P278
RECURRENCE OF COMPLEMENT FACTOR H-RELATED PROTEIN 5 (CFHR5)
NEPHROPATHY IN A RENAL TRANSPLANT
Vernon, K1, Gale, D2, de Jorge, E1, McLean, A2, Maxwell, P3, Pickering, M1,
Terence Cook, T2
1Rheumatology Section, 2Imperial College Kidney and Transplant Institute,
Imperial Academic Health Science Centre, London, 3Division of Medicine,
University College, London
INTRODUCTION: Complement dysregulation is associated with C3 glomerulonephritis
(C3GN). C3GN is characterised by mesangial and sub-endothelial glomerular basement
membrane (GBM) deposits that contain C3 in the absence of immunoglobulin, often associated
with membranoproliferative inflammation (MPGN). A heterozygous internal duplication in the
complement factor H-related protein 5 (CFHR5) gene has been associated with familial C3GN
among Cypriot individuals. This disorder, designated CFHR5 nephropathy, is characterized
clinically by persistent microscopic haematuria, synpharyngitic macroscopic haematuria and
progressive renal failure. CFHR5, a plasma protein, has complement regulatory function in vitro
and co-localises with renal complement deposits in vivo, suggesting that it may regulate
complement activation within the kidney. The mechanism through which heterozygous internal
duplication in CFHR5 predisposes to C3GN remains unknown. Here we report an individual
with CFHR5 nephropathy and end-stage renal failure (ESRF), who developed rapid recurrence
of CFHR5 nephropathy in an unrelated donor transplant kidney.
CASE HISTORY AND RESULTS: A 53-year old Cypriot male with ESRF initially thought
to be secondary to type 1 MPGN, but subsequently found to be C3GN on review of his original
renal biopsies, underwent a cadaveric renal transplant. He had a past history of episodic
macroscopic haematuria but normal cystoscopy and urine cytology. Renal transplantation
proceeded with no complications. Immunosuppression included alemtuzumab and
corticosteroids perioperatively, with tacrolimus monotherapy continued on discharge eight days
later. Although his creatinine initially fell, it subsequently stabilised at 186µmol/l and he
underwent a transplant biopsy forty-six days after transplantation. The biopsy showed scattered
sub-endothelial and mesangial electron dense deposits with isolated granular C3 staining,
features consistent with C3GN. PCR of genomic DNA together with serum CFHR5 western
blot analysis demonstrated heterozygous internal duplication of CFHR5, changes identical to
those reported in familial Cypriot CFHR5 nephropathy.
CONCLUSION: CFHR5 nephropathy rapidly recurred in the transplanted kidney,
demonstrating that the effect of the mutation is not related to synthesis of the abnormal CFHR5
protein by the kidney. The liver is the major site of synthesis of many plasma complement
regulatory proteins. We speculate that if the liver represents the major extra-renal source of
CFHR5, then analogous to complement mutations in plasma proteins in atypical haemolytic
uremic syndrome, combined liver-kidney transplantation may be required to achieve long-term
remission in CFHR5 nephropathy.