Antibody mediated rejection causing dialysis dependent acute renal failure，partially rescued with Eculizumab

Mark J Lerman， Afzal Nikaein，Michael Kuperman（. Transplant Services at Medical City Dallas Hospital， Dallas 750，Texas，American ；. Texas Medical Specialty，Inc.， Dallas 750， Texas，American ；. John Hopkins University Medical Center，Baltimore 0，Maryland，American）

A ntibody mediated rejection （AMR） in transplant recipients may cause graft dysfunction and decreased graft survival1. Most of these patients have donor specific antibodies （DSA）， C4d staining in peritubular capillaries and histological evidence of acute rejection on renal biopsy2. Current treatment options for AMR include plasma exchange （PP）， intravenous immunoglobulin （IVIG） and anti-CD 20 therapy3.Patients with severe forms of AMR usually do not respond to these treatments. Eculizumab is a humanized anti-C5 monoclonal antibody that act as an inhibitor of terminal complement activation. Recent studies have shown that Eculizumab can be used to treat patients who have developed severe forms of AMR and as a prophylaxis to prevent AMR4. We present one case of very severe acute antibody mediated rejection which was resistant to conventional therapy but responded to Eculizumab.

1 Clinical Data

45-year-old African American man status post deceased donor kidney transplant in 2013 previously doing well with normal allograft function and serum creatinine of 1.2 mg/dl. Patient presented to the emergency room 27 months post-transplant （2015）with symptoms of uremia and a serum creatinine of greater than 20 mg/dl. He admitted to having difficulty obtaining his medications including immunosuppression for several days prior to his admission. A biopsy of his renal allograft was performed which revealed severe diffuse peritubular capillary C4d staining on immunofluorescence microscopy（figure 1）. There was no significant interstitial fibrosis and normal appearing glomeruli on light microscopy. EM were also unremarkable. DSA were present against DQ9 with MFI＝13 153 at 1:32 dilution. Patient was treated with pulse Ⅳ steroids， plasmapheresis， and low-dose Ⅳ IgG. Hemodialysis was initiated and continued throughout his hospital course. He responded well to hemodialysis with resolution of his uremic symptoms.Serum creatinine improved consistent with hemodialysis but did not indicate significant return of function.Urine output was about 1 500 ml per day. A repeat renal biopsy was performed at the completion of his treatment with 5 doses of Ⅳ SoluMedrol, 5 treatments of plasma exchange and low-doseⅣ IgG. Each plasmapheresis was done with one plasma volume and 100% replacement with 5% albumin. Repeat allograft biopsy continued to show diffuse peritubular capillary C4d deposition on immunofluorescence（figure 2）.Light microscopy remained essentially unremarkable.

Figure 1 Trichrome ×40：First kidney Biopsy which shows interstitial edema and mild interstitial fibrosis

Figure 2 C4d ×100：Second kidney biopsy showing diffuse positivity for C4d in the peritubular capillaries.This biopsy is before treatment with Eculizumab

DSA to DQ9 remained high at MFI＝12 837 at 1:32 dilution （figure 3）. He remains on tacrolimus and mychophenolate. Eculizumab was begun at 1 200 mg Ⅳevery week x4. Hemodialysis was also continued 3 times a week using a PermCath. After 4 weeks and 4 doses of Eculizumab， renal function was clearly improving with a serum creatinine of 3 （figure 4）and a glomerular filtration rate （GFR） of 25 ml/（min·1.73m2）.Dialysis was discontinued and a third renal biopsy was performed. This biopsy showed complete resolution of C4d staining and very mild tubulitis and about 30% interstitial fibrosis（figure 5）. Patient received Eculizumab 900 mg every 2 weeks for another 4 doses.He has remained dialysis free for the last 19 months.Tacrolimus levels are therapeutic and he has had no significant infections other than one episode of localized herpes zoster.

Figure 3 The detection of DSA

Figure 4 The detection of serum creatinine

Figure 5 C4d ×100：Third kidney biopsy showing resolution of C4d staining in the peritubular capillaries.This biopsy is after treatment with Eculizumab.

2 Conclusion

This is a case with well documented acute AMR causing severe but reversible acute renal failure. To our knowledge， prior to this case， no patient with a serum creatinine above 20 mg/dl has responded to antirejection therapy and been able to discontinue dialysis.This patient did not respond to high dose steroids，plasmapheresis and low dose IVIG. Eculizumab treatment was temporally related to improvement in kidney function and resolution of C4d deposits on biopsy. Our patient remains stable with serum creatinine 3.5 mg/dl and has not required dialysis after almost 19 months.

We believe even severe acute renal failure due to AMR requiring dialysis， may respond to Eculizumab.Allograft biopsy demonstrating absence of chronic changes and particularly thrombosis maybe an important predictor for responsive patients regardless of renal dysfunction.