Digital Ischemia as a Rare Manifestation of C3 Glomerulopathy Associated With Monoclonal Gammopathy

Introduction

C3 glomerulopathy (C3GP) is a group of rare glomerular diseases histologically characterized by isolated or predominant C3 deposits within glomeruli associated with glomerular inflammation. Dysregulation of complement alternative pathway was shown to be the cornerstone of their pathogenesis. Patients usually display either rare and pathogenic variants in complement genes implicated in alternative pathway regulation or, more often, autoantibodies interacting with components of this pathway. Some of these antibodies stabilize the activity of C3 or C5 convertase—C3 and C5 nephritic factors—whereas others inhibit regulatory proteins such as complement factor H. In patients with C3GP, monoclonal Ig (mIg) is found in approximately 15% of patients, and even in two-thirds of patients after the age of 50 years.¹ In these cases, the mIg can seldom carry the autoantibody activity, thus defining a monoclonal gammopathy of renal significance.² The clinical presentation of C3GP is similar to that of most glomerular diseases, including glomerular proteinuria, hematuria, hypertension, and eventually chronic kidney disease sometimes leading to end-stage renal disease.^1,3 Data on extrarenal involvement in C3GP, especially cutaneous involvement, remain scarce in the literature. Herein, we report 5 patients presenting with mIg-C3GP and digital ischemia. Details on patient identification and study methods can be found in the Supplemental Material.

Results

Clinical Characteristics

The main characteristics of our patients are summarized in Table 1. Three patients were females and 2 were males, and the median age at the onset of digital ischemia was 55 years. Digital ischemia preceded the diagnosis of C3GP in 3 patients with an interval ranging from 1 to 9 years. In the 2 remaining patients, C3GP was diagnosed 2 years before the onset of digital ischemia in 1 case, and simultaneously in 1 case. Two patients underwent skin biopsy of the ischemic lesions, showing no vasculitis but thrombosis in one of them. Light microscopy of renal biopsy specimens showed endocapillary proliferation in all patients and mesangial proliferation in 2 patients. None of the patients had concomitant thrombotic microangiopathy lesions or vasculitis lesions. Immunofluorescence demonstrated the presence of isolated or predominant C3 deposits within the glomeruli in all cases.

Table 1.

Characteristics of patients with C3GP and DI

Characteristics	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Gender, age at digital ischemia onset (yr)	M, 20	F, 68	F, 55	M, 80	F, 30
Chronology	DI diagnosed 2 years before C3GP	DI and C3GP diagnosed simultaneously	C3GP diagnosed 2 years before DI	DI diagnosed 2.5 years before C3GP	DI diagnosed 9 years before C3GP
DI
Clinical description of DI	Severe Raynaud’s phenomenon with ischemic necrosis of fingers and toes requiring multiple phalangeal amputations	Chronic ischemia and necrosis of fingers and toes	Severe Raynaud’s phenomenon with ischemic necrosis of fingers and toes requiring phalangeal amputation	Severe Raynaud’s phenomenon with ischemic necrosis of fingers and toes	Livedoid and purpuric lesions of the hands and feet
Megacapillaries	Yes	No	Yes	No	NA
Cutaneous histology	NA	Superficial thrombosis in dermis capillaries without vasculitis	NA	No thrombosis or vasculitis	NA
C3GP
Clinical features	Impure NS with progressive loss of renal function	RPGN	Impure NS with acute renal failure	Mild renal dysfunction, glomerular proteinuria, hematuria, HBP	Glomerular proteinuria, hematuria, HBP
Renal histology	LM: mesangial and endocapillary proliferative GN IF: mesangial and parietal deposits of C3	LM: endocapillary proliferative GN IF: mesangial and parietal C3 deposits	LM: mesangial and endocapillary proliferative GN associated with IF: mesangial and subepithelial C3 deposits	LM: MPGN IF: mesangial and parietal C3 deposits	LM: MPGN IF: mesangial and parietal C3 deposits
Laboratory findings at C3GP diagnosis
C3 (mg/l)a	814	788	568	520	556
C4 (mg/l)a	195	380	189	254	195
sC5b-9 (ng/ml)a	1800	846	427	905	1339
CFH / CFI	normal / normal	normal / normal	normal / normal	normal / normal	normal / normal
FHA	positive (1000 UA)	positive (950 UA)	positive (1850 UA)	negative	negative
C3NeF	negative	negative	NA	negative	negative
Mutation in CFH, CFI and/or MCP genes	no	no	no	NA	no
aPL	negative	negative	negative	negative	negative
Cryoglobulinemia	absenceb	absence	absence	absence	absence
CA	absence	absence	absence	absence	absence
Other autoantibodies	ANA 1/500	absence	absence	absence	absence
mIg	IgG4κ, detected in the years following C3GP diagnosis: 0.5 g/l	IgG1λ at C3GP diagnosis: 10.4 g/l	IgGλ at C3GP diagnosis: 7.2 g/l	IgGκ at C3GP diagnosis: 5 g/l	IgG1λ at C3GP diagnosis: 7 g/l
Hematological malignancy	no	myeloma	no	no	no

ANA, antinuclear antibodies; aPL, antiphospholipid antibodies; C3GP, C3 glomerulopathy; C3NeF, nephritic factor; CA, cold agglutinins; CFH, complement factor H; CFI, complement factor I; DI, digital ischemia; FHA, anti-factor H antibodies; HBP, high blood pressure; IF, immunofluorescence; LM, light microscopy; mIg, monoclonal immunoglobulin; MPGN, membranoproliferative glomerulonephritis; NA, not available; NS, nephrotic syndrome; RPGN, rapidly progressive glomerulonephritis.

^aNormal values: C3: 660-1250 mg/l; C4: 93-380 mg/l; C5-b9: <420 ng/ml.

^bType 2 cryoglobulinemia with monoclonal IgMλ was transiently detected more than 15 years after the onset of DI and C3GP.

Biological Assessment

Complement abnormalities at C3GP diagnosis included low C3 complement fraction in 3 of 5 patients and increased soluble C5-b9 in 5 of 5 patients. In patient 1, C3 hypocomplementemia was absent at the time of C3GP diagnosis but appeared during the follow-up. C3 levels at the time of digital ischemia onset were available in 3 patients: patient 3 had C3 hypocomplementemia whereas C3 levels were normal in patients 2 and 4. Among the patients in whom digital ischemia preceded C3GP, data on kidney function at the time of digital ischemia onset was available in 1 (patient 4): his serum creatinine was within the normal range (0.97 mg/dl) and he had no proteinuria or hematuria. Antifactor H of IgG isotype was detected in 3 patients, whereas no patient had C3 nephritic factor. IgG monoclonal gammopathy was present in all patients. Patient 3 was diagnosed with systemic erythematosus lupus 18 years earlier but did not show any clinical manifestation of systemic erythematosus lupus and had undetectable antinuclear, anti-ENA and anti-dsDNA antibodies levels at the time of C3GP and digital ischemia. Finally, no patient had antiphospholipid antibodies, cryoglobulinemia, cryofibrinogenemia, or cold agglutinins; and none of them had evidence for thrombotic microangiopathy, cholesterol crystal emboli syndrome, active systemic autoimmune disease, embologenic arrhythmia, large vessel disease, and inherited or acquired thrombophilia.

Treatments and Outcome

Data on treatments and outcome are reported in Table 2. Four patients received symptomatic treatments for digital ischemia, consisting of vasodilators and antithrombotic drugs, which were effective in controlling digital ischemia in only 1 patient. All patients received antimyeloma agents (including bortezomib, lenalidomide, cyclophosphamide, and/or dexamethasone) and 3 patients received eculizumab. At the time of initiation of antimyeloma agents and/or eculizumab, 3 patients had uncontrolled digital ischemia. Eculizumab improved digital ischemia in 2 of 3 patients, whereas bortezomib alone improved digital ischemia in 1. In patient 4, digital ischemia was resolved when antimyeloma and eculizumab were initiated and it did not relapse during follow-up. In patient 5, digital ischemia improved spontaneously without treatments.

Table 2.

Patients’ treatment and outcome

Characteristics	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Follow up time (yr)	31	5	4	3	11
Treatments and outcome	Glucocorticoids, melphalan, cyclophosphamide: - chronology: Y1–Y12 - indication: DI, severe kidney disease - DI: no efficacity - C3GP: progression to ESRD requiring HD PE (every 2–3 weeks): - chronology: Y12–Y21 - indication: severe DI - DI: improvement but PE dependency Eculizumab: - chronology: Y21–Y31 - indication: DI, prevention of C3GP relapse in kidney graft - DI: sustained improvement allowing PE discontinuation - C3GP: kidney transplantation at Y23, relapse and progression to ESRD at Y24 VD regimen: - chronology: Y28–Y29 - indication: increase of the mIg (5 g/l at Y28) - no benefit on mIg or complement parameters	Iloprost: - chronology: Y1 - indication: DI - no efficacity VCD regimen: - chromoly: Y1 - indication: DI, severe kidney disease - DI: transient effectiveness - C3GP: renal function deterioration requiring hemodialysis Eculizumab (5 infusions): - chronology Y1 - indication: DI, severe kidney disease - DI: resolution of DI - C3GP: normalization of renal function, reduction of proteinuria and discontinuation of hemodialysis	Iloprost, UFH, aspirin: - chronology: Y1 - indication: DI - insufficient effectiveness leading to digital amputation Bortezomib: - chronology: Y2 - indication: DI, severe kidney disease - DI: resolution of DI - C3GP: improvement of renal function and reduction of proteinuria	Iloprost: - chronology: Y1–Y2 - indication: DI - improvement of DI Aspirin, CCB, bosentan: - chronology: Y1 - indication: DI - resolution of DI Concomitant VR regimen and eculizumab: - chronology: Y2 - indication: kidney disease, prevention of DI relapse - DI: no relapse of DI - C3GP: stabilization of renal function, reduction of proteinuria	Spontaneous improvement of DI VD regimen: - chronology: Y11 - indication: kidney disease - C3GP: disappearance of proteinuria and hematuria
Evolution of complement status	Stable titers of FHA, persistence of low C3	Undetectable FHA titers	Decrease in FHA levels, normalization of C3	Persistence of low C3	Normalization of C3
Evolution of MG	50% decrease after VD initiation	Decrease (IgG 4.5 to 2 g/l) after VCD initiation	Stability	Decrease (IgG 3 to 2.5 g/l) after VR initiation	Disappearance after VD initiation

C, cyclophosphamide; C3GP, C3 glomerulopathy; CCB, calcium channel blocker; D, dexamethasone; DI, digital ischemia; ESRD, end-stage renal disease; FHA, anti-factor H antibodies; mIg, monoclonal immunoglobulin; NA, not available; PE, plasma exchange; R, lenalidomide; UFH, unfractionated heparin; V, bortezomib; Y, year.

Regarding C3GP, improvement was noted with antimyeloma treatments in 2 patients (bortezomib alone in one, bortezomib and dexamethasone in the other), eculizumab in 1 patient and a combination of eculizumab plus antimyeloma agents (lenalidomide and dexamethasone) in 1. In the remaining patient (patient 1), eculizumab was initiated after the patient had reached end-stage renal disease and did not prevent C3GP recurrence after kidney transplantation.

After successful treatment of digital ischemia and/or C3GP, C3 complement fraction normalized in 2 of 4 patients, antifactor H antibodies decreased in 2 of 3 and monoclonal protein levels decreased in 4 of 5.

Discussion

We report here the occurrence of digital ischemia as an extrarenal manifestation of mIg-C3GP. Only one other case of C3GP associated with digital ischemia was reported by Ramirez et al.⁴ In this case, severe and relapsing ischemia affecting the nose, ears, and limbs led to amputations, and workup detected a circulating mIgG kappa; however, the presence of antifactor H antibody, C3 nephritic factor, or complement variants was not assessed.

Mechanisms underlying digital ischemia in mIg-C3GP remain unclear, raising different hypotheses. First, it could be the consequence of thrombotic vasculopathy, as observed in type 1 cryoglobulinemia, cryofibrinogenemia, or cold agglutinin disease. However, these causes were ruled out in our patients. Another mechanism could be vasculitis, as in the patient reported by Ramirez et al.,⁴ in which pathological examination of ischemic lesions showed leukocytoclastic vasculitis. Finally, one could hypothesize that a limited form of thrombotic microangiopathy could lead to microthrombotic lesions and thus cause digital ischemia.⁵ Interestingly, Ravindran et al.⁶ recently reported 5 patients presenting with concurrent C3GP and thrombotic microangiopathy on kidney biopsies. In our study, among the 2 patients who underwent skin biopsy, none of them displayed vasculitis whereas capillary thrombosis was found in 1 case. In addition, renal pathology did not show any sign of thrombotic microangiopathy or vasculitis either.

Whatever the mechanism of injury, all our patients had low serum C3 and/or elevated soluble C5-b9, supporting the activation of alternative and/or terminal complement pathways.¹ Moreover, the patient described by Ramirez et al.⁴ had C3 hypocomplementemia and skin biopsy revealed C3 deposits in the vessel walls, arguing for a pathogenic role of complement. Unfortunately, the presence of C3 deposits in skin biopsy samples could not be assessed in our patients. Previous works have highlighted the complex interplay between complement and coagulation pathways.⁷ Furthermore, because no case of digital ischemia was reported in C3GP in the absence of monoclonal gammopathy, a proper role for the mIg is highly suspected. The occurrence of digital ischemia in mIg-C3GP could nevertheless be explained by pathophysiological differences between mIg-C3GP and C3GP without mIg. Indeed, Chauvet et al.² showed that targets of anticomplement autoantibodies were different in C3GP with and without mIg; and that in patients with mIg-C3GP, the alternative pathway was more frequently activated by polyclonal IgG than by the mIg.

Finally, 3 of our patients received the anti-C5 monoclonal antibody eculizumab, effective in C3GP, which was effective on digital ischemia in 2 patients.¹ Antimyeloma agents successfully treated digital ischemia in one of our patients and combination therapy with eculizumab and antimyeloma agents might have prevented relapse in another. Therefore, the effectiveness of treatments inhibiting the complement and targeting the mIg suggests an implication of both mIg and complement in the pathogenesis of digital ischemia. In addition, mIg could activate the complement pathways, possibly through an autoantibody activity targeting complement regulatory proteins.⁸ Supporting this hypothesis, Chauvet et al.⁹ showed, in patients with mIg-associated C3GP, that treatments targeting the mIg were effective on renal disease and C3 serum levels, and that effectiveness correlated with hematological response.

Overall, digital ischemia is a rare extrarenal manifestation of mIg-C3GP, in which mIg seems to play a key role. Eculizumab and treatments targeting monoclonal gammopathy seem to be effective not only on digital ischemia but also on kidney disease. This study extends the spectrum of digital ischemia causes by highlighting this particular association which should be known by physicians given the therapeutic implications.

Disclosures

All the authors declared no competing interests.

Supplementary Material

Patients and methods