Successful treatment of factor H-related haemolytic uraemic syndrome

Jon D. Stratton and Paul Warwicker

Lister Hospital, Stevenage Herts SG1 4AB, UK Email: jon.stratton{at}ntlworld.com

Sir,

Haemolytic uraemic syndrome (HUS) is characterized by the triad of microangiopathic haemolytic anaemia, thrombocytopenia and renal failure. HUS can be classified as diarrhoeal (D+) or non-diarrhoeal (D-). D–HUS is often idiopathic, although endothelial dysfunction appears to be an important factor in the microangiopathy [1].

We suggest that a significant percentage of relapsing, and probably most cases of familial, D–HUS are caused by a complement (alternative pathway) driven endotheliopathy. A deficiency or perhaps dysfunction of complement factor H has been implicated in this process [2]. A new sub-category of H-HUS could be used to identify these patients. Factor H has several important regulatory roles in the activity of the alternative pathway (reviewed by Sim et al. [3]). There have now been over 30 reports of H-HUS in factor H-deficient families, as well as several families with inherited HUS genetically linked with the gene for factor H.

We present a patient with factor H deficiency, who developed acute renal failure with HUS and required haemodialysis. With the use of an extended course of plasma exchange in conjunction with immunoglobulin therapy he is only the second case to regain independent renal function.

Case.

A 33-year-old man was admitted with a 2-week history of intermittent headache, malaise, vomiting and oliguria. He was hypertensive (180/100 mmHg) with microscopic haematuria and proteinuria. Examination revealed pallor and acute hypertensive retinal changes with haemorrhages. Investigations demonstrated anaemia (Hb 7.9 g/dl), thrombocytopaenia (platelets 73x109/l) and renal impairment (creatinine 1066 µmo/l). Red cell fragments were seen on a blood film. A renal ultrasound was normal. Haemodialysis was initiated. An initial immunology screen revealed anti-nuclear (titre 1/320) and anti-double stranded DNA (titre 1/320) antibodies but were negative on repeat testing, negative serum ELISA for ANCA and GBM, C3 0.46 (0.85–2.0) g/l and C4 0.24 (0.15–0.5) g/l.

Three-litre plasma exchanges were initiated with oral prednisolone (60 mg/day) and cyclophosphamide (2 mg/kg). The high blood pressure was treated aggressively. He was concurrently treated with maximal doses of Perindopril, Doxazosin, Nifedipine and Losartan. This controlled his blood pressure to 125/70 mmHg. Complement factor H was 275 (450–600) mg/l; properdin and factors B and I were normal. Properdin and factors H, I and B were measured by radial immunodiffusion on commercial kits (Binding Site, UK). Reference ranges were used from the company. We found his asymptomatic mother to have a low C3 and haemideficient in factor H (230 mg/l), his father had a factor H level of 537 mg/l with normal complement levels.

He received five plasma exchanges in the first week. The platelet count improved to 116x109/l and the haemoglobin rose with transfusion. A renal biopsy was performed 13 days after admission. Mild to moderate mesangial hypercellularity was seen in 50% of the glomeruli, with double staining of the capillary walls due to mesangial interposition. Minimal acute tubular necrosis was evident. Mild interstitial fibrosis was present. The major pathology was demonstrated in the vessels with extreme luminal narrowing in the arterioles and interlobular arteries. This was secondary to mucoid intimal thickening with extravasation of fibrin and red cells into an abnormal intima. Immunofluorescence was positive for IgA, M and G in the glomerulus but negative for C3 and C1q. The microangiopathy seen on the renal biopsy were consistent with a diagnosis of D–HUS and there were no features of systemic lupus erythematosus or a necrotizing vasculitis.

Immunosupression was stopped and he continued with regular plasma exchange and haemodialysis. The haemolysis gradually diminished with reduction in LDH and the disappearance of red cell fragments. His C3 rose to 0.73 mg/l. The platelet count remained variable and fell to a nadir of 71x109/l (Figure 1Go). Pooled intravenous immunoglobulin (IVIg) (Sandoglobulin) 0.4 g/kg was administered when his platelets count fell to 100x109/l. This lead to a temporally related, transient (approximately 3 weeks), rise in platelet count. Because of apparent failure in renal recovery, the plasma exchange was stopped after 6 weeks. An almost immediate fall in his C3 to very low levels followed. Plasma exchange was re-initiated, leading to restoration of the values. Factor H levels mirrored his C3 levels (Figure 1Go).



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Fig. 1.  Response to treatment with plasma and immunoglobumin.

 
For 3 months he remained on weekly plasma exchange, regular haemodialysis, IVIg for thrombocytopaenia, and strict blood pressure control. C3 levels gradually rose. After 3 months there began a steady improvement in his urine output and 1-l plasma infusions replaced plasma exchange. A sustained rise in his renal function allowed dialysis withdrawal 120 days after initial presentation. He remains dialysis independent with a creatinine of 220 µmol/l (creatinine clearance 53 ml/min) 1 year after stopping dialysis. His LDH is normal and platelet count has leveled at 120x109/l (Figure 1Go). He remains on Doxazosin and Perindopril to control his blood pressure at 130/80 mmHg.

Discussion.

Factor H deficiency is rare [3]. It has been associated with SLE like collagen vascular disease, increased susceptibility to infection and glomerulonephritis (reviewed in [3,4]) and over 30 cases of HUS. In a study within families with inherited HUS, subjects with low C3 levels had a 16.56 relative risk of HUS (CI 1.66–162.39) [5].

Mortality of factor H-related HUS remains unacceptably high. Reported cases associated with deficiency demonstrate a mortality of 48%. Those patients that survive and require dialysis have rarely recovered independent renal function (our patient is only the second affected individual). IVIg has previously been used in H-HUS [6,7]. It is thought to act as a receptor for activated complement components such as C3b [8] thereby diverting them from target surfaces. In our patient, the platelet count response to intravenous immunoglobulin given during concurrent weekly plasma exchanges was impressive, but virtually non-existent when given during weekly plasma infusions. This synergy may be caused by the removal of the bound C3b-immunoglobulin during the plasma exchange process.

Based on these findings we suggest a prolonged ‘induction regimen’ of combined plasma exchange (using FFP as replacement fluid) and IVIg (titrated to the platelet count). If renal biopsy confirms reasonable renal preservation, treatment should not be abandoned too early, as there may still be response several months into the regimen. Factor H levels are almost normal in stored fresh frozen plasma (440 mg/l in a standard bag of FFP tested), and it is likely that plasma exchange acts as a surrogate form of factor H delivery.

Once the endothelial activation is reduced (as evidenced by stable platelets, normal LDH, reduced need for blood transfusion and improvement in renal function) the requirement for factor H supplementation appears to be reduced in our factor H haemideficient patient. He remains stable despite continued lowered C3 and factor H levels and is off all treatment except anti-hypertensives.

References

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