The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome

Mutations in the gene encoding complement factor H (CFH) that alter the C3b/polyanions-binding site in the C-terminal region impair the capacity of factor H to protect host cells. These mutations are also strongly associated with atypical hemolytic uremic syndrome (aHUS). Although most of the aHUS-associated CFH mutations seem "unique" to an individual patient or family, the R1210C mutation has been reported in several unrelated aHUS patients from distinct geographic origins. Five aHUS pedigrees and 7 individual aHUS patients were analyzed to identify potential correlations between the R1210C mutation and clinical phenotype and to characterize the origins of this mutation. The clinical phenotype of aHUS patients carrying the R1210C mutation was heterogeneous. Interestingly, 12 of the 13 affected patients carried at least one additional known genetic risk factor for aHUS. These data are in accord with the 30% penetrance of aHUS in R1210C mutation carriers, as it seems that the presence of other genetic or environmental risk factors significantly contribute to the manifestation and severity of aHUS in these subjects. Genotype analysis of CFH and CFHR3 polymorphisms in the 12 unrelated carriers suggested that the R1210C mutation has a single origin. In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations.     

Complete factor H deficiency-associated atypical hemolytic uremic syndrome in a neonate

Recent advances have shown that atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. Almost 50% of cases are associated with mutations in the three complement regulatory genes, factor H (HF1), membrane co-factor protein (MCP) and factor I (IF). The corresponding gene products act in concert and affect the same enzyme, alternative pathway convertase C3bBb, which initiates the alternative pathway and amplification of the complement system. Factor H (FH) deficiency-associated aHUS usually occurs in infants to middle-aged adults and only rarely in neonates. Moreover, the vast majority of patients are heterozygous for the HF1 gene mutations. We report on a case of neonatal-onset aHUS associated with complete FH deficiency due to novel compound heterozygous mutations in the HF1 gene. A 22-day-old baby girl developed acute renal failure and a remarkably low serum complement C3 level, which was rapidly followed by the development of micro-angiopathic hemolytic anemia. Western blot analysis revealed nearly zero plasma FH levels, and an HF1 gene study showed compound heterozygous mutations, C1077W/Q1139X. Renal pathology findings were compatible with glomerular involvement in HUS. The baby recovered completely after the repetitive infusion of fresh frozen plasma. During follow-up (until she was 20 months old) after the initial plasma therapy, the disease recurred three times; twice after the tapering off of plasma therapy, and once during a weekly plasma infusion. All recurrence episodes were preceded by an upper respiratory tract infection, and were successfully managed by restarting or increasing the frequency of plasma therapy.     

Tacrolimus-associated hemolytic uremic syndrome: a case analysis

BACKGROUND: Tacrolimus is an effective organ transplantation immunosuppressant. Hemolytic uremic syndrome (HUS) is a rare but severe complication of tacrolimus. METHODS: We report a case of tacrolimus-associated HUS and review the 15 previously reported cases. RESULTS: The results of the 16 cases indicated that tacrolimus-associated HUS is more frequent in females (56.3%), with the mean age at onset of 41.3 years. Forty-four percent of cases received renal transplantations. The average time from the first tacrolimus dose to HUS onset was 7.1 months. Prevalence was between 0.14.7%. The tacrolimus trough level did not predict the prognosis. Seven patients (43.7%) had improved graft function after treatment, including anticoagulation and antiplatelet therapy, reduction or discontinuation of tacrolimus, switch to cyclosporine (CyA), plasma exchange (PE) and dialysis. Five patients (31.3%) died and four patients (25%) lost their graft in spite of the above treatment. Mortality risk factors for transplant recipients with tacrolimus-associated HUS included: (1) non-renal transplant recipients (100% vs. 36.4%, p = 0.034); (2) lower peak serum Cr (2.58 +/- 1.23 vs. 6.16 +/- 1.96, p < 0.002); (3) liver dysfunction (60% vs. 0, p < 0.02); (4) higher serum lactate dehydrogenase (LDH) level (3119 +/- 1019 vs. 982 +/- 522, p < 0.001). A lower platelet count carried borderline mortality risk (29500 +/- 14480 vs. 59625 +/- 25584, p = 0.057). CONCLUSIONS: HUS should be included in the differential diagnosis of renal function deterioration in patients on tacrolimus post-organ transplantation. Frequent renal function monitoring and appropriate treatment should be performed aggressively to decrease morbidity and mortality, especially in patients with risk factors.     

Successful plasma therapy in hemolytic uremic syndrome with factor H deficiency

A patient with homozygous factor H deficiency presented with hemolytic uremic syndrome (HUS) at the age of 7 months. After a 2-year period of stability, renal failure and erythrocyte fragmentation recurred between the age of 3 and 4 years. Fresh frozen plasma infusions allowed renal function to be improved and erythrocyte fragmentation to be stopped. Withdrawal of plasma therapy led to a relapse of the biological signs of HUS. Received: 18 April 2000 / Revised: 18 August 2000 / Accepted: 21 August 2000     

Challenges in the management of infantile factor H associated hemolytic uremic syndrome

We describe a 1-year old with four episodes of recurrent hemolytic uremic syndrome (HUS). Family history suggested an autosomal dominant mode of inheritance. Factor H concentrations in the blood were normal in the affected family members. Mutation screening in the human complement factor H gene (HF-1) revealed a novel mutation in exon 23 (c.3546_3581dup36). The HF-1 gene encodes complement factor H and the mutation leads to the insertion of 12 additional amino acids after codon 1176 in factor H. The recurrent HUS responded to plasma infusions and renal function improved from a glomerular filtration rate of 21 to 50 ml/min per 1.73 m². The infusions of fresh-frozen plasma were necessary at once-weekly intervals at a dose of 40–45 ml/kg in order to maintain remission and resulted in significant hyperproteinemia. This was addressed by intermittent plasma exchange through an arterio-venous fistula. The prognosis and therapeutic dilemmas are discussed.     

A case of atypical hemolytic uremic syndrome with a transient decrease in complement factor H

We report a case of sporadic atypical hemolytic uremic syndrome (HUS) with a transient decrease in complement factor H. Referred for hemolysis and azotemia without diarrhea prodrome, this 31-month-old boy showed a decreased complement 3 (C3) and complement factor H (FH) level. However, the factor H gene (HF1) mutation was missing. After the hemolysis was controlled with plasma infusion, the C3 and FH levels recovered. The patients renal function fully recovered and remained normal, and there was no recurrence of the HUS.     

Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome

We investigated the phenotypic expression of factor H mutations in two patients with atypical hemolytic uremic syndrome (HUS). Factor H in serum was assayed by rocket immunoelectrophoresis, immunoblotting, and double immunodiffusion and in tissue by immunohistochemistry. Functional activity was analyzed by hemolysis of sheep erythrocytes and binding to endothelial cells. A homozygous mutation in complement control protein (CCP) domain 10 of factor H was identified in an adult man who first developed membranoproliferative glomerulonephritis and later HUS. C3 levels were very low. The patient had undetectable factor H levels in serum and a weak factor H 150 kDa band. Double immunodiffusion showed partial antigenic identity with factor H in normal serum owing to the presence of factor H-like protein 1. Strong specific labeling for factor H was detected in glomerular endothelium, mesangium and in glomerular and tubular epithelium as well as in bone marrow cells. A heterozygous mutation in CCP 20 of factor H was found in a girl with HUS. C3 levels were moderately decreased at onset. Factor H levels were normal and a normal 150 kDa band was present. Double immunodiffusion showed antigenic identity with normal factor H. Factor H labeling was minimal in the renal cortex. Factor H dysfunction was demonstrated by increased sheep erythrocyte hemolysis and decreased binding to endothelial cells. In summary, two different factor H mutations associated with HUS were examined: in one, factor H accumulated in cells, and in the other, membrane binding was reduced.     

Eculizumab therapy in a child with hemolytic uremic syndrome and CFI mutation

Background

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in childhood. It usually occurs after a prodromal episode of diarrhea and it leads to significant morbidity and mortality during the acute phase. However, cases that start as diarrhea-positive HUS whose renal function fail to recover should be screened for genetic disorders of the complement system, which is called atypical HUS (aHUS).

Case-Diagnosis/Treatment

We herein report a 10-year-old girl, who initially came with bloody diarrhea and had features of HUS with delayed renal and hematological recovery despite plasma therapy. Eculizumab (600 mg/week) was initiated on day 15 for atypical presentation and later a complement factor I (CFI) mutation was detected. The girl recovered diuresis within 24 h and after the third eculizumab infusion, hemoglobin, platelet, and C3 levels normalized; renal function improved; and proteinuria completely disappeared in 2 weeks.

Conclusion

It is our belief that eculizumab can be the treatment of choice in children who have plasma exchange-refractory HUS with defective regulation of the alternative complement pathway.     

Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation

Whilst randomised control trials are undoubtedly the best way to demonstrate whether plasma exchange or infusion alone is the best first-line treatment for patients with atypical haemolytic uremic syndrome (aHUS), individual case reports can provide valuable information. To that effect, we have had the unique opportunity to follow over a 10-year period three sisters with aHUS associated with a factor H mutation (CFH). Two of the sisters are monozygotic twins. A similar natural evolution and response to treatment would be expected for the three patients, as they all presented with the same at-risk polymorphisms for CFH and CD46 and no identifiable mutation in either CD46 or CFI. Our report of different modalities of treatment of the initial episode and of three transplantations and relapses in the transplant in two of them, strongly suggest that intensive plasma exchange, both acutely and prophylactically, can maintain the long-term function of both native kidneys and allografts. In our experience, the success of plasma therapy is dependent on the use of plasma exchange as opposed to plasma infusion alone, the prolongation of daily plasma exchange after normalisation of haematological parameters followed by prophylactic plasma exchange, the use of prophylactic plasma exchange prior to transplantation and the use of prophylactic plasma exchange at least once a week posttransplant with immediate intensification of treatment if there are any signs of recurrence.     

Cardiomyopathy: a late complication of hemolytic uremic syndrome

This report describes a child who presented with classic hemolytic uremic syndrome (HUS) and 4 months later developed a life-threatening but reversible cardiomyopathy with global cardiac dysfunction and a left ventricular ejection fraction of 14%. There was no evidence of electrolyte abnormalities, anemia, hypertension, severe fluid overload, or viral infection. Endomyocardial biopsies were consistent with a dilated cardiomyopathy. This paper highlights the importance of considering the diagnosis of associated cardiomyopathy when presenting with late-onset edema following HUS. Received February 12, 1996; received in revised form and accepted August 22, 1996     

A novel mutation in the Complement Factor B gene (CFB) and atypical hemolytic uremic syndrome

We report the case of an 8-year-old girl diagnosed with atypical hemolytic uremic syndrome (aHUS) with a complement factor B (CFB) gene mutation. aHUS is a disease of complement dysregulation. In approximately 50% of patients, mutations are identified in genes encoding regulators of complement—complement factor H (CFH), membrane cofactor protein or complement factor I (CFI)—or activators of complement—complement factor B (CFB) or C3. The mutation in this patient was identified in exon 12 of CFB and changes a lysine at amino acid position 533 to an arginine (c.1598A>G p.Lys533Arg). The two other mutations previously reported in CFB associated with aHUS are c.858C>G, p.F286L in exon 6 and c.967A>Gp.K323E in exon 7.     

The hemolytic uremic syndrome as a complication of adriamycin nephropathy

Rats treated with two injections of adriamycin (week 0 and week 12) developed glomerusclerosis and severe tubulointerstitial lesions as described in the literature. In addition, a number ofglomerular alterations were present. These included capillary loop dilation, insudation of eosinophilic material, necrosis, duplication of the glomerular basement membrane, severe mesangiolysis with disruption of the mesangial matrix and segmental double-contours. The renal arterioles and interlobular arteries showed endothelial cell swelling. The subendothelial space was infiltrated by fibrinoid material and there was intensive fibrinoid necrosis of the wall of both arteries and arterioles extending into the glomerular tuft. These alterations were very similar to those observed in the hemolytic uremic syndrome. This observation suggests that the two injections of adriamycin, with a long interval in between them, might induce renal lesions similar to those observed in the hemolytic uremic syndrome.