Abatacept for Glomerular Diseases: A New Era of Intelligent immunosuppression?

At ASN Kidney Week there was some interest in abatacept as a targeted therapy for glomerular diseases. T-cell activation requires 2 signals; (i) binding of the T-cell receptor to the antigen-MHC complex on the antigen-presenting cell and (ii) a co-stimulatory signal involving CTLA-4 on the T-cell and B7-1 on the antigen presenting cell. Abatacept is a fusion protein composed of the Fc region of IgG1 fused to the extracellular domain of CTLA-4 which inhibits the T-cell co-stimulatory pathway via B7-1 binding. 

          FSGS

The headlines must go to the small case series of abatacept in FSGS published in NEJM. The rationale for its use was the observation that B7-1 expression is not apparent in normal human podocytes but is found in certain diseased podocytes including a subset of FSGS patients. The series included 4 patients with recurrent FSGS post-transplantation (rituximab-resistant) and one with glucocorticoid-resistant primary FSGS. All patients achieved either partial or complete remission.

In vitro studies demonstrated that α3-Integrin knockout mice constitutively expressed B7-1 in podocytes and abatacept blocked B7-1 mediated podocyte migration in these cells. The molecular mechanism of B7-1-induced podocyte dysfunction was shown to be disruption of activation of the glomerular protein β1-integrin. The authors conclude that B7-1 immunostaining of biopsies may identify a subgroup of patients who would benefit from treatment with abatacept.

2       Lupus Nephritis

The late-breaking session included a randomized controlled trial of Euro-lupus regime cyclophosphamide (i.e. low dose IV) with or without abatacept for proliferative lupus nephritis [Access Trial]. Azathioprine was introduced at 3 months and stopped at 6 months in the abatacept group if they had achieved a remission. Overall, there was no difference in remission rate between the groups. Despite the neutral outcome, 2 points should be taken from the study: (i) The Euro-lupus regime appeared to work in a US cohort of patients where almost 80% were either Hispanic or African American. (ii) Abatacept patients who achieved remission maintained this at 1 year despite coming off immunosuppression at 6 months. However, with the growing confidence in Mycophenolate-based therapy for lupus nephritis and the lack of improved remission with Abatacept in this study, its place in the treatment of proliferative lupus nephritis remains uncertain.

3       Diabetic Nephropathy

An oral presentation on abatacept in Diabetic Nephropathy [FR-OR010] reported increased B7-1 expression in both murine podocytes cultured in high-glucose and on human glomerular podocytes from biopsy specimens. The use of Abatacept in diabetic mice prevented an increase in albuminuria.

Bottom Line: The FSGS case series beautifully illustrates how targeted therapies may be applied to immune-mediated renal diseases. While this case series is very small, it demonstrates the potential for reclassifying disease based on pathogenesis (i.e. B7-1-mediated) rather than crude pathological patterns (focal segmental sclerosis). This is similar to the recent re-classification of MPGN into complement or immune complex-mediated forms. With new targeted therapies like abatacept (and eculizumab for complement mediated glomerulopathies), we may be entering an era of intelligent immunosuppression based on molecular pathogenic signals rather than crude histological patterns.

Induction Therapy in Kidney Transplantation - Summary

Most kidney transplant centers in the United States utilize induction agents as part of their immunosupression protocols. The reasoning behind is that induction therapy has been shown to reduce the rate of acute rejection, however no trial has yet demonstrated an improvement in long-term graft survival.  Induction therapy has also expanded in centers using steroid-withdrawal protocols and in patients with expected delayed graft function due to prolong ischemia time (ECD/DCD kidneys), since calcineurin inhibitor initiation may be delayed (significant vasoconstriction from CNI may potentially delay recovery).

Rabbit antithymocyte globulin (rATG or Thymoglobulin) is the most common agent used in more than 55% of transplant cases in the USA, despite not being FDA-approved for this use (only for treatment of severe cellular rejection). Curiously, rATG is prepared by immunizing pathogen-free

rabbits with a cell suspension of human thymic tissue (thymocytes). After immunization, the serum is harvested from rabbits and immunoglobulins against thymocytes are isolated and subjected to a number of purification processes. Samples from more than 26,000 immunized rabbits are pooled to achieve a high level of batch-to-batch consistency!

Our center uses ATG for induction in high immunological risk patients and Basiliximab for low risk patients in combination with tacrolimus and MMF for maintenance. Steroid withdrawal is performed on most patients by the end of first week post-transplantation, with the exception of highly sensitized patients.

Below a summary table of the 3 most common induction agents in clinical use today, their target cells, dose, cost and side effects.

Antibody	Brand	Class	Lymphocyte depleting	Antigenic Target and Cells	Typical prescription	Side effects
Basiliximab	Simulect (Novartis)	Monoclonal	No	IL2 receptor (CD25)   Activated T cells	20mg x2 doses  U$4,254	Hypersensitivity reaction (rare)
Rabbit antithymocyte globulin	Thymoglobulin (Genzyme)	Polyclonal	Yes	Multiple Ag   Mainly T cells, to a lesser extent B and NK cells	1.5mg/kg 3-7 doses  U$7,824-18,256 Premedicate with steroids and Tylenol Decrease dose if WBC<3 or="" ptls="" span="">	Fever, chills, dyspnea, nausea, diarrhea, headache, general pain and pulmonary edema (cytokine release syndrome)
Alemtuzumab	Campath 1H (Berlex Laboratories)	Monoclonal	Yes (more prolonged)	CD52 Ag T, B and NK cells, monocytes, macrophages, dendritic cells, eosinophils, mast cells	30mg x1 dose  U$2,065	Generally none when given subcutaneously

More details about the use of induction therapy in transplantation on this prior blog

Insert sensationalist headline here...

A recent BMJ Minerva column alerted me to an interesting paper in the journal Transplantation. The authors used collaborative databases to compare overall and age-specific graft survival in first deceased donor transplants carried out in the US & Europe. They found that although there was broad similarity in 1-year graft survival, 5 and 10 year graft survival was considerably higher in Europe than in the US. The tendency towards worse graft survival in the US persisted across all ethnic groups and was largest for children and young adults. The gap between European and US survival was greater beyond 3 to 4 years post engraftment.

I am British and have only ever practiced in the UK NHS. I am therefore in no position to comment meaningfully on the following points made in the paper’s discussion section: "it is necessary to recall…the 3-year restriction in medication coverage for immunosuppression in the United States by Medicare…A policy change may contribute to improving graft survival and ultimately saving lives and also help to reduce health care spending." I imagine that other readers and contributors to this site may have informed and/or deeply held opinions.

Antibody-Mediated Rejection: Choose your weapons

Acute humoral or antibody-mediated rejection (AMR) is attributed to the presence of alloantibodies against the graft, which could be either antibodies against human leukocyte antigens (HLAs) Class I and/or II , non-HLA antigens or endothelial antigens. Diagnosis of AMR is made through tissue biopsy and presence of alloantibodies. Early treatment is of paramount for the preservation of graft function. Treatment strategies include removal of alloantibodies, decreasing or stopping production of alloantibodies, or attenuating the immune systems response to alloantibodies. 

Plasmapheresis/Plasma Exchange 

Removal of alloantibodies is done through the use of plasmapheresis/plasma exchange or immunoadsorption. Plasmapheresis, or removal and replacement of one plasma volume, is effective at removing approximately 60% of the intravascular IgG which accounts for about 75% of the intravascular immune response. Extravascular IgG equilibrates in about 48 hours thus reducing total body IgG concentrations and reducing the effective immune response. Immunoadsorption works similarly to plasmapheresis except that plasma immune complexes and IgG are removed via protein A bound silica matrices. In the latter, the remaining plasma components are returned to the patient without the need for plasma exchange. FFP is needed even on the first run of plasmapheresis if recent biopsy was performed (prevention of bleeding). The cost of 5 treatments is about $4,600. 

Intravenous Immune Globulin 

Infusion of intravenous immunoglobulins (IVIG) has been studied at doses of 10 grams to 2 gm/kg as monotherapy or in conjunction with plasmapheresis or B-cell depleting agents. The mechanism of action is not entirely known but it is thought that neutralization of alloantibodies occurs when bound by the anti-idiotypic antibodies in IVIG as well as diminished plasma cell production by increasing total body concentrations of immunoglobulins and direct T-cell and complement cascade effects. Cost for IVIG is $77.06/gm resulting in $770.60 or $10,788.40 (dose intensity), based on a 70kg patient for each dose. 

Decreasing or stopping the production of alloantibodies requires therapies directed against mature plasma cells, memory B-cells or plasmablasts. Targeting memory B-cells or plasmablasts has a delayed onset of action as this therapy prevents new plasma cells from being formed but does not affect currently active ones. 

Rituximab 

A chimeric anti-CD20 monoclonal antibody, is dosed 375 mg/m2 or 1000 mg IV and given for one to two doses. The CD20 receptor is found on the surface of B-lymphocytes, including memory B-cells and immature plasmablasts, but not plasma cells. Rituximab has cytotoxic activity directly reducing B-lymphocyte and antibody levels. Cost for therapy ranges from $4,923.78 for dosing based on normal body surface area to $7,589.64 for a 1000mg dose. 

Bortezomib 

A proteasome inhibitor, is dosed 1.3 mg/m2 IV and given for four doses on days 1, 4, 8, and 11. Proteasome inhibition prevents protein biosynthesis resulting in apoptosis of the plasma cell and cessation of alloantibody production. Cost per dose based on a normal body surface area is $1,134.27. 

Eculizumab 

A humanized monoclonal antibody directed against C5, is dosed 600mg to 1200mg IV and administered weekly depending on alloantibody concentrations. Prevention of AMR is mediated by inhibition of membrane attack complex formation and halting activation of the complement cascade. Eculizumab is supplied as a 300mg vial for $6,638.40 or $13,276.80 to $26,553.60 per dose. 

Increasing the dose of maintenance immunosuppressive agents, including calcineurin inhibitors, antimetabolites, and steroids are also used to attenuate the immune system and help alleviate AMR. With all of the available treatment options, a multimodal approach is usually recommended to maximize chances of preventing graft injury. However, as you might see from the numbers above, careful clinical decision must be based on both efficacy and cost in order to responsibly avoid collapsing our already broken health care system. Instead of each center using its on protocol, our society should get together and perform a randomized trial with those interventions. Though I doubt this will happen any time soon, in particular with all the NIH budget cuts...

David Reardon, PharmD, PGY2 Critical Care Resident

Steve Gabardi, PharmD

Leonardo V Riella MD PhD (editing role)

Azathioprine in pregnancy

We recently discussed this issue in conference and I thought it might be worth sharing a few interesting points:

Azathioprine is normally converted to the active metabolite 6-mercaptopurine. However, in pregnancy the placenta can metabolize azathioprine to thiouric acid, an inactive metabolite. In addition the fetal liver does not have inosinatopyrophosphorylase which therefore largely protects the fetus from exposure to active compounds.

Azathioprine has been classed as FDA category D - positive evidence of risk.
Despite conflicting data, general expert opinion suggests that azathioprine may be considered for use during pregnancy in certain situations (where the potential benefits outweigh potential risks).

In terms of breast feeding, in a small study, active metabolites have been detected in small quantities in breast milk. Overall the significance of this remains to be fully determined. Manufacturers have taken the official stance to warn against breast feeding while taking the drug.


As with all considerations of alterations in immunosuppressive dosing, careful consideration of risks and benefits should be explored in detail with the treating physician before any change is undertaken.