pediatric C3G patients were included, divided into two groups based on complement related gene mutations. Demographic and clinical-pathological findings, treatment modalities, and outcome data were compared, and Kaplan-Meier analysis was performed for kidney survival.
Results
Out of the 60 patients, 17 had mutations, with the most common mutation in the CH gene (47%). The mean age at diagnosis was significantly higher in the group with mutation (12.9 ± 3.6 vs 11.2 ± 4.1 years p = 0.039). While the patients without mutation were most frequently presented with the nephritic syndrome (44.2%), patients with the mutation were most likely to have asymptomatic urinary abnormalities (%47.1, p = 0.043). Serum parameters and histopathological characteristics were similar between the groups, but hypoalbuminemia was more common in patients without mutation. During a 45-month follow-up,10 patients progressed to CKD5, with four having a genetic mutation. The time to develop CKD5 was longer in the mutation group but not significantly different. MMF treatment had no effect on C3G progression in either group.
Conclusions
This study is the largest pediatric study examining the relationship between genotype and phenotype in C3G. We showed that in the mutation group often presented with asymptomatic urinary abnormalities, were diagnosed relatively late, but were not different from the mutation group in terms of MMF treatment response and kidney survival.
... Казалось бы, иммуномодулирующая терапия должна быть эффективной в первую очередь для спорадических, аутоиммунных случаев пС3-ГП или при возможном их сочетании с генетическими факторами [11]. Вместе с тем при скудности данных об эффективности анти-В-клеточной терапии при С3-ГП [20] в отдельных сериях наблюдений на фоне неселективной ИСТ, а именно сочетания ММФ и ГКС, почечная выживаемость была достоверно выше у лиц с пС3-ГП [11,21]. Частота ремиссий при сочетании ММФ и ГКС достигала 67-80% и была выше, чем при других вари-антах лечения -ГКС (39%), ингибиторами кальциневрина (29%), ритуксимабом (29%) и ЦФ (33%) [11,21]. ...
... Вместе с тем при скудности данных об эффективности анти-В-клеточной терапии при С3-ГП [20] в отдельных сериях наблюдений на фоне неселективной ИСТ, а именно сочетания ММФ и ГКС, почечная выживаемость была достоверно выше у лиц с пС3-ГП [11,21]. Частота ремиссий при сочетании ММФ и ГКС достигала 67-80% и была выше, чем при других вари-антах лечения -ГКС (39%), ингибиторами кальциневрина (29%), ритуксимабом (29%) и ЦФ (33%) [11,21]. Эффект терапии при аутоиммунных формах заболевания был выше и с преобладанием полных ремиссий. ...
Aim. To analyze the outcomes of C3-glomerulopathy (C3-GP) and determine the associated factors.
Materials and methods. A retrospective single-center study included 60 patients with newly diagnosed C3-GP (with primary C3-GP pC3-GP 82%). Of these, 48 (80%) patients had clinical data to assess the following disease outcomes: development of remission and disease progression (by a composite endpoint that included initiation of chronic dialysis or a decrease in estimated glomerular filtration rate eGFR 15 mL/min/1.73 m2 or a decrease in eGFR30% of baseline at the time of renal biopsy). The median follow-up period was 25 (7; 52) months.
Results. At early follow-up (median 4 [3; 9] months) remission was registered in 35% of patients; at the end of follow-up, in 48% (for pC3-GP, 32 and 41%). Disease progression occurred in 17 patients. In the overall group the likelihood of achieving early remission was higher with treatment (Exp=6.4, 95% confidence interval CI 1.429.3; p=0.017). Early remission was associated with the presence of remission at the end of follow-up (Exp=6.3, 95% CI 2.218.4; p=0.001). Specific treatment (Exp=0.308, 95% CI 0.1080.881; p=0.028) and late remission (Exp=0.079, 95% CI 0.0170.368; p=0.001) were associated with reduced risk of disease progression in multivariable models (adjusted for eGFR, mean blood pressure). The same results were obtained for the group of patients with pC3-GP.
Conclusion. C3-GP is a variant of severe complement-mediated glomerular damage with unfavorable renal prognosis, which requires timely personalized expert-level diagnostics with clarification of etiopathogenesis of the disease followed by therapy aimed at achieving remission to improve outcomes.
... Her medication regimen was escalated to high-dose MMF monotherapy (3 g/day), based on previous data suggesting effectiveness in C3GN. 13,14 However, despite adequate medication adherence (assessed by patient's self-report) and tolerability, her proteinuria failed to improve, with a persistent UPCR of approximately 4 g and intermittent microscopic hematuria on urinalysis despite five months of MMF therapy. Therefore, rituximab 1000 mg (2 doses, 14 days apart) was added to her regimen. ...
... 10 Previous studies have demonstrated the efficacy of MMF in C3GN. 13,14 Although data on rituximab success in C3GN is limited, several case reports have shown efficacy, primarily when C3GN is mediated by autoantibodies causing complement dysregulation. 27,28 Eculizumab, a monoclonal antibody targeting the complement component C5, has been shown to be effective in both lupus nephritis 29,30 and C3GN. ...
Introduction:
Activation of the complement pathway by immune complexes is a key feature of systemic lupus erythematosus (SLE) and SLE glomerulonephritis, which translates into low levels of C3 and C4 during active disease. C3 glomerulonephritis (C3GN) is part of a broader group of rare renal diseases, the C3 glomerulopathies, characterized by prominent C3 accumulation in the glomeruli with minimal to no immunoglobulin (Ig) deposition secondary to dysregulation of the alternative pathway of the complement system. Distinguishing lupus nephritis from other complement-mediated kidney disorders, including C3GN, represents a diagnostic challenge with potential therapeutic implications.
Methods:
We report an unusual case of a 55-year-old woman with SLE and previous biopsy-proven class IV lupus nephritis, subsequently diagnosed with C3GN. Furthermore, we review the available literature published from January 2010-March 2021 on the clinical features and management of C3GN in the setting of SLE.
Results:
In addition to our case, very few reports exist in the literature regarding C3GN in association with SLE. The underlying pathogenic mechanism of C3GN consists of dysregulation of the alternative pathway of the complement system, either due to genetic variation in complement-related genes or to acquired autoantibodies targeting C3 or C5 convertases; the latter mechanism could explain the occurrence of C3GN in the setting of autoimmune diseases, although it was not definitively identified in our patient or others with SLE. Similar to some of the previous reports, after suboptimal renal response on mycophenolate mofetil and rituximab, our patient has been successfully treated with eculizumab, thus far with >50% improvement in proteinuria.
Conclusions:
C3GN represents an additional mechanism of renal injury in SLE mediated by alternative complement pathway dysregulation. Although rare, patients with SLE and persistent proteinuria with very low C3 would benefit from expedited renal biopsy to evaluate for C3GN as well as genetic testing, since this entity could require a different therapeutic approach.
... In a previous report [14], all seven pediatric patients with C3GN treated with ACE-I or ARB alone also achieved remission. In contrast, cohorts of adults with C3G [25,26] reported that 67-79% of patients treated with MMF and steroids achieved at least partial remission, with only 10-14% progressing to kidney failure, indicating a favorable outcome. None of the patients in the prednisolone-free group in this study had nephrotic syndrome, with an eGFR of 126.8 ml/min/1.73 ...
Background
Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses.
Methods
In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients.
Results
Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5–8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m ² . Patients with C3GN presenting mild to moderate proteinuria ( n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up.
Conclusions
Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis.
Graphical abstract
... Based on case series reports 66% of patients responded to MMF or steroid treatment. [13,14] Periodic plasma infusions have been found to be bene icial in patients with a defect in Factor H [15]. For patients with rapidly progressive renal failure, glucocorticoids in combination with either cyclophosphamide or MMF should be considered. ...
Background: The C3 glomerulopathies are a group of rare forms of glomerulonephritis with an incidence of 1-2 cases per million. It is mainly characterized by dysregulation of the alternative complement pathway. It is further classified morphologically based on electron microscopy ultrastructural findings into Dense Deposition Disease (DDD) and C3 glomerulonephritis. DDD is normally characterised by C3 Deposits. Case: We report a rare case of a young Emirati male who presented with sub nephrotic proteinuria and microscopic haematuria on routine evaluation. Renal biopsy showed features of DDD with combined C3 and C4 deposits. The retinal evaluation showed features of Drusen classically seen in DDD. Genomic study showed heterozygous mutation in c.5842G>C (p.Asp1948His) variant of uncertain significance in MYH9 gene. Discussion: C3 Glomerulopathy is a type of immune mediated disease previously classified as membranoproliferative glomerulonephritis. DDD is mainly characterised by C3 deposits in the glomerular basement Membrane. Our case has both C3 and C4d deposits, which is a rare entity. It shows the activation of both classical and alternate pathways. Conclusion: Dense deposition disease is a rare complement mediated glomerulopathy. It is characterised by C3 deposits. Dense deposition disease with combined C3 and C4d deposits is a new entity. The treatment and prognosis of such cases will be different and unique compared to the normal cases of DDD.
... A Spanish study found that patients treated with MMF in combination with GCs had better renal remission and survival rates compared with those receiving other immunosuppressive therapies (ie, only GCs or GCs plus cyclophosphamide). 132 However, another small study by Avasare et al 133 showed that the combination of MMF with GCs led to remission only in 67% of the patients with C3G. In accordance, further data suggest a variable response to immunosuppressive therapy with MMF in patients with different triggering factors, [134][135][136][137] and clinical features suggest the need for individualized therapy approaches. ...
... Notably, five patients also possessed MASP2 mutations; these mutations have also been described previously in C3G patients [21]. MASP2 is one of key serine proteases for complement activation in the lectin pathway (LP) and cleaves C2 and C4 to form the C3 convertase C4b2a. ...
Postinfectious glomerulonephritis with C3-dominant glomerular deposition (C3-PIGN) involves C3-dominant glomerular deposition without immunoglobulin. Atypical C3-PIGN involves persistent hypocomplementemia. We investigated the clinical features and explored complement-related gene mutations in atypical PIGN patients.
We enrolled atypical C3-PIGN patients and collected data regarding the clinical presentation and pathological characteristics and follow-up data. We measured the levels of complement associated antibodies and performed whole-exome sequencing (WES) to detect mutations in complement-related genes.
The analysis included six atypical C3-PIGN patients. All patients were antistreptolysin-O (ASO) positive. All patients had varying degrees of hematuria, and four patients had proteinuria. None of the patients were positive for complement-related antibodies. All patients possessed mutations of genes related to the complement pathway, including alternative complement pathway genes—CFI, CFH, CFHR3, CFHR5; the lectin pathway gene—MASP2; and the common complement pathway gene—C8A. The rare variant of CFHR3 has been reported in C3 glomerulonephritis. During 56–73 months of follow-up, the levels of urine markers in three patients recovered within 6 months, and the remaining patients had abnormal urine test results over 12 months. Patients who received glucocorticoid therapy recovered faster.
Our study suggested that complement-related gene mutations may be an important cause of persistent hypocomplementemia in atypical C3-PIGN patients. In addition to variations in alternate pathway-related genes, we also found variations in lectin pathway-related genes, especially MASP2 genes. Although the overall prognosis was good, atypical C3-PIGN patients exhibited a longer period for recovery. Our results suggested that atypical C3-PIGN patients should receive more medical attention and need testing for mutations in complement-related genes.
... Remission rates with MMF ranged between 36% and 65%, with around onethird of patients relapsing after therapy discontinuation. 11,12 Patients who had positive C3 nephritic factors appeared to respond better to MMF therapy. Given the lack of high-grade evidence to guide therapy, we encourage patients to enroll in clinical trials. ...
C3 glomerulopathy (C3G) is a rare kidney disease that causes kidney dysfunction as a result of dysregulation of the complement system alternate pathway (AP). C3G encompasses 2 separate disorders, C3 glomerulonephritis and dense deposit disease. The presentation and natural history is variable and kidney biopsy is needed to confirm the diagnosis. The overall prognosis is poor with high recurrence rates after transplant. A better understanding of C3G is needed as is high-quality evidence to guide therapy, which currently includes mycophenolate mofetil and steroids for moderate to severe disease, and terminal complement blockade with anti-C5 therapy in unresponsive cases.
... One of the important features of these diseases is that individuals with variants of complement genes may not develop aHUS or C3G until adulthood [16]. This incomplete penetrance indicates that a genetic mutation alone is insufficient to cause aHUS or C3G; instead, carriers of complement gene variants require a second or third trigger, such as viral infection, cancer, pregnancy, or medications, to progress to clinically significant aHUS or C3G [20,21]. ...
Background:
Atypical hemolytic syndrome (aHUS) and C3 glomerulopathy (C3G) are complement-mediated rare diseases with excessive activation of the alternative pathway. Data to guide the evaluation of living-donor candidates for aHUS and C3G are very limited. The outcomes of living donors to recipients with aHUS and C3G (Complement disease-living donor group) were compared with a control group to improve our understanding of the clinical course and outcomes of living donation in this context.
Methods:
Complement disease-living donor group [n = 28; aHUS(53.6%), C3G(46.4%)] and propensity score-matched control-living donor group (n = 28) were retrospectively identified from 4 centers (2003-2021) and followed for major cardiac events (MACE), de novo hypertension, thrombotic microangiopathy (TMA), cancer, death, estimated glomerular filtration rate (eGFR) and proteinuria after donation.
Results:
None of the donors for recipients with complement-related kidney diseases experienced MACE or TMA whereas two donors in the control group developed MACE (7.1%) after 8 (IQR, 2.6-12.8) years (p = 0.15). New-onset hypertension was similar between complement disease and control donor groups (21.4% vs 25%, respectively, p = 0.75). There were no differences between study groups regarding last eGFR and proteinuria levels (p = 0.11 and p = 0.70, respectively). One related donor for a recipient with complement-related kidney disease developed gastric cancer and another related donor developed a brain tumor and died in the 4th year after donation (2, 7.1% vs none, p = 0.15). No recipient had donor-specific human leukocyte antigen antibodies at the time of transplantation. Median follow-up period of transplant recipients was 5 years (IQR, 3-7). Eleven (39.3%) recipients [aHUS (n = 3) and C3G (n = 8)] lost their allografts during the follow-up period. Causes of allograft loss were chronic antibody-mediated rejection in 6 recipients and recurrence of C3G in 5. Last serum creatinine and last eGFR of the remaining patients on follow up were 1.03 ± 038 mg/dL and 73.2 ± 19.9 m/min/1.73 m2 for aHUS patients and 1.30 ± 0.23 mg/dL and 56.4 ± 5.5 m/min/1.73 m2 for C3G patients.
Conclusion:
The present study highlights the importance and complexity of living related-donor kidney transplant for patients with complement-related kidney disorders and motivates the need for further research to determine the optimal risk-assessment for living donor candidates to recipients with aHUS and C3G.
... The active phase of the disease plays a crucial role in treatment. In recent retrospective studies (22,23), MMF and corticosteroids were shown to be effective in treating active disease. Moreover, a previous study suggested that TFH1, TFH2, and TFH17 are indicators of the active state (24). ...
Background:
Primary nephrotic syndrome (PNS) is an immune-mediated glomerular disease that often reoccurs. However, the characteristics of circulating lymphocyte subsets in PNS children remain unclear. Immunosuppressive therapy can lead to temporary or persistent remissions, but also increases the risk of infection, and whether the circulating lymphocyte subsets can be used to predict the secondary infection also remains unclear. Here, we explored the distribution of lymphocyte subpopulations in the different stages of PNS, and its predictive value of secondary infection in pediatric patients.
Methods:
We included 89 children who were first PNS episodes or diagnosed with PNS admitted to Nanfang Hospital from September 2019 to April 2021, and 19 healthy children were recruited as controls (C). PNS patients were divided into three groups according to their serum biochemical tests: active group (A), partial remission (PR) group, and complete remission (CR) group. PNS patients with infection symptoms were divided into a co-infection group, others were divided into the non-infection group. The peripheral lymphocyte subsets were analyzed by flow cytometry. The relationship between the peripheral lymphocyte subsets and PNS activity or infection was analyzed.
Results:
Compared to the healthy controls, the PNS patients' CD8+CD28+ T cell (TC) (C: 16.6%, 450.8/µL;
A: 29.1%, P=0.000, 886.1/µL, P=0.012; PR: 25.7%, P=0.000, 817.3/µL, P=0.012; CR: 24.9%, P=0.001, 747.9/µL, P=0.020), and CD4+CD45RO+ ("memory" helper) T cells (C: 13.2%, 358.9/µL; A: 15.7%, P=0.036, 578.7/µL, P=0.001; PR: 17.6%, P=0.002, 610.0/µL, P=0.000; CR: 13.7%, P=0.676, 398.1/µL, P=0.525) were elevated. In addition, the regulatory T cells counts (non-infection: 117.9/µL; Co-infection: 73.3/µL, P=0.001) were significantly lower in patients with infection. We found that the predictive value measured by the area under the curve (AUC) showed that the AUC (t) Treg cell counts (61.5-84.5%) were almost always higher than the AUC for the (t) CD4+ T cell counts (55.1-77.1%).
Conclusions:
In this study, we found that T cell subpopulations had different characteristics in PNS during different disease phases. The CD8+CD28+ T cells, and CD4+CD45RO+ T cells increased at the disease quiescence of PNS. Moreover, CD4+ T cell subsets (regulatory T cell <82.5/µL) had higher predictive value than CD4+ T cell counts for PNS infection.
... In our patient, the hypocomplementemia, MPGN pattern of glomerular injury, and co-dominant C3 and IgA immunofluorescence on renal biopsy suggested a more pronounced role of complement in the pathogenesis of his IgAVN. This has led to treating the patient with a regimen of immunosuppression typical in the treatment of patients with IC-MPGN and C3G (19)(20)(21)(22), with a concomitant improvement in the patient's hypocomplementemia, proteinuria, hypoalbuminemia, and renal function after 3 months of aggressive treatment. Looking through the literature, one case report presented a patient similar to ours who recovered renal function after 2 years with corticosteroid monotherapy; however, this patient did not have a comprehensive complement evaluation (23). ...
IgA vasculitis (IgAV, also known as Henoch-Schönlein purpura or HSP) is a vasculitis of small vessels involving multiple organs, particularly of the joints, gastrointestinal tract, skin, and kidneys. Growing laboratory evidence has shown that complement plays a key role in the pathogenesis of IgAV, although direct evidence of this association in patients is lacking. We report a child with IgAV associated with clinical features of hypertension, nephrotic range proteinuria, acute kidney injury, and low serum C3, with histopathologic findings on renal biopsy of membranoproliferative glomerulonephritis with C3 and IgA co-dominance, and extensive complement derangements. This case report suggests that complement modifies the pathogenesis of IgAV, and further investigation into complement-targeted therapy in cases of refractory IgAV may be beneficial.
... The disease ranges from genetic mutations to autoantibody-mediated dysregulation of the alternative complement system. In dense deposit disease, 25 of 32 patients (78%) were positive for an autoantibody stabilizing the alternative C3 convertase (10 of 30 patients treated with MMF were classified as responders to immunosuppression (17). The largest study investigating the therapeutic effect of MMF in C3 glomerulopathy includes 97 patients (C3G n=81; DDD n=16). ...
Since the re-classification of membranoproliferative glomerulonephritis the new disease entity C3 glomerulopathy is diagnosed if C3 deposition is clearly dominant over immunoglobulins in immunohistochemistry or immunofluorescence. Although this new definition is more orientated at the pathophysiology as mediated by activity of the alternative complement pathway C3 glomerulopathy remains a heterogenous group of disorders. Genetic or autoimmune causes are associated in several but not in all patients with this disease. However, prognosis is poorly predictable, and clinicians cannot directly identify patients that might benefit from therapy. Moreover, therapy may range from supportive care alone, unspecific immune suppression, plasma treatment, or plasma exchange to complement inhibition. The current biopsy based diagnostic approaches sometimes combined with complement profiling are not sufficient to guide clinicians neither (i) whether to treat an individual patient, nor (ii) to choose the best therapy. With this perspective, we propose an interdisciplinary diagnostic approach, including detailed analysis of the kidney biopsy for morphological alterations and immunohistochemical staining, for genetic analyses of complement genes, complement activation patterning in plasma, and furthermore for applying novel approaches for convertase typing and complement profiling directly in renal tissue. Such a combined diagnostic approach was used here for a 42-year-old female patient with a novel mutation in the Factor H gene, C3 glomerulopathy and signs of chronic endothelial damage. We present here an approach that might in future help to guide therapy of renal diseases with relevant complement activation, especially since diverse new anti-complement agents are under clinical investigation.
... Una vez se realiza el diagnóstico histopatológico, con rmado por la inmuno uorecencia de la biopsia renal se decide manejo con micofenolato, basados en la recomendación de expertos, esto debido a la ausencia de estudios controlados, aleatorizados y con una muestra signi cativa. No obstante, dos estudios prospectivos de pacientes con gromerulopatía por C3 mostraron mejor respuesta clínica en comparación a otros medicamentos inmunosupresores [17,18]. ...
La enfermedad glomerular comprende un grupo heterogéneo de entidades que se caracterizanpor la pérdida de la arquitectura o función del glomérulo secundario a proceso inflamatoriodel mismo de etiología autoinmune, infecciosa, paraneoplásica, que puede ser identificada conestudios de histopatología. Su reconocimiento durante la gestación representa un reto diagnóstico por la sobreposición de cambios fisiológicos, el debut de enfermedades autoinmunitariaso de enfermedades genéticas, entre otros. La presentación clínica suele encajar en grupossindromáticos específicos, sin embargo, es frecuente que sean clínicamente indistinguibles osobrepuestos. El debut de la enfermedad renal con curso clínico de rápida instauración y deevolución desfavorable con respecto a la función renal, hace mandatorio un estudio completodesde el abordaje clínico hasta la interpretación de los hallazgos histopatológicos, encaminadoen la distinción de causas primarias y secundarias. Si bien las glomerulonefritis primarias noson las más frecuentes en la gestación, la identificación certera del diagnóstico y su adecuada clasificación permite el manejo dirigido y óptimo de las mismas. Se presentan los casos clínicosde dos gestantes con enfermedad glomerular primaria, con discrepancia en su diagnóstico,enfatizando en sus manifestaciones durante el curso de la gestación, el algoritmo diagnósticoutilizado, el tratamiento inicial y de mantenimiento utilizado. Se resalta la utilidad de la biopsiarenal, específicamente la inmunofluorencia para aclarar el mismo.
... 543 Similarly, Avasare et al. reported the kidney outcomes for 30 patients with C3G after MMF. 546 After a mean follow-up of 3 years, two-thirds had an either stabilized or reduced SCr level and reduced proteinuria. Ravindran et al. reported the kidney outcomes on a subcohort of 144 patients with C3G. ...
... Immunosuppressive treatment with Mycophenolate and steroids is indicated in patients with proteinuria over 500 mg in 24 hours despite supportive treatment, those at risk of progressive disease, or with moderate inflammation on biopsy [12]. This treatment has been used in 2 case series with a small population group, showing partial or complete response in up to 66% of the patients; those who did not respond were characterized by a worse proteinuria and renal function deterioration upon admission [13,14]. ...
C3 Glomerulonephritis (C3GN) is a rare disease with an estimated incidence of 1-2 cases per million, caused by an alteration in the alternative complement pathway, although its complete physiopathology remains uncertain. Treatment evidence is poor. Immunosuppressive therapy can be initiated in more severe cases. Progression rates to end stage kidney disease are of up to 50% within a decade, and the posttransplant recurrence rates of 45-60%. We describe the case of a young man without any past medical history, with lower extremities edema, dyspnea, and kidney function deterioration. The patient was ultimately diagnosed with C3GN.
... The therapy for the C3G is variable due to no randomized clinical trials for treatments, though some recommendations were made to follow but none has been proven effective and bene cial, mainly including glucocorticoid combined immunosuppressive agents (such as mycophenolate mofetil, tacrolimus, etc.) [11,12] biological agents (such as rituximab, ekuzumab) [13] plasma infusion [14] , and the development of new drugs (such as C3 invertase inhibitor cp40, recombinant human factor H, factor B inhibitor) [15][16][17] . It has been reported that factor B (FB) inhibitors shows a signi cant bene t for C3G in phase 2 clinical trials, phase 3 clinical trials are under way. ...
Background: C3 glomerulonephritis(C3GN) is one type of C3 nephropathy(C3G) which is a rare glomerular disease associated with abnormal regulation of the alternative complement pathway. This review reports a rare case of C3GN with repeated urinary tract infection and summarizes the clinical features, differential diagnosis, treatment, and outcome of patients with C3GN.
Case Presentation: A 44-years-old woman was pathologially diagnosed as C3GN. We were confused with her recently upper respiratory tract infection and repeated urinary tract infection before the diagnosis is confirmed. We conducted gene testing and found C3 and CD46 gene mutations, which were related to C3G and atypical thermochemical syndrome in previous reports. After antibiotic treatment, the level of complement C3 was higher than before. We strongly suspect that the urinary tract infection are related to C3 glomerulonephritis.
Conclusion: Clinical diagnosis of C3GN is difficult to make due to there are many differential diagnosis, especially post infection nephritis. This case emphasizes the importance of renal biopsy in the diagnosis of C3GN, but the relationship between gram-negative bacilli and C3GN is still unclear. In addition, gene mutation is also involved in the pathogenesis of C3GN, and the treatment of C3GN still needs to be explored.
... In another study Caliskan et al. showed that there were no differences in terms of proteinuria remission or in the decline of renal function between MMF-based treatment group, prednisolone or cyclophosphamide-treated group, and conservative care alone group in patients with C3GP [29]. In contrast, Avasare et al. [30] demonstrated that 67% of patients with C3GP had remission with the treatment of MMF plus corticostreoids. Hence, neither the ideal candidate for complement pathophysiology nor the most suitable immunosuppressive regimen (eg corticosteroids, mycophenolate mofetil, or rituximab) has been identified. ...
The complement system plays a significant role within the pathological process of C3 glomerulopathy (C3GP) and atypical hemolytic uremic syndrome (aHUS). In daily practice, clinicians should differentiate the subgroups of C3GP because of they should apply different treatment modalities. In the past, C3GP was considered as a part of membranoproliferative glomerulonephritis (MPGN). MPGN is defined as glomerular capillary thickening secondary to the synthesis of the new glomerular basement membrane and mesangial cellular hyperplasia with mesangial matrix expansion. Atypical hemolytic uremic syndrome is an ultra-rare disease that can be outlined by the triad of Coombs negative microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recent advances demonstrated that these diseases share common abnormalities of the control of the alternative complement system. Therefore, nowadays, most researchers advocate that there may be overlap in the pathogenesis of C3GP and aHUS. This review will provide recent novel mechanisms and treatment options in these diseases. For the purposes that we mentioned above and to help clinicians, we aimed to describe the etiology, pathophysiology, and treatment of C3GP and aHUS in this comprehensive review.
... Current therapeutic strategies in C3G are scarce, although some observational studies have found a benefit from the prescription of corticosteroids plus mycophenolate mofetil (MMF) 6,7 , as well as eculizumab in cases associated with rapidly progressive disease 8,9 . ...
Rationale & Objective
A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy proposed a prognostic Histologic Index (C3G-HI) that has not yet been validated. Our objective was to validate performance of the C3G-HI in a new patient population.
Study Design
Multicenter, retrospective cohort study.
Setting & Participants
111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN).
Predictors
Demographic, clinical parameters, the C3G-HI Total Activity Score and the C3G-HI Total Chronicity Score.
Outcome
Time to kidney failure.
Analytical Approach:Intraclass correlation coefficients and the kappa statistic were used to summarize inter-rater reproducibility for assessment of histopathology on kidney biopsies. The nonlinear relationships of risk of kidney failure with the Total Activity Score and the Total Chronicity Score were modeled using Cox proportional hazards analysis that incorporated cubic splines.
Results
The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall mean age of 35±22 years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the Total Activity Score (ICC=0.63), and excellent for Total Chronicity Score (ICC=0.89). Baseline eGFR, 24-hour proteinuria and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables., Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the Total Activity Score and Total Chronicity Score were added to the model, only the latter was identified as an independent predictor of kidney failure.
Limitations
Only a subset of the kidney biopsies was centrally reviewed. Residual confounding.
Conclusions
We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure.
... 69 Although no specific therapy for C3G is currently available, retrospective studies suggest that immunosuppressive treatment with mycophenolate mofetil and corticosteroids is beneficial compared with conservative treatment. 64,67,70 Given the remarkable heterogeneity of presentation, associated disease, and pathogenesis, with poor outcomes, the discovery of a viable biomarker is critical. ...
Recent advances in glomerular biology have expanded our understanding of glomerular diseases, leading to more precise therapeutic options. Since the discovery of the autoantigen phospholipase A2 receptor in primary membranous nephropathy 10 years ago, the serologic evaluation of glomerular diseases has become more detailed and nuanced for nephrologists. In addition to phospholipase A2 receptor antibodies, circulating autoantibodies now include thrombospondin type 1 domain-containing 7A and most recently, neural epidermal growth factor-like 1 protein for membranous nephropathy. Additionally, discoveries in C3 glomerulopathy and fibrillary glomerulonephritis are poised to improve the diagnostic approach to these disorders by using novel biomarkers to complement traditional histologic patterns on kidney biopsy. Although kidney biopsies are considered the gold standard in profiling glomerular diseases, validated novel glomerular biomarkers contribute substantially to the diagnostic and therapeutic approaches through their ability to improve sensitivity, permit dynamic longitudinal monitoring of disease activity, and capture genetic heterogeneity. We describe the value of specific biomarkers in selected glomerular diseases, with the major focus on their clinical applicability.
... KDIGO recommends the management of C3G based on disease severity [2]. For mild and moderate disease, supportive treatment, along with steroids and mycophenolate, are advised, respectively [2,89]. Rituximab and plasma-exchange have been tried with mixed results [30,[90][91][92]. ...
Background:
C3 glomerulopathy (C3G), a rare glomerular disease mediated by alternative complement pathway dysregulation, is associated with a high rate of recurrence and graft loss after kidney transplantation (KTx). We aimed to assess the efficacy of different treatments for C3G recurrence after KTx.
Methods:
Databases (MEDLINE, EMBASE, and Cochrane Database) were searched from inception through 3 May, 2019. Studies were included that reported outcomes of adult KTx recipients with C3G. Effect estimates from individual studies were combined using the random-effects, generic inverse variance method of DerSimonian and Laird., The protocol for this meta-analysis is registered with PROSPERO (no. CRD42019125718).
Results:
Twelve studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3G (73 C3 glomerulonephritis (C3GN) and 49 dense deposit disease (DDD)) were included. The pooled estimated rates of allograft loss among KTx patients with C3G were 33% (95% CI: 12-57%) after eculizumab, 42% (95% CI: 2-89%) after therapeutic plasma exchange (TPE), and 81% (95% CI: 50-100%) after rituximab. Subgroup analysis based on type of C3G was performed. Pooled estimated rates of allograft loss in C3GN KTx patients were 22% (95% CI: 5-46%) after eculizumab, 56% (95% CI: 6-100%) after TPE, and 70% (95% CI: 24-100%) after rituximab. Pooled estimated rates of allograft loss in DDD KTx patients were 53% (95% CI: 0-100%) after eculizumab. Data on allograft loss in DDD after TPE (1 case series, 0/2 (0%) allograft loss at 6 months) and rituximab (1 cohort, 3/3 (100%) allograft loss) were limited. Among 66 patients (38 C3GN, 28 DDD) who received no treatment (due to stable allograft function at presentation and/or clinical judgment of physicians), pooled estimated rates of allograft loss were 32% (95% CI: 7-64%) and 53% (95% CI: 28-77%) for C3GN and DDD, respectively. Among treated C3G patients, data on soluble membrane attack complex of complement (sMAC) were limited to patients treated with eculizumab (N = 7). 80% of patients with elevated sMAC before eculizumab responded to treatment. In addition, all patients who responded to eculizumab had normal sMAC levels after post-eculizumab.
Conclusions:
Our study suggests that the lowest incidence of allograft loss (33%) among KTX patients with C3G are those treated with eculizumab. Among those who received no treatment for C3G due to stable allograft function, there is a high incidence of allograft loss of 32% in C3GN and 53% in DDD. sMAC level may help to select good responders to eculizumab.
Background
Data on prognostic factors of C3 glomerulopathy (C3G) are limited, and validation of the new C3G histologic index (C3G-HI) in different settings is still needed. We aimed to evaluate the chronicity score of C3G-HI and probable prognostic factors in our population.
Methods
In this registry study, 74 patients from 20 centers with adequate follow-up data were included. Total chronicity score (TCS) was calculated according to percentages of glomerulosclerosis, interstitial fibrosis, tubular atrophy, and presence of arterio- and arteriolosclerosis. Primary composite outcome was defined as doubling of serum creatinine from baseline, undergoing dialysis or transplantation, development of stage 5 chronic kidney disease, or death.
Results
Median age was 34 (IQR: 24-46) years, and 39 patients (52.7%) were male. Median follow-up duration was 36 (IQR: 12-60) months, and median TCS was 3 (IQR: 1-5). Overall 19 patients (25.7%) experienced primary composite outcome. Multivariate Cox regression model showed that only hemoglobin [adjusted HR (aHR): 0.67, 95% CI: 0.46-0.97, p=0.035] predicted primary composite outcome, and TCS fell short of the statistical significance (aHR: 1.26, 0.97-1.64, p=0.08). ROC analysis demonstrated that TCS showed an AUC value of 0.68 (0.56-0.78, p=0.028) in discriminating primary composite outcome at 3 years, and 3-year kidney survival was lower in patients with TCS ≥4 (72.4%) compared to TCS <4 (91.1%) in Kaplan-Meier analysis (p=0.036).
Conclusions
Low hemoglobin levels predicted dismal outcomes in patients with C3G. TCS ≥4 was associated with a worse 3-year kidney survival, which validated the 3-year prognostic value of the TCS of C3G-HI in our population.
Membranoproliferative glomerulonephritis (MPGN) is a complex group of renal diseases characterized by a specific pattern of glomerular injury that includes thickening of the capillary wall and mesangial expansion, leading to a heterogeneous group of conditions. This review article offers a comprehensive overview of MPGN, its new classification, pathophysiology, diagnostic evaluation, and management options.
C3 glomerulopathy (C3G) is a complement-mediated disease. Although genetic studies are not required for diagnosis, they are valuable for treatment planning and prognosis prediction. The aim of this study is to investigate the clinical phenotypes, kidney survival, and response to mycophenolate mofetil (MMF) treatment in pediatric C3G patients with and without mutations in complement-related genes.
Sixty pediatric C3G patients were included, divided into two groups based on complement-related gene mutations. Demographic and clinical-pathological findings, treatment modalities, and outcome data were compared, and Kaplan–Meier analysis was performed for kidney survival.
Out of the 60 patients, 17 had mutations. The most common mutation was in the CFH gene (47%). The mean age at diagnosis was higher in the group with mutation (12.9 ± 3.6 vs. 11.2 ± 4.1 years, p = 0.039). While the patients without mutation most frequently presented with nephritic syndrome (44.2%), the mutation group was most likely to have asymptomatic urinary abnormalities (47.1%, p = 0.043). Serum parameters and histopathological characteristics were similar, but hypoalbuminemia was more common in patients without mutation. During 45-month follow-up,10 patients progressed to chronic kidney disease stage 5 (CKD5), with 4 having genetic mutation. The time to develop CKD5 was longer in the mutation group but not significant. MMF treatment had no effect on progression in either group.
This study is the largest pediatric C3G study examining the relationship between genotype and phenotype. We showed that the mutation group often presented with asymptomatic urinary abnormalities, was diagnosed relatively late but was not different from the without mutation group in terms of MMF treatment response and kidney survival.
A higher resolution version of the Graphical abstract is available as Supplementary information
Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are types of membranoproliferative glomerulonephritis classified as C3 glomerulopathies. These conditions are characterized by an increased number of intraglomerular cells and diffuse thickening of the glomerular capillary walls, along with the deposition of C3 and minimal or absent immunoglobulin deposits. The underlying cause of both DDD and C3Gn is an abnormal activation of the alternative complement pathway, which can result from acquired or genetic alteration. In acquired forms of DDD and C3GN, the dysregulation of the alternative pathway is commonly induced by the presence of C3 nephritic factors (C3NeFs), which are autoantibodies that stabilize C3 convertase. Both DDD and C3GN can affect individuals of any age, but DDD is primarily diagnosed in children, whereas C3GN tends to be diagnosed at a significantly higher age. The presenting features of these diseases are variable and may include proteinuria, hematuria, hypertension, or kidney failure. A common finding in these diseases is low serum C3 levels with normal serum C4 levels. Chronic deterioration of renal function is commonly observed in DDD and C3GN, often leading to end-stage renal disease (ESRD), especially in DDD. Kidney transplantation outcomes in patients with these conditions are characterized by histological recurrence, which may contribute to higher rates of allograft failure.
Background
Complement activation in atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephropathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) may be associated with rare genetic variants. Here we describe gene variants in the Swedish and Norwegian populations.
Methods
Patients with these diagnoses (N=141) were referred for genetic screening. Sanger or next-generation sequencing were performed to identify genetic variants in 16 genes associated with these conditions. Nonsynonymous genetic variants are described when they have a minor allele frequency of <1% or were previously reported as being disease-associated.
Results
In patients with aHUS (n=94, one also had IC-MPGN) 68 different genetic variants or deletions were identified in 60 patients, of which 18 were novel. Thirty-two patients had more than one genetic variant. In patients with C3G (n=40) 29 genetic variants, deletions or duplications were identified in 15 patients, of which 9 were novel. Eight patients had more than one variant. In patients with IC-MPGN (n=7) five genetic variants were identified in five patients. Factor H variants were the most frequent in aHUS and C3 variants in C3G. Seventeen variants occurred in more than one condition.
Conclusion
Genetic screening of patients with aHUS, C3G and IC-MPGN is of paramount importance for diagnostics and treatment. In this study, we describe genetic assessment of Nordic patients in which 26 novel variants were found.
Introduction
Dysregulated complement activation is likely the primary driver of disease in C3 glomerulopathy (C3G) and contributes to other complement-mediated diseases, including immunoglobulin A nephropathy (IgAN), lupus nephritis (LN), and primary membranous nephropathy (PMN). No complement inhibitors are proven to halt disease progression in these diseases. Pegcetacoplan, a targeted C3 and C3b inhibitor, may mitigate complement-mediated kidney damage in C3G and other glomerular diseases in which complement may have a pathogenic role.
Methods
This open-label, phase 2, 48-week study evaluated the preliminary efficacy and safety of subcutaneous pegcetacoplan for patients with complement-mediated glomerular diseases. The primary end point was proteinuria reduction, measured as 24-hour urine protein-to-creatinine ratio. Secondary end points included remission status, changes in estimated glomerular filtration rate (eGFR), and pharmacodynamic biomarkers. Treatment-emergent adverse events (TEAEs) were monitored.
Results
Efficacy results for the C3G cohort are reported herein, along with safety results for the study population. In the C3G cohort, mean proteinuria reduction from baseline to week 48 was 50.9% in the intent-to-treat (ITT) population (n = 7) and 65.4% in the per-protocol (PP) population (n = 4). Mean serum albumin normalized and mean eGFR was stable over 48 weeks. Mean serum C3 levels increased 6-fold and mean soluble C5b-9 levels decreased by 57.3% at week 48. The most common adverse events (AEs) were upper respiratory tract infection, injection site erythema, nausea, and headache. No meningitis or sepsis cases were reported, and no serious treatment-related AEs were observed.
Conclusion
Pegcetacoplan may provide therapeutic benefit for C3G and has a favorable safety profile across the 4 glomerular diseases studied.
The complement system is paramount in the clearance of pathogens and cell debris, yet is increasingly recognized as a key component in several pathways leading to allograft injury. There is thus a growing interest in new biomarkers to assess complement activation and guide tailored therapies after kidney transplantation. C5 blockade has revolutionized post-transplant management of atypical hemolytic uremic syndrome, a paradigm of complement-driven disease. Similarly, new drugs targeting the complement amplification loop hold much promise in the treatment and prevention of recurrence of C3 glomerulopathy. Although unduly activation of the complement pathway has been described following brain death and ischemia-reperfusion, any clinical attempts to mitigate the ensuing renal insults have so far provided mixed results. However, the intervention timing, strategy, and type of complement blocker need to be optimized in these settings. Furthermore, the fast-moving field of ex-vivo organ perfusion technology opens new avenues to deliver complement-targeted drugs to kidney allografts with limited iatrogenic risks. Complement plays also a key role in the pathogenesis of donor-specific ABO- and HLA-targeted alloantibodies. However, C5 blockade failed overall to improve outcomes in highly-sensitized patients and prevent the progression to chronic antibody-mediated rejection. Similarly, well-conducted studies with C1-inhibitor in sensitized recipients yielded disappointing results so far, in part due to subtherapeutic dosage used in clinical studies. The emergence of new complement blockers raises hope to significantly reduce the negative impact of ischemia-reperfusion, antibody-mediated rejection, and nephropathy recurrence on outcomes after kidney transplantation.
Since the publication of the latest Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on glomerular diseases, rare complement-mediated forms of glomerulonephritis (GN) have again been sorted primarily into the group of GN with a membranoproliferative GN (MPGN) pattern: however, the growing knowledge about the pathophysiological relationship is more indicative of a disease spectrum of idiopathic forms of immune complex-mediated MPGN (IC-MPGN) and C3 glomerulopathy (C3G). These diseases share numerous aspects in terms of secondary causes, autoantibodies and genetic analyses and show the MPGN pattern less frequently than assumed. Knowledge of the underlying pathophysiology is fundamental for extended differential diagnostics for clarification of secondary causes. A comprehensive complement analysis, antibody screening and genetic analysis should be consistently carried out. Chronic damage, high proteinuria and a measurably activated complement system appear to be prognostically unfavorable. Adequate systematic interventional studies still do not exist so that treatment recommendations must include nonspecific immunosuppressive treatment. Patients should be enrolled in ongoing phase 3 studies on specific complement blockade whenever possible.
Membranoproliferative glomerulonephritis (MPGN) and C3 glomerulopathy (C3G) define a disease pattern characterized by proteinuria, hypertension and impaired kidney function with a significant risk of disease progression and post transplant recurrence. Based on the appreciation of predominant glomerular C3 deposition on renal histopathology and the identification of a key role for the complement alternative pathway (CAP) mediated by genetic mutations or autoantibodies, the term C3 glomerulopathy (C3G) is proposed.C3G is further sub-divided by electron microscopy into dense deposit disease (DDD) with electron-dense deposits located in the lamina densa of the glomerular basement membrane (GBM), and C3 glomerulonephritis (C3GN) with deposits in subendothelial, subepithelial and/or mesangial localization. By contrast, cases with co-appearance of C3 and immunoglobulins are classified as idiopathic immune-complex MPGN (IC-MPGN). While no treatment standard exists, current therapeutic practice includes besides conservative measures immunosuppression with corticosteroids and mycophenolate mofetil (MMF). Overall prognosis is poor, with roughly 20% of children reaching end-stage kidney disease (ESKD) within 10–15 years. Future treatment strategies are expected to include therapies that block the CAP and thereby prevent glomerular C3 accumulation.KeywordsMembranoproliferative glomerulonephritisImmune complex glomerulonephritisC3 glomerulopathyC3 glomerulonephritisDense deposit diseaseComplement alternative pathway
Background:
C3 glomerulopathy (C3G) is a rare kidney disease, which makes it difficult to collect large cohorts of patients to better understand its variability. The aims of this study were to describe the clinical profiles and patterns of progression of kidney disease.
Methods:
Retrospective, observational cohort study. Patients diagnosed with C3G between 1995-2020 were enrolled. Study population was divided into clinical profiles by combining the following predictors: eGFR under/above 30 ml/min/1.73m2fn2, proteinuria under/above 3.5 g/day, histologic chronicity score under/above 4. The change in eGFR and proteinuria over time was evaluated in a subgroup with consecutive measurements of eGFR and proteinuria.
Results:
115 patients with a median age of 30 years (IQR 19-50) were included. Patients were divided into 8 clinical profiles. Kidney survival was significantly higher in patients with a chronicity score <4 and proteinuria <3.5g/day, both in those presenting with an eGFR under/above 30 ml/min/1.73m2. Median eGFR slope of patients who reached kidney failure was -6.5 ml/min/1.73m2/per year (IQR -1.6; -17). Patients who showed a reduction in proteinuria over time did not reach kidney failure. Based on the rate of eGFR decline patients were classified as faster eGFR decline (≥5 ml/min/1.73m2/year), slower (<5 ml/min/1.73m2/year), and those without decline. A faster eGFR decline was associated with higher probability of kidney failure.
Conclusions:
Kidney survival is significantly higher in patients with a chronicity score <4 and proteinuria <3.5 g/day regardless of baseline eGFR, and a faster rate of decline in eGFR is associated with higher probability of kidney failure.
Based on the results provided by electron microscopy, membranoproliferative glomerulonephritis (MPGN) has been conventionally categorized as primary type I, type II, or type III. This chapter reviews the most important advances regarding pathogenesis, prognosis, and current therapeutic options for MPGN and some additional MPGN associated conditions. The morphological pattern of MPGN includes a marked and diffuse thickening of the glomerular capillary walls. According to the novel classification, three types of MPGN have been suggested: immune‐complex‐mediated MPGN, complement‐mediated MPGN, and nonimmune complex mediated. The complement system includes three pathways, the classical, lectin and alternative pathways, and patients with C3Glomerulopathy have abnormal control of the alternative pathway of complement. Patients with mutations involving deficiency of regulatory proteins of the alternative complement pathway may benefit from replacement of factors with plasma therapy.
Primary immune complex‐mediated membranoproliferative glomerulonephritis (IC‐MPGN) and C3 glomerulopathies (C3G) have attracted a substantial body of basic and clinical research in the last decade. Renal pathological features are obviously different in each subtype of MPGN. C3G is a prototypic complement‐mediated disease. Similarly, it is assumed that renal injury in IC‐MPGN is mediated by complement activation triggered by immune complex deposition. Several studies have outlined an association between monoclonal gammopathy and C3GN. Mycophenolate mofetil was associated with steroids in 93% of cases. Eculizumab most probably treats only one aspect of the disease with no or very limited impact on C3 and immunoglobulins deposits. Experimental and clinical studies have transformed the perspective in the management of C3G and IC‐MPGN. There is to date no specific treatment of C3G and IC‐MPGN, which directly targets the initial driver of the disease, C3, and possibly immunoglobulins deposition.
Monoclonal gammopathies occur secondary to a broad range of clonal B lymphocyte or plasma cell disorders, producing either whole or truncated monoclonal immunoglobulins. The kidneys are often affected by these monoclonal proteins, and, although not mutually exclusive, can involve the glomeruli, tubules, interstitium, and vasculature. The nephrotoxic potential of these monoclonal proteins is dependent on a variety of physicochemical characteristics that are responsible for the diverse clinicopathologic manifestations, including glomerular diseases with organized deposits, glomerular diseases with granular deposits, and other lesions, such as C3 glomerulopathy and thrombotic microangiopathy with unique pathophysiologic features. The diseases that involve primarily the tubulointerstitial and vascular compartments are light chain cast nephropathy, light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulin-induced nephropathy with distinct acute and chronic clinicopathologic features. The diagnosis of a monoclonal gammopathy-related kidney disease is established by identification of an underlying active or more commonly, low-grade hematologic malignancy, serologic evidence of a monoclonal gammopathy when detectable, and most importantly, monoclonal protein-induced pathologic lesions seen in a kidney biopsy, confirming the association with the monoclonal protein. Establishing a diagnosis may be challenging at times, particularly in the absence of an overt hematologic malignancy, with or without monoclonal gammopathy, such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Overall, the treatment is directed against the underlying hematologic disorder and the potential source of the monoclonal protein.
Background and objectives
C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years.
Design, setting, participants, & measurements
To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome.
Results
Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores.
Conclusions
Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.
C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy. It is characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus as resolved by immunofluorescence microscopy. The underlying pathophysiology is driven by dysregulation of the alternative pathway of complement in the fluid‐phase and in the glomerular microenvironment. Characterization of clinical features and a targeted evaluation for indices and drivers of complement dysregulation are necessary for optimal patient care. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found. Approximately half of patients progress to end‐stage renal disease within 10 years of diagnosis, and, while transplantation is a viable option, there is high risk for disease recurrence and allograft failure. This poor outcome reflects the lack of disease‐specific therapy for C3G, relegating patients to symptomatic treatment to minimize proteinuria and suppress renal inflammation. Fortunately, the future is bright as several anti‐complement drugs are currently in clinical trials.
Introduction
Membranoproliferative glomerulonephritis (MPGN) represents a histologic pattern of glomerular injury which may be due to several etiologies. Few studies have comprehensively analyzed the recurrence of MPGN according to the current classification system.
Methods
We collected a multicenter, retrospective cohort of 220 kidney graft recipients with biopsy-proven native kidney disease due to MPGN between 1981–2021 in 11 hospitals. Demographic, clinical and histologic parameters of prognostic interest were collected. The main outcomes were time to kidney failure, time to recurrence of MPGN, and disease remission after recurrence.
Results
The study group included 34 complement-mediated and 186 immune complex-mediated MPGN. Eighty-one patients (37%) reached kidney failure in a median follow-up of 79 months. The main predictors of this event were the development of rejection episodes, and disease recurrence. Fifty-four patients (25%) had a disease recurrence in a median of 16 months after kidney transplantation. The incidence of recurrence was higher in patients with dysproteinemia (67%) and complement-mediated MPGN(62%). In the multivariable model, complement-mediated MPGN emerged as a predictor of recurrence. Thirty-three patients reached kidney failure after recurrence. The main determinants of no remission were: early time to recurrence (<15 months), eGFR < 30 ml/min/1.73m2 and serum albumin < 3.5 g/dl at the time of recurrence.
Conclusions
One-fourth of patients with native kidney disease due to MPGN developed clinical recurrence in the allograft, especially in cases with complement-mediated disease or in those associated with dysproteinemia. The kidney outcomes of disease recurrence with currently available therapies are heterogeneous and thus, more effective and individualized therapies are needed.
The classical roles of the complement (C) system are known to contribute in part to innate host immunity. In addition, bridging roles of the C system to adaptive immunity were found in the late 21st Century. Since anti-C agents such as C1-inhibitor and anti-C5 antibodies have started to be used in clinical practice during recent decades, the C system has become more familiar to clinicians. Analyses of aspects of the C system are now starting to clarify pathological mechanisms related to the C system and anti-C agents are under development. In the field of nephrology, unexpected C activation has been associated with the incidence, development and/or progression of glomerular and interstitial injuries. Moreover, atypical hematolytic uremic syndrome and C3 nephropathy were referred to as C-associated diseases. However, issues associated with C3 glomerulopathy, its pathogenesis, etiology and therapeutic approaches remain unclear. This mini-review provides a short summary and discussion of renal pathogeneses associated with the C system and its dysregulation, with particular focus on recent insights into C3 glomerulopathy.
Points essentiels
La glomérulopathie à dépôts de C3 est une néphropathie rare
Elle est le prototype d’une néphropathie due à une dysrégulation du complément.
Il a une présentation clinique, biologique et anatomopathologique variable d’un patient à un autre et chez un même patient au cours de son évolution.
Il n’y a à ce jour pas de traitement spécifique efficace de la glomérulopathie à dépôts de C3.
Le développement de la nouvelle classe médicamenteuse des inhibiteurs du complément aboutira très probablement à une thérapie ciblée de cette néphropathie.
Introduction
C3 glomerulopathy associated with monoclonal gammopathy (C3G-MIg) is a rare entity. Herein, we analyzed the clinical and histologic features of a cohort of C3G-MIg patients.
Methods
Retrospective, multicenter, observational study. Patients diagnosed with C3G-MIg between 1995–2021 were enrolled. All had genetic studies of the alternative complement pathway. The degree of disease activity and chronicity was analyzed using the C3G histologic index. Descriptive statistics and propensity-score matching (PSM) analysis were used to evaluate the main outcome of the study (kidney failure [KF]).
Results
The study group included 23 patients: median age 63 years (IQR 48–70), 57% males. IgG kappa was the most frequent MIg (65%). The diagnosis of C3G-MIg was made in transplanted kidneys in 7 patients (30%). Five (22%) had C3 nephritic factor and 5 (22%) anti-factor H antibodies. One patient carried a pathogenic variant in CFH gene.
During a follow-up of 40 months (IQR 14–69), 9 patients (39%) reached KF, and these patients had a significant higher total chronicity score in kidney biopsy. Patients who received clone-targeted therapy had a significant higher survival compared to other management. Those who achieved hematological response had a significant higher kidney survival. Outcome was remarkably poor in kidney transplant recipients, 5 of them (71%) reaching KF.
By PSM (adjusting for age, kidney function, proteinuria and chronicity score), no significant differences were observed in kidney survival between C3G patients with/without MIg.
Conclusions
The C3G histologic index can be used in patients with C3G-MIg to predict kidney prognosis, with higher chronicity scores being associated with worse outcomes. Clone-targeted therapies and the development of hematological response, are associated with better kidney prognosis.
Background and objectives : Membranoproliferative Glomerulonephritis (MPGN) and C3 Glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific aetiological data for paediatric MPGN/C3 glomerulopathy are lacking, and outcome data are based upon retrospective studies without aetiological data.
Design, setting, participants, and measurements : Eighty prevalent pediatric patients with MPGN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using COX proportional hazards model. Kidney and transplant graft survival was determined using Kaplan-Meier method.
Results : Central histology review determined 39 C3 glomerulopathy, 31 immune-complex MPGN and 10 immune-complex glomerulonephritis (GN) cases. Patients were aged 2-15 (median 9 (IQR 7-11) years. Median complement C3 and C4 levels were 0.31g/L and 0.14g/L respectively; acquired (anti-complement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% patients respectively, across all groups including immune-complex GN. Median follow-up was 5.18 (IQR 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure with 9 transplants performed in 8 patients, 2 of which failed due to recurrent disease. Presence of >50% crescents on initial biopsy was the sole variable associated with kidney failure in multivariable analysis (Hazard Ratio 6.2, p = 0.045; 95% CI 1.05 to 36.6). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on initial biopsy.
Conclusions : Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric MPGN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.
The thrombotic microangiopathies (TMAs) and C3 glomerulopathies (C3Gs) include a spectrum of rare diseases such as atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, C3GN, and dense deposit disease, which share phenotypic similarities and underlying genetic commonalities. Variants in several genes contribute to the pathogenesis of these diseases, and identification of these variants may inform the diagnosis and treatment of affected patients. We have developed and validated a comprehensive genetic panel that screens all exons of all genes implicated in TMA and C3G. The closely integrated pipeline implemented includes targeted genomic enrichment, massively parallel sequencing, bioinformatic analysis, and a multidisciplinary conference to analyze identified variants in the context of each patient's specific phenotype. Herein, we present our 1-year experience with this panel, during which time we studied 193 patients. We identified 17 novel and 74 rare variants, which we classified as pathogenic (11), likely pathogenic (12), and of uncertain significance (68). Compared with controls, patients with C3G had a higher frequency of rare and novel variants in C3 convertase (C3 and CFB) and complement regulator (CFH, CFI, CFHR5, and CD46) genes (P<0.05). In contrast, patients with TMA had an increase in rare and novel variants only in complement regulator genes (P<0.01), a distinction consistent with differing sites of complement dysregulation in these two diseases. In summary, we were able to provide a positive genetic diagnosis in 43% and 41% of patients carrying the clinical diagnosis of C3G and TMA, respectively.
Copyright © 2015 by the American Society of Nephrology.
C3 glomerulopathy (C3G) is characterized by C3 deposits with minimal immunoglobulin deposition caused by alternative complement
pathway dysregulation. Unfortunately, no therapeutic intervention has consistently improved outcomes for patients with C3G.
Eculizumab, a monoclonal antibody to C5, is currently the only approved complement-specific agent with some efficacy in the
treatment of C3 glomerulonephritis (C3GN). Here, we describe a patient with acute crescentic C3GN with no identified complement
mutation or family history of renal disease who required dialysis for 6 months. Five months after initiation of eculizumab,
she became dialysis independent, showing improvement is possible after adequate time on eculizumab.
C3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing end-stage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis.Kidney International advance online publication, 29 July 2015; doi:10.1038/ki.2015.227.
Disclaimer: These ACMG Standards and Guidelines were developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient’s record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.¹ In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes, and epigenetic assays for genetic disorders. By virtue of increased complexity, this shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context the ACMG convened a workgroup in 2013 comprising representatives from the ACMG, the Association for Molecular Pathology (AMP), and the College of American Pathologists to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP, and College of American Pathologists stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. This report recommends the use of specific standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified in genes that cause Mendelian disorders. Moreover, this recommendation describes a process for classifying variants into these five categories based on criteria using typical types of variant evidence (e.g., population data, computational data, functional data, segregation data). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
Genet Med17 5, 405–423.
C3 glomerulopathy (C3GP) is a membranoproliferative glomerulonephritis without immunoglobulin deposits. Activation of the alternative pathway of the complement system is central in its pathogenesis. The presence of a C3 nephritic factor (C3Nef), or deficient factor H or I is associated with C3 GP. The treatment is not codified. Here we describe a case of a Caucasian male with a dense deposit disease (a form of C3GP) revealed by nephritic syndrome. C3Nef was present. We treated him with rituximab as the sole immunosuppressive regimen and obtained a complete remission on proteinuria. The effect was sustained at more than 2 years with only two courses of treatment and an excellent tolerance. Rituximab could be proposed as a treatment of C3GP associated with antibodies interfering with complement alternative pathway.
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.
C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.Kidney International advance online publication, 30 October 2013; doi:10.1038/ki.2013.377.
Background:
Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.
Methods:
We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.
Results:
Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.
Conclusions:
We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).
C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H-related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G.
In the past decade, a large body of evidence has accumulated in support of the critical role of dysregulation of the alternative complement pathway in atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies. These findings have paved the way for innovative therapeutic strategies based on complement blockade, and eculizumab, a monoclonal antibody targeting the human complement component 5, is now widely used to treat aHUS. In this article, we review 28 case reports and preliminary data from 37 patients enrolled in prospective trials of eculizumab treatment for episodes of aHUS involving either native or transplanted kidneys. Eculizumab may be considered as an optimal first-line therapy when the diagnosis of aHUS is unequivocal and this treatment has the potential to rescue renal function when administered early after onset of the disease. However, a number of important issues require further study, including the appropriate duration of treatment according to an individual's genetic background and medical history, the optimal strategy to prevent post-transplantation recurrence of aHUS and a cost-efficacy analysis. Data regarding the efficacy of eculizumab in the control of C3 glomerulopathies are more limited and less clear, but several observations suggest that eculizumab may act on the most inflammatory forms of this disorder.
Controlled activation of the complement system, a key component of innate immunity, enables destruction of pathogens with minimal damage to host tissue. Complement factor H (CFH), which inhibits complement activation, and five CFH-related proteins (CFHR1-5) compose a family of structurally related molecules. Combined deletion of CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, we report an autosomal dominant complement-mediated GN associated with abnormal increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal copies of these genes, affected individuals carry a unique hybrid CFHR3-1 gene. In addition to identifying an association between these genetic observations and complement-mediated kidney disease, these results provide insight into the protective role of the combined deletion of CFHR3 and CFHR1 in IgA nephropathy.
Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.
The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial.
In this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria >1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark.
The subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria.
Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.
Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.
Dense deposit disease (first reported in 1962) was classified as subtype II of membranoproliferative glomerulonephritis in the early 1970s. Over the last 30 years, marked differences in etiology and pathogenesis between type I membranoproliferative glomerulonephritis and dense deposit disease have become apparent. The sporadic observation that dense deposit disease can be seen with markedly different light microscopy appearances prompted this study. The goal was to examine a large number of renal biopsies from around the world to characterize the histopathologic features of dense deposit disease. Eighty-one cases of dense deposit disease were received from centers across North America, Europe and Japan. Biopsy reports, light microscopy materials and electron photomicrographs were reviewed and histopathologic features scored. Sixty-nine cases were acceptable for review. Five patterns were seen: (1) membranoproliferative n=17; (2) mesangial proliferative n=30; (3) crescentic n=12; (4) acute proliferative and exudative n=8 and (5) unclassified n=2. The age range was 3-67 years, with 74% in the range of 3-20 years; 15% 21-30 years and 11% over 30 years. Males accounted for 54% and females 46%. All patients with either crescentic dense deposit disease or acute proliferative dense deposit disease were between the ages of 3 and 18 years. The essential diagnostic feature of dense deposit disease is not the membranoproliferative pattern but the presence of electron dense transformation of the glomerular basement membranes. Based upon this study and the extensive data developed over the past 30 years, dense deposit disease is clinically distinct from membranoproliferative glomerulonephritis and is morphologically heterogeneous with only a minority of cases having a membranoproliferative pattern. Therefore, dense deposit disease should no longer be regarded as a subtype of membranoproliferative glomerulonephritis.
Complement factor H and related proteins (CFHR) are key regulators of the alternative complement pathway, where loss of function mutations lead to a glomerulopathy with isolated mesangial C3 deposits without immunoglobulins. Gale et al. (12) reported on 26 patients with the first familial, hematuric glomerulopathy caused by a founder mutation in the CFHR5 gene in patients of Cypriot descent living in the United Kingdom. CFHR5 nephropathy is clinically characterized by continuous microscopic hematuria whereas some patients present with additional episodes of synpharyngitic macrohematuria, associated with infection and pyrexia. A subgroup of patients, particularly men, develop additional proteinuria, hypertension, and chronic renal disease or ESRD.
We herewith expand significantly on the study by Gale et al., reporting on histologic, molecular, and clinical findings in 91 patients from 16 families with the same founder mutation.
Eighty-two patients (90%) exhibited microscopic hematuria; 51 (62%), exhibited only microscopic hematuria, whereas the remaining 31 additionally had proteinuria (38%); 28 proteinuric patients developed chronic renal failure (CRF). Among carriers of CFHR5 mutation aged >50 years, 80% of the men and 21% of the women developed CRF; 18 developed ESRD (14 men [78%], 4 women [22%]).
The diagnosis of CFHR5-related, isolated C3 glomerulopathy was established in 2009 using newly described mutation analysis after decades of follow-up with unclear diagnoses, occasionally confused with IgA nephropathy. This larger patient cohort establishes the clinical course, significant variable expressivity, and marked gender difference regarding the development of CRF and ESRD.
Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C(3923ΔDG), which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H₂O) by spontaneous thioester hydrolysis, C(3923ΔDG) generated an active AP C3-convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C(3b923ΔDG) and C3(H₂O)(923ΔDG) were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase-restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3-convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments.
Genetic studies have shown that mutations of complement inhibitors such as membrane cofactor protein, Factors H, I, or B and C3 predispose patients to atypical hemolytic uremic syndrome (aHUS). Factor I is a circulating serine protease that inhibits complement by degrading C3b and up to now only a few mutations in the CFI gene have been characterized. In a large cohort of 202 patients with aHUS, we identified 23 patients carrying exonic mutations in CFI. Their overall clinical outcome was unfavorable, as half died or developed end-stage renal disease after their first syndrome episode. Eight patients with CFI mutations carried at least one additional known genetic risk factor for aHUS, such as a mutation in MCP, CFH, C3 or CFB; a compound heterozygous second mutation in CFI; or mutations in both the MCP and CFH genes. Five patients exhibited homozygous deletion of the Factor H-related protein 1 (CFHR-1) gene. Ten patients with aHUS had one mutation in their CFI gene (Factor I-aHUS), resulting in a quantitative or functional Factor I deficiency. Patients with a complete deletion of the CFHR-1 gene had a significantly higher risk of a bad prognosis compared with those with one Factor I mutation as their unique vulnerability feature. Our results emphasize the necessity of genetic screening for all susceptibility factors in patients with aHUS.
The alternative pathway of complement is activated continuously in vivo through the C3 'tick-over' pathway. This pathway is triggered by the hydrolysis of C3, resulting in the formation of C3 convertase. This, in turn, generates C3b, which mediates many of the biological functions of complement. Factor H, the main regulator of this activation, prevents formation and promotes dissociation of the C3 convertase enzyme, and, together with factor I, mediates the proteolytic inactivation of C3b. Factor H deficiency, described in 29 individuals from 12 families and in pigs, allows unhindered activation of fluid-phase C3 and severe depletion of plasma C3 (ref. 11). Membranoproliferative glomerulonephritis (MPGN) occurs in factor H-deficient humans and pigs. Although MPGN has been reported in other conditions in which uncontrolled activation of C3 occurs, the role of C3 dysregulation in the pathogenesis of MPGN is not understood. Here we show that mice deficient in factor H (Cfh(-/-) mice) develop MPGN spontaneously and are hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in the gene encoding complement factor B, which prevents C3 turnover in vivo, obviates the phenotype of Cfh(-/-) mice. Thus, uncontrolled C3 activation in vivo is essential for the development of MPGN associated with deficiency of factor H.
Several studies have demonstrated genetic predisposition in non-shigatoxin-associated hemolytic uremic syndrome (HUS), involving regulatory proteins of the complement alternative pathway: Factor H (FH) and membrane co-factor protein (CD46). Regarding the observations of thrombotic thrombocytopenic purpura patients, in whom a von Willebrand factor protease (ADAMST-13) deficiency may be inherited or acquired secondary to IgG antibodies, it was speculated that HUS might occur in a context of an autoimmune disease with the development of anti-FH antibodies leading to an acquired FH deficiency. The presence of FH autoantibodies was investigated by an ELISA method using coated purified human FH in a series of 48 children who presented with atypical HUS and were recruited from French university hospitals. Anti-FH IgG antibodies were detected in the plasma of three children who presented with recurrent HUS. The anti-FH specificity was conserved by the Fab'2 fraction. The plasma FH activity was found to be decreased, whereas plasma FH antigenic levels and FH gene analysis were normal, indicating that the presence of anti-FH antibodies led to an acquired functional FH deficiency. This report supports for the first time that HUS may occur in a context of an autoimmune disease with the development of anti-FH-specific antibody leading to an acquired FH deficiency. This new mechanism of functional FH deficiency may lead to the design of new approaches of diagnosis and treatment with a particular interest in plasma exchanges or immunosuppressive therapies.
Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology.
Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded.
Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls.
We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.
C3 glomerulonephritis (C3GN) and dense deposit disease comprise the two classes of C3 glomerulopathy. Studies from Europe and Asia have aided our understanding of this recently defined disorder, but whether these data apply to a diverse United States patient population remains unclear. We, therefore, reviewed clinical and histopathological data, including generation of a C3 Glomerulopathy Histologic Index to score biopsy activity and chronicity, to determine predictors of progression to end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) in 111 patients (approximately 35% non-white) with C3 glomerulopathy: 87 with C3GN and 24 with dense deposit disease. Complement-associated gene variants and autoantibodies were detected in 24% and 35% of screened patients, respectively. Our C3 Glomerulopathy Histologic Index denoted higher activity in patients with C3GN and higher chronicity in patients with dense deposit disease. Over an average of 72 months of follow-up, remission occurred in 38% of patients with C3GN and 25% of patients with dense deposit disease. Progression to late-stage CKD and ESRD was common, with no differences between C3GN (39%) and dense deposit disease (42%). In multivariable models, the strongest predictors for progression were estimated glomerular filtration rate at diagnosis (clinical variables model) and tubular atrophy/interstitial fibrosis (histopathology variables model). Using our C3 Glomerulopathy Histologic Index, both total activity and total chronicity scores emerged as the strongest predictors of progression. Thus, in a large, diverse American cohort of patients with C3 glomerulopathy, there is a high rate of progression to CKD and ESRD with no differences between C3GN and dense deposit disease.
Background:
C3 glomerulopathy (C3GP) is a recently identified and described disease that has a high risk of progressing into end-stage renal disease. We aimed to evaluate the effects of various immunosuppressive regimens on C3GP progression because there are conflicting data on the treatment modalities.
Methods:
In this retrospective study of 66 patients with C3GP, 27 patients received mycophenolate mofetil (MMF)-based treatment, 23 received non-MMF-based treatment (prednisolone or cyclophosphamide), and 16 received conservative care. The study groups were compared with each other with specific focus on primary outcomes defined as (1) kidney failure and (2) estimated glomerular filtration rate (eGFR) decline ≥50% from the baseline value.
Results:
Overall, 17 (25.8%) patients reached the primary outcome after a median period of 28 months. The number of patients who reached the primary outcome were similar among the study groups (MMF-based: 8/27 [29.6%], non-MMF-based: 4/23 [17.4%], and conservative care: 5/16 [31.3%], p = 0.520). In the Cox regression analysis, age (HR 0.912, p = 0.006), eGFR (HR 0.945, p = 0.001), and proteinuria levels (HR 1.418, p = 0.015) at the time of biopsy, percentage of crescentic (HR 1.035, p = 0.001) and sclerotic glomeruli (HR 1.041, p = 0.006), severity of interstitial fibrosis (HR 1.981, p = 0.048), as well as no remission of proteinuria (HR 2.418, p = 0.002) predicted the primary outcome.
Conclusion:
Although patients receiving immunosuppressive treatments had higher proteinuria and lower serum albumin at baseline, there were no differences between these patients and those receiving conservative care alone in proteinuria remission or in the decline of renal function. Younger age, higher proteinuria, lower eGFR, and the presence of crescentic and sclerotic glomeruli, severity of interstitial fibrosis, and no remission of proteinuria predicted the progression of kidney disease.
Background: Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR). Objective: To develop an equation to predict GFR from serum creatinine concentration and other factors. Design: Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease. Patients: 1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample ; the remaining 558 patients constituted the validation sample. Methods: The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample. Results: To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively. Conclusion: The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
C3 glomerulopathy (C3G) is a prototypic complement-mediated kidney disease. Rapidly progressive forms of C3G usually respond poorly to conventional treatments. We report on the efficacy of the terminal complement inhibitor eculizumab in 3 adult patients with rapidly progressive C3G. In all 3 patients, serum creatinine levels had increased by >50% in the 2 months preceding initiation of eculizumab treatment despite the use of conventional immunosuppressive drugs and/or plasma exchanges in 2 of these individuals. Of note, 2 patients had long-standing nephrotic syndrome. Kidney biopsy performed prior to eculizumab treatment disclosed marked glomerular inflammatory changes and increased C5b-9 deposition in all patients. Eculizumab use was associated with significant improvement in kidney function, with estimated glomerular filtration rates of patients increasing 22 to 38mL/min/1.73m(2). Eculizumab use also was associated with remission of nephrotic syndrome in the 2 affected patients, an effect observed as early as one week after treatment initiation. Repeat kidney biopsy disclosed regression of glomerular inflammatory changes and decreases in glomerular staining for C5b-9 in all patients. These results warrant further assessment of eculizumab for treatment of rapidly progressive forms of C3G with markedly increased glomerular C5b-9 deposits.
Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Atypical hemolytic uremic syndrome (aHUS) is characterized by dysregulated complement activity, the development of a thrombotic microangiopathy (TMA) and widespread end organ injury. aHUS remains a clinical diagnosis without an objective laboratory test to confirm the diagnosis. We performed a retrospective analysis of 103 patients enrolled in the Ohio State University TTP/aHUS Registry presenting with an acute TMA. Nineteen patients were clinically categorized as aHUS based upon the following criteria: 1) platelet count <100 x 10(9)/L, 2) serum creatinine >2.25 mg/dl, and 3) ADAMTS13 activity >10%. Sixteen of 19 patients were treated with plasma exchange therapy, with 6/16(38%) responding to PEX. Nine patients were treated with eculizumab with 7/9 (78%) responding to therapy. In contrast to TTP patients, no aHUS patients demonstrated ULWVF multimers at presentation. Median markers of generalized complement activation (C3a), alternative pathway (Bb), classical/lectin pathway (C4d), and terminal complement activation (C5a and C5b-9) were increased in the plasma of these 19 patients. Compared to a cohort of ADAMTS13 deficient TTP patients (n=38), C5a and C5-9 were significantly higher in the 19 patients clinically characterized as aHUS, suggesting that pretreatment measurements of complement biomarkers C5a and C5b-9 may confirm the diagnosis of aHUS and differentiate it from TTP.
The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome.
All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model.
Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD.
Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.
Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1-3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of 'C3 only' captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, 'C3 only' is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation.Kidney International advance online publication, 25 September 2013; doi:10.1038/ki.2013.340.
Background:
Hyperactivity of the alternative complement pathway is the principle defect in C3 glomerulopathies (C3G). Eculizumab, a monoclonal antibody that binds C5 to prevent formation of the membrane attack complex, has been shown to be beneficial in some patients with this disease.
Methods:
In this open-label, proof-of-concept efficacy-and-safety study, a patient with the initial diagnosis of dense deposit disease (DDD) and allograft recurrence of C3 glomerulonephritis (C3GN) was treated with eculizumab every other week for 1 year. The patient had pathological evidence of C3GN and proteinuria >1 g/day at enrollment. He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months.
Results:
Although no mutations were identified in complement genes, functional studies were positive for C3 nephritic factors and elevated levels of soluble membrane attack complex (sMAC). On therapy, sMAC levels normalized and although proteinuria initially decreased, it increased reaching pre-treatment levels at 12 months. Although serum creatinine remained stable, repeat allograft biopsies showed progression of disease.
Conclusions:
Clinical and histopathologic data suggest a partial response to eculizumab in this patient. While eculizumab blocked activation of the terminal complement cascade, persistent dysregulation of the alternative pathway remained, indicating eculizumab alone cannot control disease in this patient. Additional research is required to identify effective anticomplement therapy for this group of C3G patients.
Complement is a key component of the innate immune system, and variation in genes that regulate its activation is associated with renal and other disease. We aimed to establish the genetic basis for a familial disorder of complement regulation associated with persistent microscopic haematuria, recurrent macroscopic haematuria, glomerulonephritis, and progressive renal failure.
We sought patients from the West London Renal and Transplant Centre (London, UK) with unusual renal disease and affected family members as a method of identification of new genetic causes of kidney disease. Two families of Cypriot origin were identified in which renal disease was consistent with autosomal dominant transmission and renal biopsy of at least one individual showed C3 glomerulonephritis. A mutation was identified via a genome-wide linkage study and candidate gene analysis. A PCR-based diagnostic test was then developed and used to screen for the mutation in population-based samples and in individuals and families with renal disease.
Occurrence of familial renal disease cosegregated with the same mutation in the complement factor H-related protein 5 gene (CFHR5). In a cohort of 84 Cypriots with unexplained renal disease, four had mutation in CFHR5. Overall, we identified 26 individuals with the mutation and evidence of renal disease from 11 ostensibly unrelated kindreds, including the original two families. A mutant CFHR5 protein present in patient serum had reduced affinity for surface-bound complement. We term this renal disease CFHR5 nephropathy.
CFHR5 nephropathy accounts for a substantial burden of renal disease in patients of Cypriot origin and can be diagnosed with a specific molecular test. The high risk of progressive renal disease in carriers of the CFHR5 mutation implies that isolated microscopic haematuria or recurrent macroscopic haematuria should not be regarded as a benign finding in individuals of Cypriot descent.
UK Medical Research Council and Wellcome Trust.
C3 nephritic factor (C3NeF) defined by the capacity of nephritic serum and its fractions to initiate loss of the B antigen of C3 in normal serum was purified from the serum of three different donors and shown to function by stabilization of membrane-bound and fluid phase alternative pathway C3 convertase. C3NeF converts cell-bound C3B sites in a dose-related manner to CEB(NeF) sites, which exhibit an approximate 10-fold increase in half-life. The linear relationship between the C3NeF input and the residual hemolytic sites on EAC43B present after incubation for 20 min at 30 degrees C, during which labile C3B sites have decayed, indicates that the number of residual C3B sites is directly related to the dose of C3NeF. The capacity of C3NeF to stabilize the C3B convertase in a temperature- and dose-dependent manner, which is independent of binding or consumption of C3NeF, in a fluid phase reaction mixture of 125I-B, 131I-C3 and D permits isolation of a 10S complex containing radiolabeled C3 and B and exhibiting C3, convertase activity on an exogenous C3 source. Thus, the stabilizing effect of C3NeF is not limited to membrane-bound C3B but is also sufficient to permit recovery of a fluid phase C3 convertase formed during the interaction of C3, B, and D.
Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR).
To develop an equation to predict GFR from serum creatinine concentration and other factors.
Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease.
1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample; the remaining 558 patients constituted the validation sample.
The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample.
To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively.
The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
Mutations in the plasma complement regulator factor H (CFH) and the transmembrane complement regulator membrane co-factor protein (MCP) have been shown to predispose to atypical hemolytic uremic syndrome (HUS). Both of these proteins act as co-factors for complement factor I (IF). IF is a highly specific serine protease that cleaves the alpha-chains of C3b and C4b and thus downregulates activation of both the classical and the alternative complement pathways. This study looked for IF mutations in a panel of 76 patients with HUS. Mutations were detected in two patients, both of whom had reduced serum IF levels. A heterozygous bp change, c.463 G>A, which results in a premature stop codon (W127X), was found in one, and in the other, a heterozygous single base pair deletion in exon 7 (del 922C) was detected. Both patients had a history of recurrent HUS after transplantation. This is in accordance with the high rate of recurrence in patients with CFH mutations. Patients who are reported to have mutations in MCP, by contrast, do not have recurrence after transplantation. As with CFH- and MCP-associated HUS, there was incomplete penetrance in the family of one of the affected individuals. This study provides further evidence that atypical HUS is a disease of complement dysregulation.
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