Complement-mediated renal diseases after kidney transplantation - current diagnostic and therapeutic options in de novo and recurrent diseases

Table 1 Morphological features of C3 glomerulopathy

	Morphological features of C3G
Light microscopy	Active lesions
	Mesangial expansion with or without hypercellularity
	Endocapillary hypercellularity including monocytes and/or neutrophils
	Capillary wall thickening with double contours (combination of capillary wall thickening + mesangial increase is referred to as a membranoproliferative pattern)
	Fibrinoid necrosis
	Cellular/fibrocellular crescents
	Chronic lesions
	Segmental or global glomerulosclerosis
	Fibrous crescents
IF microscopy	Typically dominant C3 staining
Electron microscopy	DDD: Dense osmiophilic mesangial and intramembranous electron dense deposits.
	C3GN: Amorphous mesangial with or without capillary wall deposits including subendothelial, intramembranous and subepithelial EDD
	Subepithelial “humps” may be seen in both DDD and C3GN

Adapted from Goodship et al[12]. C3G: C3 glomerulopathy; DDD: Dense deposit disease; C3GN: C3 glomerulonephritis; EDD: Electron dense deposits, fibrinoid necrosis.

Table 2 Morphological features in microangiopathy

Active lesions	Chronic lesions
Glomeruli: Thrombi - Endothelial swelling or denudation - Fragmented RBCs - Subendothelial flocculent material. EM: Mesangiolysis - Microaneurysms	Glomeruli: LM: Double contours of peripheral capillary walls, with variable mesangial interposition - EM: New subendothelial basement membrane - Widening of the subendothelial zone
Arterioles: Thrombi - Endothelial swelling or denudation - Intramural fibrin - Fragmented red blood cells - Intimal swelling - Myocyte necrosis	Arterioles: Hyaline deposits
Arteries: Thrombi - Myxoid intimal swelling - Intramural fibrin - Fragmented red blood cells	Arteries: Fibrous intimal thickening with concentric lamination (onion skin)

Adapted from Goodship et al[12]. EM: Electron microscopy; LM: Light microscopy.

Table 3 Extrarenal manifestations reported in atypical hemolytic uremic syndrome, dense deposit disease, and C3 glomerulonephritis

aHUS	DDD/C3GN
Digital gangrene, skin	Retinal drusen
Cerebral artery thrombosis/stenosis	Acquired partial lipodystrophy
Extracerebral artery stenosis
Cardiac involvement/myocardial infarction
Ocular involvement
Neurologic involvement
Pancreatic, gastrointestinal involvement
Pulmonary involvement
Intestinal involvement

Adapted from Goodship et al[12]. aHUS: Atypical hemolytic uremic syndrome; C3GN: C3 glomerulonephritis; DDD: Dense deposit disease.

Table 4 Overview of mutations in complement factor H-related protein genes

Genetic defect	Phenotypical expression
Duplication in CFHR5 gene	C3 glomerulopathy (CFHR5 nephropathy)
Duplication in CFHR1 gene	C3 glomerulopathy
Hybrid CFHR3/CFHR1	C3 glomerulopathy
Hybrid CFHR2/CFHR5	C3 glomerulopathy
Hybrid CFH/CFHR1	aHUS
Hybrid CFH/CFHR3	aHUS

Adapted from Salvadori et al[1]. aHUS: Atypical hemolytic uremic syndrome; CFH: Complement factor H.

Table 5 Recommended therapy approach for C3 glomerulopathy based on small prospective trial, case reports, and expert opinion

All patients	Moderate disease	Severe disease
Lipid control	Urine protein > 500 mg/24 h despite supportive therapy, or	Urine protein > 2000 mg/24 h despite immunosuppression and supportive therapy or
Optimal BP control (< 90% in children and ≤ 120/80 mm Hg in adults)	Moderate inflammation on renal biopsy or	Severe inflammation represented by marked endo- or extracapillary proliferation with/without crescent formation despite immunosuppression and supportive therapy or
Optimal nutrition for both normal growth in children and healthy weight in adults	Recent increase in serum creatinine suggesting risk for progressive disease	Increased S. Cr suggesting risk for progressive disease at onset despite immunosuppression and supportive therapy
	Recommendation	Recommendations
	Prednisone	Methylprednisolone pulse-dosing as well as other anti-cellular immune suppressants have had limited success in rapidly progressive disease
	Mycophenolate mofetil	Data are insufficient to recommend eculizumab as a first-line agent for the treatment of rapidly progressive disease

Adapted from Goodship et al[12].

Table 6 Monitoring eculizumab therapy

CH50 (total complement activity)	AH50 (alternative pathway hemolytic activity)	Eculizumab trough	Alternative assays
Measures the combined activity of all of the complement pathways	Measures combined activity of alternative and terminal complement pathways	May be a free or bound level	The following assays are under investigation
Tests the functional capability of serum complement components to lyse 50 % of sheep erythrocytes in a reaction mixture	Tests functional capability of alternate or terminal pathway complement components to lyse 50% of rabbit erythrocytes in a Mg2+-EGTA buffer	ELISA: using C5-coated plates, patient sera, and an anti-human IgG detection system	Free C5
Low in congenital complement deficiency (C1-8) or during complement blockade	Will be low in congenital C3, FI, FB, properdin, FH, and FD deficiencies or during terminal complement blockade	Not affected by complement deficiencies	In vitro human microvascular endothelial cell test
Normal range: Assay dependent	Normal range is assay-dependent.	Recommended trough level during complement blockade: 50-100 μg/mL	SC5b-9 (also referred to as sMAC and TCC) remain detectable in aHUS remission, so not recommended as a monitoring tool
Recommended goal during therapeutic complement blockade: < 10% of normal	Recommended goal during complement blockade: < 10% of normal

Adapted from Goodship et al[12]. aHUS: Atypical hemolytic uremic syndrome; C3: Complement component 3; C5: Complement component 5; EGTA: Ethyleneglycol tetraacetic acid; ELISA: Enzyme-linked immunosorbent assay; FB: Complement factor B; FD: Complement factor D; FH: Complement factor H; FI: Complement factor I; sC5b-9: Soluble C5b-9; sMAC: Soluble membrane attack complex; TCC: Terminal complement complex.

Table 7 Transplant considerations in C3 glomerulopathy¹

Timing	Donor selection	Risk reduction
Avoid transplantation during acute period of renal loss	No specific recommendation can be made on donor choice. When considering living donors, high risk of recurrence should be weighed against presumed risk of waiting on cadaveric donor list	C3G histological recurrence is as high as 90%[7,87]
Avoid transplantation during acute inflammation		Limited data suggest: rapid progression to ESRD in native kidneys increases recurrence risk[87]
No data supporting whether specific complement abnormalities (e.g., high titer C3Nef, low C3 or high soluble C5b-9) predict increased risk for relapse		There are no known strategies to reduce recurrence risk of C3G
		Clinical recurrence should drive decision to treat[7]
		In absence of clinical trials, use of anti-complement therapy is based solely on a small open-label trial and positive case reports[62] (the impact of publication bias is unknown)
		C3G associated with monoclonal gammopathy has a high rate of recurrence[7]

¹Based on limited retrospective cohort data. Adapted from Goodship et al[12]. C3: Complement component 3; C3G: C3 glomerulopathy; C3Nef: C3 nephritic factor; ESRD: End-stage renal disease.

Table 8 Eculizumab dosing in atypical hemolytic uremic syndrome based on dosing goal

Minimal dose	Discontinuation
Desire to continue dosing with the minimal dose required to achieve a pre-identified level of complement blockade1	Desire to discontinue complement blockade
Dose reduction or interval extension	No consensus exists regarding tapering of dose
Goal CH50 < 10% (recommended)
Goal AH50 < 10% (recommended)
Goal eculizumab trough >100 μg/mL

¹Additional monitoring may be required during intercurrent events (e.g., infection, surgery, vaccination) to detect unblocked complement activity. Adapted from Goodship et al[12]. AH50: Alternative pathway hemolytic activity; CH50: Total complement activity.

Table 9 Risk of atypical hemolytic uremic syndrome recurrence according to the implicated genetic abnormalities

Gene mutation	Location	Functional Impact	Mutation frequency in aHUS (%)	Recurrence after transplantation (%)
CFH	Plasma	Loss	20-30	75-90
CFI	Plasma	Loss	2-12	45-80
CFB	Plasma	Gain	1-2	100
C3	Plasma	Gain	5-10	40-70
MCP	Membrane	Loss	10-15	15-20
THBD	Membrane	Loss	5	One case
Homozygous CFHR1 del (3%-8%)	Circulating	Undetermined	14-23 (> 90% with anti-CHF AB)	NA

Adapted from Salvadori et al[1]. aHUS: Atypical hemolytic uremic syndrome; NA: Not available; CFH: Complement factor H; CFI: Complement factor I; CFB: Complement factor B; C3: Complement 3; MCP: Membrane cofactor protein; THBD: Thrombomodulin.