Introduction

Homozygous factor H deficiency leads to permanent alternate complement activation with undetectable plasma levels of C3 and factor H and is usually associated with membranoproliferative glomerulonephritis. However, a few cases of chronic hemolytic uremic syndrome (HUS) with early onset have been reported [1, 2]. Repeated infusions of fresh frozen plasma (FFP) have been demonstrated to prevent biological relapses of HUS and progression to renal failure. We report here the case of a patient who was successfully treated for 4 years but acquired a resistance to FFP.

Case report

The patient and the initial period of treatment with FFP has been reported in a previous paper [1]. Factor H deficiency was due to homozygosity of a nucleotide substitution (2770 T→A) in the factor H gene leading to a stop codon in the SCR 15 at positions 899 [2]. Viroattenuated FFP containing functional factor H antigen (91% of normal values) was infused using an implantable catheter in the right internal jugular vein from the age of 4 [1] to the age of 8 years. He received 200 ml (13.5 ml/kg once weekly) of plasma during the first year of treatment then 400 ml (22 ml/kg once weekly). Despite severe nephron loss (60% of global glomerular sclerosis), creatinine clearance remained over 100 ml/min per 1.73 m2, and plasma haptoglobin was steadily in the normal range (Fig. 1, days −336 to −53). Blood pressure was controlled with an angiotensin converting enzyme (ACE) inhibitor only, and proteinuria was below 0.5 g/l during this period. However, residual levels of plasma factor H and C3 were steadily low. No blood transfusion was needed during this period, and erythropoietin therapy was withdrawn 6 months following the onset of plasma therapy. By the end of the fourth year of treatment (Fig. 1, day 0–91), he developed massive proteinuria (4.6 g/day) with hypoalbuminemia (27 g/l) while plasma haptoglobin suddenly began being undetectable. Kidney biopsy showed no additional worsening of global glomerular sclerosis, but recent thrombi were observed in several arterioles and glomerular capillary lumens. In order to circumvent inadequate dosage of plasma, the infused volume of FFP was increased to 600 ml (20 ml/kg once weekly) then to 1,800 ml (60 ml/kg once weekly) through a plasma exchange, but it did not lead to a significant biological improvement. A series of 11 plasma exchanges of 1,800 ml were then performed for 13 days, but plasma haptoglobin could not be stabilized within the normal range despite an increased circulating level of antigenic factor H up to 24% of normal value. Bilateral nephrectomy was done by day 103 due to uncontrolled life-threatening hypertension and rapidly increasing plasma creatinine. Several attempts in searching for factor H antibodies (methods reported in [3]) were negative over this 3-month period. Long-term follow-up showed normal or increased values (960–3,540 mg/l) of plasma haptoglobin after bilateral nephrectomy when treated with hemodialysis (for 1 year following day 103) or with peritoneal dialysis while factor H and C3 remained steadily undetectable.

Fig. 1
figure 1

Course of plasma haptoglobin (thin lines) and plasma creatinine (bold lines) 1 year before the relapse of hemolytic uremic syndrome (left part of the panel, days −296 to −53) and after the relapse of hemolytic uremic syndrome (right part of the panel, days 0–91). Day 0 is defined by the first observation of the fall of plasma haptoglobin under normal values (500–1,350 mg/l). The upper side of the panel shows the rate and volume of plasma infusions during the course. Follow-up of circulating C3 (normal values 660–1,250 mg/l) and antigenic factor H (normal values 65–140%) are indicated underneath

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Discussion

Factor H deficiency due to homozygous mutations in the factor H gene is usually reported to be associated with membranoproliferative glomerulonephritis but in a few cases with early developed HUS and authentic thrombotic microangiopathy [1, 4, 5]. Those patients have undetectable plasma level of C3 and factor H. According to previous reports, low dosages of FFP were able to prevent hemolytic anemia and the progression to renal failure in homozygous patients [1, 5, 6], but the duration of reported follow-up is limited, from 8 to 18 months. Consistent with these data, our patient was successfully treated for more than 4 years with low dosages of plasma infusion once weekly, leading to a stable normal creatinine clearance, low range of proteinuria, normal blood pressure while being treated with an ACE inhibitor only, and normal plasma haptoglobin. Unexpectedly, he became dramatically resistant to plasma therapy and developed biological and histological features of a relapse of HUS despite increased volume of plasma infusion and daily delivery. Rapidly progressive renal failure was certainly due to resumed damage to his renal vasculature in addition to severe nephron loss acquired prior to plasma therapy. As a matter of fact, removal of renal endothelium with bilateral nephrectomy led to the normalization of plasma haptoglobin while complement activation remained uncontrolled with undetectable plasma factor H. Different mechanisms might explain the secondary plasma resistance of our patient. We considered the possibility of antifactor H immunization [3] but were unable to find any circulating antifactor H antibodies. Moreover, the effect of renal endothelium removal through bilateral nephrectomy [6] raises the question of a special link between factor H and kidney vasculature that could involve cooperation between factor H and adrenomedullin, a short peptide involved in antenatal development and postnatal regulation of renal vasculature [7, 8].

In conclusion, our data suggests that protracted administration of FFP might not be a successful long-term strategy to prevent HUS attacks in homozygous factor H deficiency.