Severe early acute humoral rejection resulting in allograft loss in a renal transplant recipient with Campath-1H induction therapy
Prue Hill,
Elena Gagliardini1,
Piero Ruggenenti1 and
Giuseppe Remuzzi1
Department of Anatomical Pathology, St Vincent's Hospital, Fitzroy 3065, Australia and 1 Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo
Correspondence and offprint requests to: Associate Professor Prue Hill, Department of Anatomical Pathology, St Vincent's Hospital, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia. Email: hillpa{at}svhm.org.au
Keywords: acute humoral rejection; Campath-1H; renal allograft
 |
Introduction
|
---|
One of the major goals in organ transplantation is to reduce immunosuppression by reprogramming the immune system so as to encourage tolerance. This process has been shown in animal models to be facilitated by lymphocyte depletion at the time of the transplant, and the degree of lymphocyte depletion substantially impacts the efficacy of such treatment [1,2]. Campath-1H is a humanized CD52-specific depleting complement-fixing cytotoxic IgG1 monoclonal antibody. CD52 antigen is located on the surface of T and B lymphocytes, natural killer (NK) cells, and less densely on monocytes [3]. Campath-1H profoundly depletes T lymphocytes from the peripheral blood for several months as well as having less marked effects on B lymphocytes, NK cells, monocytes and CD34-positive immature stem cells [3]. Campath-1H was initially used to treat acute renal allograft rejection [4] and later used successfully together with low dose cyclosporin (CsA) as induction therapy in renal transplantation [3]. Several other centres have also now reported their experiences with the use of Campath-1H together with various combinations of immunosuppressive agents in renal transplantation [59]. In some of the series there was a higher than usual incidence of acute humoral or antibody-mediated rejection (AHR) among the acute rejection (AR) episodes [6,8]. We report a case of early severe AHR resulting in renal allograft loss in a patient treated with Campath-1H induction therapy.
 |
Case
|
---|
A 38-year-old woman with end-stage renal disease due to membranoproliferative glomerulonephritis received a cadaveric renal allograft. Tissue typing for the donor was: HLA A: 2,66; B: 44,35; DR: 4,11; and for the recipient was: HLA A: 2,24; B: 35,51; DR: 7,13. Transplantation was performed after a 20 mg intravenous (IV) infusion of Campath-1H (Alemtuzumab, Schering Plough, Milano, Italy) accompanied by methyl-prednisolone (MPL) 500 mg IV. The surgery was uneventful and diuresis immediate. Immediately post surgery an IV CsA infusion (1 mg/kg/min) was commenced and was changed on day 1 to oral CsA (3 mg/kg/day) and oral mofetil mycophenolate (MMF) 250 mg twice daily. Serum creatinine (Cr) fell to 1.3 mg/dl. IV MPL was rapidly tapered and withdrawn on day 7. One day later she developed oligo-anuria and serum Cr was 4 mg/dl. Ultrasound showed a dilated renal pelvis. At surgical revision the transplanted ureter was markedly edematous and a ureteric stent was inserted; three IV pulses of MPL were planned with the aim of reducing ureteric inflammation and preventing subsequent fibrosis. Diuresis promptly recovered but serum Cr remained at 3.9 mg/dl. Two days later urine output again decreased and ultrasound revealed a hyperechogenic kidney with poor cortico-medullary definition and increased intraparenchymal vascular resistance. A renal biopsy was performed. The glomeruli showed extensive thrombosis with no accumulation of polymorphonuclear leucocytes (PMNL) (Figure 1A). One artery present showed no evidence of intimal arteritis or myocyte necrosis. Tubules showed acute tubular necrosis (ATN) (Figure 1B). Peritubular capillaries (PTC) appeared mildly ectatic with no accumulation of PMNL. C4d immunohistochemistry was performed using a rabbit polyclonal anti-human C4d antibody (Biomedica Gruppe, Wien; catalogue no. BI-RC4D). There was strong staining of PTC (Figure 1C), as well as glomerular capillaries (GC). The C4d immunostain highlighted the ectasia of the PCT (Figure 1D).

View larger version (121K):
[in this window]
[in a new window]
|
Fig. 1. Renal allograft biopsy. (A) This glomerulus shows most GC occluded by fibrin thrombi (arrows). Haematoxylin and eosin (H&E). Original magnification x400. (B) Tubules show patchy dilatation, vacuolization and several are necrotic (arrows) H&E. Original magnification x100. (C) On C4d immunohistochemistry there is diffuse strong circumferential staining of peritubular capillaries (PCT). Immunoperoxidase (IP). Original magnification x100. (D) Note at higher magnification the marked ectasia of PCT with occasional marginated leucocytes (arrows) IP. Original magnification x250.
|
|
The flow panel reactive antibody test detected the presence in the recipient of anti-HLA antibody against the Class I donor antigen B44. The patient was given three daily pulses of MPL 500 mg/day IV, progressively tapered to 125 mg/day and then changed to oral prednisolone in combination with a course of five plasma exchanges. Oral CsA was replaced with oral sirolimus (4 mg/day). Graft function failed to recover and haemodialysis was commenced. Due to ongoing anaemia and leukopaenia, allograft nephrectomy was performed on day 30. The kidney was swollen and dusky and the ureter diffusely thickened. Microscopically there were features of haemorrhagic infarction with transmural arteritis and glomerular thrombosis. There was also a dense interstitial inflammatory cell infiltrate including significant numbers of plasma cell and severe tubulitis. PTC were ectatic with accumulation of leucocytes and C4d immunohistochemistry showed strong staining of PTC and GC. The ureter showed edema and severe transmural arteritis of submucosal vessels.
 |
Discussion
|
---|
The reported series of renal allograft recipients given Campath-1H as induction therapy show variation in the incidence of AR [3,59]. Most series used two doses of Campath-1H with the first dose given at the time of transplantation and the second dose 24 days later. In the current case only a single dose of Campath-1H was given immediately prior to transplantation. The administration of Campath-1H is accompanied by an IV bolus of MPL to minimise reactions to cytokine release. The incidence of AR in the reported series using Campath-1H together with other immunosuppressive drugs ranges from 9 to 27%. There was considerable variation in the accompanying drug regimens, including CsA monotherapy [3], sirolimus monotherapy [6], low dose tacrolimus and MMF [7,8], and tacrolimus or CsA together with MMF and very low dose steroids [9]. In the series using Campath-1H alone without other immunosuppressive agents there was an incidence of AR of 85% [5]. Knetchle et al. [9] found that, compared with other groups that were given either anti-CD25 or anti-thymocyte globulin (ATG) together with a calcineurin inhibitor, MMF and higher dose steroids, their Campath-1H group showed an overall lower incidence of acute rejection. We have also observed a low incidence of acute rejection (two episodes in 21 patients), in a prospective pilot study in renal transplantation in which patients were given a single dose of Campath-1H as induction therapy and were randomized to two groups to receive either additional lower than conventional dose CsA and MMF, or sirolimus and MMF (unpublished data). Most of the episodes of AR in the various series responded well to additional immunosuppression [3,59]. In two series there was an unusually high incidence of AHR within the cases of AR [6,8]. In the pilot study of Knetchle et al. [6] 50% of the cases that developed episodes of AR showed features of either AHR alone or AHR combined with acute cellular rejection (ACR). Ciancio et al. [8] reported one case of AHR within only four cases of AR in their series of 44 patients. AHR usually forms only 1020% of cases of AR in series of acute renal allograft rejection [1012].
Although Campath-1H profoundly depletes T-lymphocytes from the peripheral blood, it has been shown that memory T-lymphocytes may be somewhat more refractory to Campath-1H [5,8]. This relative preservation of central memory T-cells could serve as the source of primed alloreactive T-cells that may respond by clonal expansion. Monocytes together with a few memory T-cells (CD45RO+) were the predominant cell seen in the allografts with acute rejection in the series of Kirk et al. [5]. They postulate that the rejection seen in Campath-1H treated recipients was mediated predominantly by activated Campath-1H resistant monocyte and macrophage lineage cells responding to a small population of allospecific cross reactive memory T-cells. They further suggest that monocyte and macrophage lineage cells release cytokines in the graft, perhaps in an attempt to recruit effector T-cells, and in doing so in themselves induce renal dysfunction [5]. The high incidence of AHR in some series may be partly explained by the fact that plasma cells, which do not express the CD52 epitope in detectable concentrations, are not depleted by Campath-1H [7]. The degree of immune cell depletion achieved in these patients by Campath-1H may also cause dysregulation of the humoral immune response. In the current case, plasma cells were prominent within the interstitial infiltrate in the allograft nephrectomy specimen.
The current case showed the criteria necessary for a diagnosis of AHR: (i) glomerular thrombosis and ATN, (ii) C4d deposition in PTC, and (iii) circulating donor specific antibodies [1113]. However, we stress that the more characteristic accumulation of PMNL in PTC and GC and vascular fibrinoid necrosis were not present, hence the importance of the C4d immunostain in establishing the pathological diagnosis. C4d deposition has been shown to correlate with donor-specific antibodies, these being present in 90% of cases [1214]. In the present case, anti-HLA antibody to Class I donor antigen was detected. C4d positivity is associated with more resistance to anti-rejection therapy and a greater rate of graft loss [1214].
The severe ureteric edema causing the clinical picture of acute urinary tract obstruction may have been an early manifestation of AR in this case. A renal biopsy performed at the time of surgical exploration may have been contributory in making an earlier diagnosis. AHR can occur alone or together with ACR. In our case the initial allograft biopsy showed features of AHR alone, whereas the allograft nephrectomy specimen also showed features of ACR (interstitial inflammation with severe tubulitis and transmural arteritis). AHR, when present, has a markedly poorer prognosis than ACR alone, with a 2740% 1 year graft loss [1014]. The AR in our patient was refractory to treatment with steroids and plasmapharesis and resulted in allograft loss. It was decided not to administer ATG, anti-CD3 (OKT3), anti-interleukin-2 receptor or another infusion of Campath-1H because of concerns regarding the increased risk of post-transplant lymphoproliferative disorder.
The optimal dosing strategy and maintenance therapy for Campath-1H are subjects of ongoing study and it is clear that Campath-1H alone does not reliably prevent rejection in human renal allograft recipients. The combination of tacrolimus and MMF with no maintenance steroids has shown some excellent results [6,7]. However, our case highlights that AHR may occur early and present with both unusual clinical and pathological features in these patients.
 |
Acknowledgments
|
---|
The authors gratefully acknowledge Sara Conti for technical assistance and for the immunohistology.
Conflict of interest statement. None declared.
 |
References
|
---|
- Myburgh JA, Smit JA, Browde S, Hill RR. Transplantation tolerance in primates following total lymphoid irradiation and allogeneic bone marrow injection. I. Orthotopic liver allografts. Transplantation 1980; 29: 401404[ISI][Medline]
- Knetchle SJ, Vargo D, Fechner J et al. FN18-CRM9 immunotoxin promotes in primate renal allografts. Transplantation 1997; 63: 16[ISI][Medline]
- Calne R, Moffat SD, Friend PJ et al. Campath 1H allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 1999; 68: 16131616[CrossRef][ISI][Medline]
- Friend PJ, Rebello P, Oliveira D et al. Successful treatment of renal allograft rejection with a humanized antilymphocyte monoclonal antibody. Transplant Proc 1995; 27: 869870[ISI][Medline]
- Kirk AD, Hale DA, Mannon RB et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody Alemtuzumab (Campath-1H). Transplantation 2003; 76: 120129[CrossRef][ISI][Medline]
- Knechtle SJ, Pirsch JD, Fechner JH et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003; 3: 722730[CrossRef][ISI][Medline]
- Leventhal JR, Gallon L, Kaufman DB et al. Alemtuzumab (Campath-1H) facilitates prednisone-free immunosuppression (IP) in kidney transplant recipients. Am J Transplant 2003; 3 [Suppl 5]: 310, Abstract 620
- Ciancio G, Burke GW, Gaynor JJ et al. The use of Campath-1H as induction therapy in renal transplantation: preliminary results. Transplantation 2004; 78: 426433[CrossRef][ISI][Medline]
- Knechtle SJ, Fernandez LA, Pirsch JD et al. Campath-1H in renal transplantation: The University of Wisconsin experience. Surgery 2004; 136: 754760[CrossRef][ISI][Medline]
- Crespo M, Pascual M, Tolkoff-Rubin N et al. Acute humoral rejection in renal allograft recipients: I. Incidence, serology and clinical characteristics. Transplantation 2001; 71: 652658[CrossRef][ISI][Medline]
- Mauiyyedi S, Crespo M, Collins AB et al. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. J Am Soc Nephrol 2002; 13: 779787[Abstract/Free Full Text]
- Racusen LC, Colvin RB, Solez K et al. Antibody-mediated rejection criteria an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003; 3: 708714[CrossRef][ISI][Medline]
- Racusen LC, Halloran PF, Solez K. Banff 2003 meeting report: new diagnostic insights and standards. Am J Transplant 2003; 4: 15621566[CrossRef]
- Regele H, Exner M, Watschinger B et al. Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection. Nephrol Dial Transplant 2001; 16: 20582066[Abstract/Free Full Text]
Received for publication: 2. 3.05
Accepted in revised form: 7. 4.05