La glomerulopatia da C3

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Camillo Carrara

Camillo Carrara1, 2

1 Unità di Nefrologia e Dialisi, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italia
2 IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Ranica

Corresponding author:
Camillo Carrara
E-mail: ccarrara@asst-pg23.it

 

Abstract

In recent years, the complement system, which plays a crucial role in the innate immunity, fostered renewed scientific interest. This process has brought a rare kidney disorder, named C3 glomerulopathy, in the center of a real revolution, highlighting the complex interactions between genotype, triggers and kidney microenvironment, which together contribute to the final phenotype of the disease. At the same time, experimental studies and clinical trials testing new complement inhibitors have multiplied enormously. It’s a very promising time for patients affected by C3 glomerulopathy, which didn’t have so far effective therapies in preventing the progression to the end-stage kidney disease.

Keywords: Membranoproliferative glomerulonephritis, C3 glomerulopathy, complement system, alternative pathway, kidney biopsy

Sorry, this entry is only available in Italian.

La glomerulopatia da C3 (C3G) è una rara malattia che si manifesta tipicamente in età pediatrica o nel giovane adulto, caratterizzata da intensi depositi di C3 alla biopsia renale. Essa è considerata un sottotipo di glomerulonefrite membranoproliferativa (MPGN) [1].

La classificazione storica della MPGN, basata sull’osservazione al microscopio elettronico (EM), prevedeva la seguente suddivisione in MPGN: di tipo I, caratterizzata da depositi elettrondensi subendoteliali; di tipo II, anche chiamata malattia a depositi densi (DDD), con depositi intensamente elettrondensi, in sede intramembranosa; di tipo III, con depositi sia sottoendoteliali che subepiteliali. Tuttavia questa classificazione della MPGN si è dimostrata essere limitata per l’assenza di una chiara connessione con la patogenesi della malattia, con scarsi risvolti clinici per il paziente.

Recentemente, in base al reperto alla immunofluorescenza (IF), Sethi S. e collaboratori hanno proposto un nuovo sistema classificativo della MPGN, che ha portato alla distinzione di due sottotipi [2]. Il primo, nel quale sono evidenziabili alla IF depositi glomerulari di immunoglobuline e complemento, è quello della MPGN mediata da immunocomplessi (IC-MPGN), causata dalla deposizione glomerulare di immunocomplessi o immunoglobuline nel contesto di malattie sistemiche o infettive, con prevalente attivazione della via classica del complemento. Il 20-30% di queste forme non riconosce una causa specifica ed è pertanto idiopatica. Il secondo sottotipo comprende la forma di MPGN mediata dalla disfunzione della via alterna del complemento, chiamata anche C3G, caratterizzata da deposizione glomerulare dominante di C3 (intensità del C3 all’IF di almeno due ordini di grandezza superiore alle altre immunoglobuline). Infine, sulla base dei reperti all’esame EM, la C3G è stata ulteriormente suddivisa in DDD e C3 glomerulonefrite (C3GN).

La presenza di depositi osmiofilici, intensamente elettrondensi e localizzati tipicamente all’interno della membrana basale glomerulare, caratterizza la DDD. Gli esperti di complemento hanno specificato che la C3G è molto eterogenea in quanto oltre ad un “pattern” di tipo membranoproliferativo può mostrare altri fenotipi glomerulari (ad esempio: proliferativo endocapillare, proliferativo mesangiale, necrotizzante ed extracapillare) [3]. Gli studi nell’animale e nell’uomo hanno permesso di identificare le anomalie biochimiche (es. consumo selettivo C3), genetiche (mutazioni nei geni che codificano per le proteine del sistema del complemento: C3, fattore B, fattore H, fattore I, MCP/CD46 e THBD, varianti di suscettibilità etc.) e i fattori acquisiti (C3Nef, C5Nef, anticorpi contro i fattori regolatori del complemento) che caratterizzano la malattia [4].

Va tuttavia sottolineato che alcuni gruppi di ricerca hanno dimostrato che anomalie genetiche a carico dei fattori regolatori della via alterna del complemento e peculiari anomalie biochimiche, quali ad esempio bassi livelli di C3 ed elevati livelli di sC5b9, sono presenti nella stessa proporzione di pazienti affetti da C3G e IC-MPGN idiopatica [5, 6]. Questa osservazione potrebbe mettere in discussione l’attuale classificazione della MPGN e ci induce a considerare queste patologie all’interno di uno spettro di condizioni cliniche, per le quali la via alterna del complemento è il principale meccanismo patogenetico.

Ma come funziona la cascata del complemento? Esistono tre vie di attivazione del sistema del complemento: classica, lectinica ed alterna [7]. La via classica è attivata dall’interazione fra C1q e gli immunocomplessi, mentre la via lectinica necessita di lectine e ficoline leganti gruppi mannosio, per poter identificare molecole di carboidrati che si trovano sulla superficie di una vasta gamma di microrganismi. Il trigger iniziale delle vie classica e lectinica porta alla conseguente attivazione delle componenti C2 e C4 e alla formazione di C3 convertasi, C4bC2a. Al contrario, la via alterna è continuamente attivata dall’idrolisi spontanea del C3 (meccanismo “tickover”), che risulta in un cambio conformazionale tale da consentire il legame del fattore B (CFB). Una volta legato, il fattore B diventa un substrato per una serino proteasi, detta fattore D (CFD). Il clivaggio del fattore B da parte del fattore D promuove la formazione della C3 convertasi propria della via alterna C3(H2O)Bb, che, in modo simile alla C3 convertasi della via classica, può clivare C3 in C3a e C3b. La generazione di C3b permette alla via alterna di essere pienamente attivata con la formazione del “loop” di amplificazione e del complesso C3bBb. Tutte e tre le vie convergono nel momento in cui C3 viene clivato dalla C3 convertasi per produrre il frammento C5a, un importante agente infiammatorio, e C5b, il componente iniziale della via terminale del complemento. Il legame in sequenza di C5b con C6, C7, C8 ed infine C9 risulta nell’assemblaggio di C5b-9 o complesso di attacco di membrana (MAC). La via alterna è fortemente controllata grazie all’esistenza di diversi regolatori che operano ancorati alla membrana oppure in fase fluida. Fra questi ultimi riconosciamo, ad esempio, il fattore I (CFI) ed il fattore H (CFH). Ci si può facilmente rendere conto che se i regolatori non funzionano correttamente, la conseguenza diretta è l’iperattivazione della via alterna. Era noto già dagli anni ’70 che esistessero glomerulonefriti ipocomplementemiche con pattern membranoproliferativo. Purtroppo, non abbiamo mai avuto a disposizione farmaci specifici per il trattamento di queste malattie. I comuni immunosoppressori si rivelano spesso scarsamente efficaci, ne consegue che la maggior parte dei pazienti progredisce verso l’uremia.

L’immunosoppressore che sembra consentire migliori risultati è il micofenolato, come mostrato da un’analisi retrospettiva del GLOSEN group spagnolo [8]. Si tratta di dati limitati. Il primo inibitore specifico del complemento ad essere utilizzato nelle C3G è l’eculizumab, un anticorpo monoclonale umanizzato in grado di bloccare il C5 e prevenire la formazione di C5a e del complesso di attacco di membrana. Il razionale per utilizzare il farmaco nell’uomo deriva da studi nel modello animale, topi incapaci di produrre fattore H che sviluppano la glomerulonefrite in modo spontaneo [9]. Provocando la delezione genica del C5 lo stesso animale sviluppa una malattia molto più lieve.

Nel 2012, vengono pubblicati i primi casi aneddotici di giovani pazienti con C3G trattati con eculizumab, che hanno risposte convincenti in termini di riduzione della proteinuria e stabilizzazione della funzionalità renale [10, 11]. Nello stesso anno viene pubblicata la prima “case series” del gruppo di nefrologi della Columbia University [12]. Lo studio sembra suggerire che i pazienti con alti livelli di sC5b9 sono quelli che rispondono meglio all’anticorpo monoclonale. È sulla base di questi risultati che l’Istituto Mario Negri di Bergamo ha disegnato uno studio clinico che ha incluso 10 pazienti con C3G e IC-MPGN [13]. Il protocollo di trattamento prevedeva uno schema on-off-on-off. Nel primo anno di studio i livelli di sC5b9 si sono ridotti rapidamente e si è assistito ad un iniziale miglioramento della proteinuria. Tuttavia, durante il periodo di wash out, è stata osservata un’esacerbazione della malattia con peggioramento dei parametri laboratoristici, che non miglioravano in modo significativo nel successivo anno di trattamento. L’eculizumab è un farmaco molto costoso e che richiede ai pazienti di recarsi in ospedale ogni due settimane per la somministrazione. Inoltre, è un trattamento cronico che non può essere interrotto. Un’osservazione interessante è stata fatta a livello istologico. Nelle biopsie renali dopo due anni di terapia gli infiltrati di leucociti intracapillari sono drasticamente ridotti. A supporto del potente effetto anti infiammatorio dell’eculizumab esiste anche uno studio retrospettivo, che mostra come i pazienti con C3G che ottengono una risposta migliore dalla terapia sono quelli con una presentazione clinica rapidamente progressiva e con una maggior percentuale di semilune floride all’esordio [14].

Negli ultimi anni si è assistito ad un vertiginoso impulso nella ricerca e sperimentazione nel campo dei nuovi inibitori selettivi del complemento. Un caso esemplare riguarda l’inibitore orale del fattore D, danicopan, che blocca l’azione della C3 convertasi e che è stato oggetto di ricerca presso l’Istituto Maro Negri di Bergamo. I dati di questo studio non sono ancora stati pubblicati. Sono state osservate risposte molto variabili con questo farmaco nei pazienti affetti da C3G. In parte, la variabilità delle risposte è dipesa da un problema di tipo farmacocinetico/farmacodinamico. Infatti, il fattore D è molto difficile da inibire. Si pensi che sono sufficienti l’1,8% dei livelli di fattore D per mantenere attiva la via alterna del complemento. La company in oggetto sta cercando di produrre un inibitore più potente del fattore D, che speriamo essere disponibile a breve. Tuttavia, non sono mancate le sorprese incoraggianti. Vale la pena citare il caso di un giovane di 18 anni affetto da DDD, che all’esordio aveva una sindrome nefrosica con peggioramento della funzione renale. Ebbene, dopo poche settimane di trattamento con danicopan, il C3 plasmatico si è normalizzato, così come la proteinuria e la funzione renale. Dal punto di vista istologico si è assistito ad una regressione delle lesioni infiammatorie.

In conclusione, gli studi con questi nuove molecole sono molto difficili da condurre poiché si tratta di malattie rare, molto eterogenee, con un’importante variabilità nei meccanismi patogenetici tra un soggetto e l’altro. Queste malattie complesse ci insegnano che oggi è sempre più necessario adottare una medicina di precisione. L’analisi di cluster è un metodo biostatistico che potrebbe essere molto utile in tal senso. Questo metodo è stato applicato con successo al registro delle MPGN e C3G del Centro di Ricerca per le Malattie Rare dell’Istituto Mario Negri di Bergamo [15]. Utilizzando i dati di 173 pazienti del registro, è stato possibile identificare 4 clusters di malattia con caratteristiche comuni. Suddividendo i pazienti in clusters si sono ottenuti dei sottogruppi di pazienti omogenei dal punto di vista degli aspetti patogenetici. Rispetto alle curve di sopravvivenza dei pazienti suddivisi per gruppo istologico (IC-MPGN, C3GN, DDD), quelle dei pazienti suddivisi nei 4 clusters hanno una maggior rilevanza e significatività in termini prognostici. L’intento è quello di identificare sottogruppi di soggetti che possano beneficiare di specifiche terapie.

Questo è un momento storico molto promettente per i pazienti affetti da C3G. La comprensione dei meccanismi che generano la malattia e la disponibilità di nuovi farmaci capaci di inibire il sistema complemento a diversi livelli della cascata sta rivoluzionando il panorama di questa condizione. Tuttavia, le sfide aperte sono ancora molteplici. In particolare, tenuto conto dell’estrema variabilità genetica e biochimica della malattia, risulta difficile prevedere quale paziente potrà maggiormente beneficiare di un determinato farmaco. Le nuove tecnologie e i metodi biostatistici, come ad esempio l’analisi di cluster, potranno consentire di addentrarci nel campo di una medicina di precisione, che tenga in conto delle variabilità inter individuale dei pazienti.

 

Bibliografia

  1. Smith KD, Alpers CE. Pathogenic mechanisms in membranoproliferative glomerulonephritis. Curr Opin Nephrol Hypertens 2005;14(4):396-403. https://doi.org/1097/01.mnh.0000172729.60122.f9.
  2. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis – a new look at an old entity. N Engl J Med 2012;366(12):1119-31, https://doi.org/1056/NEJMra1108178.
  3. Pickering MC, D’Agati VD, Nester CM, et al. C3 glomerulopathy: consensus report. Kidney Int 2013;84(6):1079-89. https://doi.org/1038/ki.2013.377.
  4. Zhang Y, Nester CM, Martin B, et al. Defining the complement biomarker profile of C3 glomerulopathy. Clin J Am Soc Nephrol 2014;9(11):1876-82. https://doi.org/2215/CJN.01820214.
  5. Servais A, Noël LH, Roumenina LT, et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 2012;82(4):454-64. https://doi.org/1038/ki.2012.63.
  6. Iatropoulos P, Noris M, Mele C, et al. Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol Immunol 2016;71:131-42. https://doi.org/1016/j.molimm.2016.01.010.
  7. Fakhouri F, Frémeaux-Bacchi V, Noël LH, et al. C3 glomerulopathy: a new classification. Nat Rev Nephrol 2010;6(8):494-9. https://doi.org/1038/nrneph.2010.85.
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  11. Radhakrishnan S, Lunn A, Kirschfink M, et al. Eculizumab and refractory membranoproliferative glomerulonephritis. N Engl J Med 2012;366(12):1165-6. https://doi.org/1056/NEJMc1106619.
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  15. Iatropoulos P, Daina E, Curreri M, et al. Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN. J Am Soc Nephrol. 2018 Jan;29(1):283-94. https://doi.org/1681/ASN.2017030258.

C3 Glomerulopathy, a pathology with scarce evidence. A case report

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Andres Felipe Barragan Amado

Andrés Felipe Barragán1, Elías Quintero-Muñoz1, Daniel Quintero-Muñoz2, Paula V Rodriguez-Segura3

1 Internal Medicine Resident; La Sabana University, Chía, Colombia
2 MD, La Sabana University, Chía, Colombia
3 MD, Internist, Nephrologist, Hospital Universitario de La Samaritana - Grupo de investigación UROHUS, Bogotá, Colombia.

Corresponding author:
Elías Quintero Muñoz, M.D.
Universidad de La Sabana
Chía, Colombia
Phone:  +57 311 2388078
E-mail: eliasquintero121@gmail.com

 

Abstract

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.

Key words: C3 glomerulopathy, glomerulonephritis, alternative complement pathway

Introduction

C3 Glomerulopathy (C3G) is a renal disease caused by a primary alteration in the complement, presenting a dysregulation in the alternative complement pathway, which induces hyperactivity. The term was first described in 2007 in a series of 19 patients characterized by the histopathological finding of C3 deposits in renal tissue without any other significant immunocomplex [1]. The renal symptoms were hypertension, kidney disease, proteinuria, hematuria, and nephrotic syndrome.

C3G has been classified as an independent glomerulopathy in the 2013 consensus of International Society of Nephrology, organized by Mathew Pickering and Terence Cook. Included in this pathology are two entities: Dense Deposit Disease (DDD) and Complement 3 Glomerulonephritis (C3GN). The difference lies in the appearance and distribution of deposits on electron microscopy of the glomerulus: DDD is characterized by the presence of highly electron-dense deposits within the glomerular basement membrane (GBM), while in C3GN the deposits are located in the mesangium or along the subendothelial side of the GBM [2,3]. Another classification has arisen from the need to correlate pathophysiological, clinical, histological, and genetic data. This new classification could be more useful to clinicians because, unlike the pathological one, addresses the underlying pathogenesis of the disease. It recognizes 4 different groups, indicating four different pathogenic patterns. Patients in groups 1-3 show predominantly fluid phase complement activation, often present with low serum C3 levels, and have a high prevalence of genetic complement abnormalities; patients in group 4 have predominantly solid phase complement activation, normal serum C3 levels, and are associated with worse renal outcomes. This classification, however, has not yet been validated and may be subject to limitations [4].

The rarity of this disease has made it difficult to estimate precise epidemiologic data; the data available comes from small cohort studies. The United States estimates an incidence of C3G of 1-3 cases per 1.000.000 of the population and a prevalence of <5 cases per 1.000.000. Other European data show a lower incidence, estimated in 0.2-1 cases per 1.000.000 people and a prevalence of 1.4 per 1.000.000 [5]. The progression rates to end stage kidney disease are of up to 50%, and in renal allografts transplantation the recurrence rate is 45-60% [6].

Treatment recommendations for C3GN are based on a series of cases, case reports, and a few open-label trials. Poor evidence with immunosuppression, plasma infusion, or plasmapheresis has been described in small cohorts with inconclusive results. However, new evidence indicates an alternative treatment with Eculizumab, a humanized monoclonal antibody that binds C5 to prevent the formation of the membrane attack complex [6].

We describe here the case of a young man, without any relevant medical history, who came to the emergency room with signs and symptoms compatible with nephrotic syndrome and was ultimately diagnosed with C3GN through histopathology. This case illustrates the clinical presentation of this disease and the importance of being aware of it for an adequate diagnostic and therapeutic approach.

 

Case report

A 27-year-old man without any past personal or family health history presented to the emergency department with lower extremities edema and dyspnea on moderate exertion; reportedly, the symptoms had appeared 6 days before. When asked about other symptoms, the patient also reported upper respiratory symptoms in the last 15 days. On physical examination, vital signs were: BP, 150/102 mmHg; HR, 144 beats per minute; BR, 18 breaths per minute. Besides hypertension and tachycardia, the only abnormal finding was a grade II lower extremities pitting edema. Laboratory results indicated the presence of anemia, severely impaired renal function (Figure 1), proteinuria and hematuria. Additionally, the patient was found to have hypocalcemia, hyperphosphatemia, hyperuricemia, hyperparathyroidism (Table I).

Figure 1: Renal function over time. Renal replacement therapy was initiated on the third day of hospitalization. (A) Serum creatine concentration; (B) Serum BUN concentration
Figure 1: Renal function over time. Renal replacement therapy was initiated on the third day of hospitalization. (A) Serum creatine concentration; (B) Serum BUN concentration
Laboratory results:
Hemoglobin

8.9 g/dl
Hematocrit

27.5%
Platelets

327000/microL
Serum Creatinine

9.63 mg/dl
BUN

72.64 mg/dl
Iron

33.8 ug/mL
TIBC

403.66 ug/dL
Folic Ac

15.83 ng/mL
Vitamin B12

674 pg/mL
TSH

1.07
Albumin

2.65 g/dL,
PTH

412 pg/dL (12-88)
Calcium

8.58 mg/dL
Potassium

4.12 mEq/L
Phosphorus

6.72 mg/dL
Total Cholesterol

163.57 mg/dl
High density lipoprotein

62.6 mg/dl
Low density lipoprotein

95.48 mg/dl
Antibodies:
ANCA PR-3: Negative – MPO: Negative
C3

39.9 mg/dl (79-152)
C4

31.8 mg/dl (18-55)
DNA, ENA Negative
ANA 1:80 Homogeneous pattern
Anti GBM Negative
Protein electrophoresis low albumin and moderate increase in α fraction
Urine analysis:
Protein

500.0 mg/dl
Blood

300.00 ery/ul
Sediment leukocytes: 15 cel/ul

low erythrocytes: 120 cel/ul

dysmorphic erythrocytes: 12cel/ul

cylinders: hialines/3
Proteins in urine 24 hours

4072.88 mg
Urine volume

1400 mL
Table I: Laboratory results

The patient was assessed by the Nephrology department, with a preliminary diagnosis of rapidly progressive glomerulonephritis (RPGN). The diagnosis was supported by the lab results and by the patient’s vital signs at admission: hypertension, edema, hematuria, and rapid progression to renal failure. However, findings such as hypocalcemia, hyperphosphatemia, hyperuricemia, hyperparathyroidism, suggested a chronicity element, even though renal ultrasonography findings were normal.

Due to the nephrotic proteinuria and nephritic clinical behavior, additional exams were performed with the following findings: Hypoalbuminemia; Low C3; Normal C4; ANA (1:80); negatives ENA; Anti-neutrophil Cytoplasmic Antibodies (ANCA) with negative anti-proteinase 3 (PR-3) and anti-myeloperoxidase (MPO); Negative Anti–glomerular basement membrane (anti-GBM); abnormal protein electrophoresis. In addition, tests for Hepatitis B, Hepatitis C, Treponema Pallidum, and HIV were negative (Table I). Transthoracic echocardiogram showed a reduced left ventricular ejection fraction (20%) with an associated dilatation of the left cavities.

Considering these data, a working diagnosis of rapidly progressive glomerulonephritis was made, while waiting for the results of the renal biopsy. Therefore, it was decided to start steroid pulses with 1 gram/day of methylprednisolone for 3 days, followed by oral steroids. Before administration of steroids, anthelmintic therapy with ivermectin and albendazole was given and the patient was isolated according to hospital protocol. In addition, cutaneous biopsy was performed, ruling out any deposit disease.

Notwithstanding steroid treatment, BUN and creatinine concentration kept rising, as well as water overload. Renal replacement therapy was thus initiated on the third day of hospitalization. Optimal dry weight and blood pressure control was achieved, also thanks to calcium channel blockers and beta blockers. At the same time, erythropoietin therapy was initiated to treat anemia. The echocardiographic findings (reduced left ventricular ejection fraction and dilatation of left cavities) were thought to be related to water overload. After initiating the renal replacement therapy, the patient managed to lose 15 kg, his functional class improved, and his left ejection fraction achieved normal values.

Renal biopsy contained 31 glomeruli, 19 of which were globally sclerotic (61%) and 6 had segmentary sclerosis (19%). There was remarkable glomerulomegaly, endocapillary proliferation, mesangial matrix enlargement, images in double contour, and thickening of the basement membrane (3+). Moreover, there was severe interstitial fibrosis and tubular atrophy (80%). Immunofluorescence showed only bright staining for C3 in capillary wall and mesangium (3+). The vessels were unremarkable. Ultrastructurally, two glomeruli were examined, one was globally sclerotic and the other had segmentary sclerosis. Additionally, there was endocapillary hypercellularity and images in double contour in relation with subendothelial and intramembranous electron-dense deposits (3+). A total renal chronicity score of 8 was calculated (See Figure 2 and Figure 3).

Figure 2: Renal biopsy. (A) Glomerulus with membranoproliferative pattern of injury and globally sclerotic glomeruli. Tubulointerstitial compartment has marked chronic changes with tubular atrophy and interstitial fibrosis (HE stain); (B) Glomerulus with prominent mesangial expansion and mesangial cell hypercellularity. Glomerular basement membrane is thickened (PAS stain); (C) Same glomerulus showing double contours with large mesangial and subendothelial deposits staining red in trichrome stain; (D) Direct immunofluorescence for C3 showing 3+ staining in capillary wall and mesangium.
Figure 2: Renal biopsy. (A) Glomerulus with membranoproliferative pattern of injury and globally sclerotic glomeruli. Tubulointerstitial compartment has marked chronic changes with tubular atrophy and interstitial fibrosis (HE stain); (B) Glomerulus with prominent mesangial expansion and mesangial cell hypercellularity. Glomerular basement membrane is thickened (PAS stain); (C) Same glomerulus showing double contours with large mesangial and subendothelial deposits staining red in trichrome stain; (D) Direct immunofluorescence for C3 showing 3+ staining in capillary wall and mesangium.
Figure 3: Electron microscopy image. Electron microscopy shows a thickened glomerular basement membrane with cellular interposition associated with the presence of electron-dense subendothelial and intramembranous permeating deposits (so-called “MPGN type 3 patter of Strife and Anders”). In addition, there is overlying podocyte foot process effacement.
Figure 3: Electron microscopy image. Electron microscopy shows a thickened glomerular basement membrane with cellular interposition associated with the presence of electron-dense subendothelial and intramembranous permeating deposits (so-called “MPGN type 3 patter of Strife and Anders”). In addition, there is overlying podocyte foot process effacement.

After receiving the renal biopsy results and given the lack of response to steroids, it was decided to place a long-term hemodialysis catheter to continue dialysis after discharge. Follow-up in the patient’s hometown was arranged, for additional studies and to enlist the patient for a kidney transplant. Unfortunately, however, contact with the patient was lost.

 

Discussion

C3 glomerulopathy has been gaining recognition since its first description in 2007. However, if knowledge of the diseased has increased, many aspects of its physiopathology and treatment remain unknowns. It was initially considered as a membranoproliferative glomerulonephritis, but was later reclassified in a group of its own [3].

The physiopathology has not been established yet. Evidence shows that activation of the alternative complement pathway can be compromised by the presence of genetic alterations of regulatory and activation processes (H factor, C3 nephritic factor which fulfills regulatory functions over the conversion of activated C3). These genetic alterations affect the functionality of the complement system directly. Moreover, the genetic alterations cause the production of antibodies against these intermediaries. However, a genetic alteration in the complement can be found (H factor, B factor, and FHR proteins) just in 25% of patients with C3 glomerulopathy. On the other hand, acquired factors have been considered to play a role, given that C3G is not a familial disease in most cases; but no trigger has been established. Antibodies against C3bBb can be found in 46% of C3G; likewise, different antibodies against B factor, H factor and C5 convertase have been reported, but their clinical relevance remains uncertain. The resulting aberrant complement activation will ultimately activate the C5 common complement pathway. Regardless, no etiologic agent in the genetic alterations or any acquired factor have so far proved sufficient to explain the phenomena [2,7,8].

Clinical manifestations are variable. Hematuria or proteinuria is found in 100% of patients but it has been demonstrated that nephrotic syndrome or nephritic syndrome can occur as initial manifestation in 30-50% and 16-38% of cases, respectively (or both, as in our case). Regarding renal function, it can oscillate between a preserved renal function, rapidly progressive glomerulonephritis, or even advanced chronic renal disease, as in the case described [5,9,10].

C3G can affect both the pediatric and adult population, with an average age of onset of 25 years, as described in the literature. It has been associated more commonly with dense deposit disease among the pediatric population. In the case of the adults, especially those older than 50, associated monoclonal gammopathy must be ruled out [11].

Regarding treatment, there are no randomized clinical trials or clinical guides at the moment. Recommendations are based on a series of cases, case reports and clinical expertise extrapolated from others glomerulopathies. Regardless of the complexity of the disease, in all patients the treatment consists in optimal nutrition, controlling dyslipidemia and blood pressure, prioritizing the use of ACE inhibitors or Angiotensin I receptor blockers to inhibit the renin-angiotensin system and reduce urinary protein [2,12,13].

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].

Eculizumab (Monoclonal Antibodies against C5) has been tested on small samples, showing partial or complete response in 46% of the cases, especially on those with creatine >1,5 upon admission and a rapid progression [15]. Likewise, Welte T. et al used eculizumab in seven patients previously diagnosed with C3G, including five patients with C3GN and 2 with DDD. Four patients showed improved or stable renal function, defined as a decrease of serum creatinine, urinary protein, or hematuria after 3 months of treatment of 30% or around 30%, respectively. The time of response was between 2 weeks to 6 months [6].

Regarding other therapies, such as rituximab or plasma therapy, there is not enough data at present to give any recommendation. McCaughan reported the case of 29-year-old woman who required a kidney transplant for a DDD. After 4 weeks of transplantation, because of worsening proteinuria and renal function, treatment with rituximab, corticosteroid and plasmapheresis was initiated but the deterioration in renal function continued [16].

There are ongoing trials investigating novel therapeutic anti-complement drugs such as avacopan, danicopan, pegcetacoplan or iptacopan. Avacopan, an oral C5aR1 inhibitor, is being tested in a phase 2 randomized, double blind, placebo-controlled trial (NCT03301467). The objective is to evaluate efficacy based on histologic changes in kidney biopsies taken at baseline and after 26 weeks of treatment. Danicopan (ACH-0144471), an oral factor D inhibitor, is being evaluated in three different trials (NCT03369236, NCT03459443 and NCT03124368). Pegcetacoplan (APL-2), a subcutaneously a C3 inhibitor, is being tested for proteinuria reduction (NCT03453619). Finally, iptacopan (LNP023) is an oral, reversible inhibitor of factor B, evaluated for change in proteinuria and histopathological changes in kidney biopsy (NCT03832114). No results are available yet.

In terms of prognosis, there is no difference between dense deposit disease or rapidly progressive glomerulonephritis and has been reported that more than 50% of the patients will progress to chronic renal disease despite treatment [2]. According to the series published in 2014 by Ladan Z. et al, 66.7% of patients with kidney transplantation developed recurrent C3GN in the allograft, with a median time of 28 month; most of these patients had hematuria (45%), low C3 (78%) and all had proteinuria at the time of recurrence. Allograft biopsies showed bright C3 staining (2–3+), with six biopsies also showing trace/1+ staining for IgM and/or IgG. Finally, 50% had lost their graft secondary to recurrence. Three patients had a second recurrence, and four cases of recurrence were identified by protocol kidney allograft biopsies, which showed C3 deposits in the absence of clinical symptoms [17].

 

Conclusions

In the case described here, the patient initial manifestations were related to a nephritic syndrome with a nephrotic component, with a severe impaired renal function, depletion of C3 complement, and without response to steroid pulse, therefore requiring hemodialysis. Prognosis was bad, even upon admission. Renal biopsy showed mesangioproliferative glomerulonephritis with C3 staining and severe chronic changes greater than 80%. This rare disease is a diagnostic and therapeutic challenge given its poor prognosis. More studies must be conducted, clinical guides must be established in order to manage this disease, and protocols should emphasize pre-transplant studies of complement pathologies.

 

Acknowledgment

We thank Dr. Lina María Espinosa and Fundación Santa Fe de Bogotá for providing microscopic biopsy images and their description.

 

References

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