Diagnosis And Treatment Of CFHR5 Gene-related Diseases

The CFHR5 gene is located at lq31.3 encoding the CFHR5 protein.The strong association of CFHR5 protein with tissue complement deposits in vivo suggests that the CFHR5 protein has an important function in complement regulation.Mutations in the CFHR5 gene cause CFHR5 gene-related diseases including C3 glomerulopathy(C3G),atypical hemolytic uremic syndrome(aHUS),systemic lupus erythematosus(SLE)and so on.Electron microscopy(EM)of C3G is used to distinguish a clinically relevant distinction between C3GN and DDD.CFHR5 nephropathy is a special form of C3GN.CFHR5 gene-related diseases are usually manifested as hematuria and proteinuria in the clinic,accompanied by a decrease in serum complement C3 levels.In terms of renal pathology,CFHR5 gene-related C3G mainly manifested as membrane proliferative glomerulonephritis(MPGN).CFHR5 gene-related aHUS showed obvious thrombosis,nonthrombotic features including endothelial swelling and denudation,mesangiolysis,double contours of the glomerular basement membrane,and subendothelial accumulation of electronlucent,flocculent material.CFHR5 gene-related SLE with common renal biopsy pathological types are type IV,V and IV/V usually manifesting as lupus nephritis(LN).Diagnosis of CFHR5 gene-related diseases is based on clinical pathological features and genetic testing.CFHR5 gene-related diseases are generally treated with symptomatic treatment,angiotensin-converting enzyme inhibitors/angiotensin ? receptor antagonists(ACEI/ARB)to reduce urinary protein,hormones and cytotoxic drugs which suppress immunity,culizumab and plasma exchange.When the patients progress to end stage renal disease(ESRD),they are required to operate renal replacement therapy including hemodialysis,peritoneal dialysis or kidney transplantation.The prognosis of CFHR5 gene-related diseases is poor.Although the renal function of the patients with CFHR5 gene-related C3G is relatively stable,the probability of progression to ESRD is not high,but CFHR5 gene-related aHUS and CFHR5 gene-related SLE have a poor prognosis.Different CFHR5 gene-related diseases caused by different mutations in CFHR5 are different in clinical manifestations,pathogenesis,diagnosis,treatment and prognosis.In the CFHR5 gene-related C3GN,the heterozygous CFHR5 sequence variantc.485dupA(p.Glu163Argfs*34)is a risk factor for the development of chronic kidney disease.Eculizumab seems to be ineffective in this subtype for patients with CFHR5 mutation of Cys269Arg.Complement C3 levels are normal in the patients with C3GN caused by CFHR5-CFHR2 gene fusion.CFHR5 nephropathy refers to the internal replication of exons 2 and 3 of the CFHR5 gene,which causes abnormal regulation of the complement alternative pathway,with normal plasma complement C3 concentration.A subgroup of patients with CFHR5 nephropathy,particularly men,develop easily ESRD with poor prognosis.The patient with CFHR5 gene-associated DDD caused by replication(c.486dupA)in the CFHR5 gene initially showed nephrotic syndrome and progressive deterioration of renal function.However,the patient's urine protein was controlled at a lower level,and serum complement C3 recovery to normal level with immunosuppressive therapy.The patient with the mutation of CFHR2-CFHR5 gene fusion was refractory to plasma replacement and exchange therapy,as evidenced by the hybrid protein quickly returning to pretreatment plasma levels.Renal transplantation is less effective and relapses for the patients with CFHR5 gene-related aHUS.The recurrence rate of aHUS is almost 100%after renal transplantation in patients with CFHR5 gene-related aHUS which is necessary to operate a combination of liver and kidney transplantation.plasma CFHR5 levels were higher in the patients with lupus nephritis caused by mutaitons in the CFHR5 gene than those in healthy individuals.CFHR5 concentrations increase with increasing SLE activity index values.CFHR5 levels in the patients with lupus nephritis were positively correlated with proteinuria and levels of creatinine(Cr)and anti-dsDNA,while they were negatively correlated with plasma C3 levels and eGFR.The most common renal biopsy pathological types are type IV,type V and type IV/V in the patients with lupus nephritis caused by variants of CFHR5.At present,the treatment is more difficult for the patients with CFHR5 gene-related diseases.Although symptomatic treatments are used to delay the progression to ESRD,and renal replacement therapy is finally used,gene therapy is expected to become a clinical treatment for the patients with CFHR5 gene-related diseases in the future.