Current state of renal transplant immunosuppression: Present and future

Table 1 Food and drug administration approved immunosuppressive medications used for transplantation

Drug	Dose	Side effects
Induction
Basiliximab	20 mg IV × 2 doses	Hypersensitivity reactions
Anti-thymocyte globulin
Rabbit	1.5 mg/kg IV × 3-14 d	Rash, fever, thrombocytopenia, leukopenia
Horse	15 mg/kg IV × 3-14 d
Maintenance
Prednisone	Maintenance: 2.5-10 mg/d	Mood disturbances, psychosis, cataracts, hypertension, fluid retention, peptic ulcers, osteoporosis, muscle weakness, impaired wound healing, glucose intolerance, weight gain
	Rejection: 250-1000 mg/d × 3 d IV
Cyclosporine	4-5 mg/kg po twice daily	Neurotoxicity, gingival hyperplasia, hirsutism, hypertension, hyperlipidemia, glucose intolerance, nephrotoxicity, electrolyte disturbances
Tacrolimus	0.05-0.075 mg/kg po twice daily	Neurotoxicity, alopecia, hypertension, hyperlipidemia, glucose intolerance, nephrotoxicity, electrolyte disturbances
Sirolimus	2-10 mg/d po daily	Hypertriglyceridemia, anemia, thrombocytopenia, mouth sores, hypercholesterolemia, gastrointestinal disturbances, bone marrow suppression, poor wound healing, edema
Everolimus	0.75 mg po twice daily	Hypertriglyceridemia, anemia, thrombocytopenia, mouth sores, hypercholesterolemia, gastrointestinal disturbances, bone marrow suppression, poor wound healing, edema
Azathioprine	1-2.5 mg/kg per day po daily	Leukopenia, thrombocytopenia, gastrointestinal disturbances, pancreatitis, hepatotoxicity
Mycophenolate mofetil	500-1500 mg po twice daily	Leukopenia, thrombocytopenia, gastrointestinal disturbances
Mycophenolate sodium	360-1080 mg po twice daily	Leukopenia, thrombocytopenia, gastrointestinal disturbances
Belatacept	10 mg/kg administered, prior to implantation, on day 5, and at the end of weeks 2, 4, 8, and 12, then 5 mg/kg every 4 wk (plus or minus 3 d)	Post-transplant lymphoproliferative disorder, progressive multifocal leukoencephalopathy

Table 2 Classification of immunosuppressive agents

Classification	Drug (Generic)	Drug (Trade)	Generic	Dosage form
Interleukin-2 receptor blockers	Basiliximab	Simulect®	No	Injection
Anti-T cell therapy	Antithymocyte globulin - horse	Atgam®	No	Injection
	Antithymocyte globulin - rabbit	Thymoglobulin®	No	Injection
Corticosteroids	Methylprednisolone	Solumedrol®	Yes	Injection, oral
	Prednisone	Deltasone®	Yes	Oral
Calcineurin inhibitors	Cyclosporine, CsA	Sandimmune®	Yes	Injection, oral
	Cyclosporine microemulsion	Neoral®	Yes	Injection, oral
	Tacrolimus, FK506	Prograf®	Yes	Oral
mTOR inhibitors	Sirolimus, rapamycin	Rapamune®	No	Oral
	Everolimus	Zortress®	No	Oral
Anti-proliferative	Azathioprine, AZA	Imuran®	Yes	Injection, oral
	Mycophenolate mofetil, MMF	Cellcept®	Yes	Injection, oral
	Mycophenolate sodium,EC-MPS	Myfortic®	No	Oral
Costimulation blockade	Belatacept	Nulojix®	No	Injection

Table 3 Non-food and drug administration approved/investigational agents and their mechanism

Name	Mechanism of action
Induction
Alemtuzumab	Monoclonal antibody, CD52
Efaluzimab	Humanized antibody, CD11a/LFA-1
Alefacept	Costimulation inhibitor, CD2 LFA3
Maintenance
Prolonged release tacrolimus	Calcineurin inhibitor
Voclosporin, ISA247	Calcineurin inhibitor
Mizoribine	Purine synthesis inhibitors
Sotrastaurin, AEB071	Protein kinase C inhibitor
Tofacitinib, CP-690550	JAK 3 inhibitor
Treatment of antibody medicated rejection
Bortezomib	Proteasome inhibitor
Eculizumab	Monoclonal antibody, C5 complement protein

Table 4 Comparative adverse effects of prolonged release Tacrolimus and Tacrolimus (%)

ADR	Prolonged released Tacrolimus	Tacrolimus twice daily
Gastrointestinal
Diarrhea	45.3	44.3
Loose stools	5.1	7.1
Metabolism and nutritional
Hyperlipidemia	16.4	17.5
Diabetes mellitus	14.0	11.3
Hyponatremia	2.8	0.9
Infections and infestations
Sinusitis	7.0	3.3
Gastroenteritis	6.5	0.5
Peripheral edema	35.5	34.9
Nervous system
Tremor	35.0	34.4
Paraesthesia	5.6	1.4
Vascular
Orthostatasis	7.0	4.7
Lymphocele	0.5	0.9
Psychiatric
Insomnia	25.7	30.2
Skin
Alopecia	6.5	7.1

Table 5 Summary of the Belatacept trials

Study	Phase II			Benefit			Benefit-EXT
Author	Vincenti			Vincenti			Durrbach
Induction	Basiliximab			Basiliximab			Basiliximab
Study drug	MI bela	LI bela	CsA	MI bela	LI bela	CsA	MI bela	LI bela	CsA
Maintenance	MMF + steroids			MMF + steroids			MMF + steroids
Demographics
No. of patients	74	71	73	225	230	231	193	193	192
Age (yr)	47	42	46	44	43	44	57	56	56
Deceased donor (%)	69	73	78	42			100	100	100
Female (%)	27	32	33	31	35	25	35	26	37
Re-transplantation (%)	1	6	3	4	3	6	Not reported
PRA > 20% (%)	1	3	1	11	13	8	0	1	3
African-American (%)	8	9	8	7	10	8	14	14	12
CIT (h)	20	20	18	16.3			Not reported
CIT (> 24 h) (%)	Not reported			Not reported			39	43	44
Delayed graft function (%)	Not reported			16	14	18	47	47	49
Endpoints 6-12 mo	6 mo			12 mo			12 mo
Acute rejection (%)	7	6	8	22	17	7	18	18	14
Acute Rejection (Grade II) (%)	4	5	6	17	11	4	14	15	12
Measured GFR (mL/min)	66	62	54	65	63	50	52	50	45
NODAT (%)	Not reported			7	4	10	2	5	9
CAN (Stage II or III) (%)	8	9	9	4	6	7	10	12	4
Endpoints 12 mo
Graft survival (%)	99	100	95	98	98	96	91	91	89
Patient survival (%)	96	99	97	97	98	97	96	98	96
Cancer	2	0	2	4	3	1	4	4	6
PTLD	2	0	0	1	1	0	3	3	0
Endpoints 2 yr
Acute rejection				24	17	9	17	18	15
Measured GFR (mL/min)				65	68	51	52	50	45
Graft survival (%)				94	95	91	83	84	93
Patient survival (%)				97	97	94	93	94	94
Endpoints 3 yr
Acute rejection (%)				24	17	10	18	19	16
Measured GFR (mL/min)				65	66	44	43	42	32
Patient/graft survival (%)				92	92	89	80	82	80

CsA: Cyclosporine; MI: More intensive; LI: Less intensive; PTLD: Post-transplant lymphoproliferative disorder; NODAT: New onset of diabetes mellitus after transplantation; CIT: Cold ischemia time; GFR: Glomerular filtration rate.

Table 6 Food and drug administration indications of immunosuppressive agents

Generic	Brand	FDA indication	Company
Basiliximab	Simulect	Prevention of acute rejection in kidney transplantatation	Novartis
Rabbit anti-thymocyte globulin	Thymoglobulin	Treatment of corticosteroid resistant rejection in kidney transplantation	Genzyme
Alemtuzumab	Campath	Treatment of B-cell chronic lymphocytic leukemia	Berlex Laboratories
Efaluzimab	No longer FDA approved Raptiva	Management of moderate to severe chronic plaque psoriasis in adults	Genentech-Merck
Alefacept	Amevive	Treatment of moderate-to-severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy	Astellas
Tacrolimus prolonged release	Advagraf (in Canada)	Not FDA approved	Astellas
Cyclosporine	Neoral	Prevention of acute rejection in renal transplant recipients	Novartis
Tacrolimus	Prograf	Prevention of acute rejection in renal transplant recipients	Astellas
Voclosporin		Not FDA approved	Isotechnika Pharma
Everolimus	Afinitor, Zortress	Treatment of advanced renal cell cancer (Afinitor®); treatment of subependymal giant cell astrocytom associated with tuberous sclerosis (Afinitor®); treatment of advanced, metastatic or unresectable pancreatic neuroendocrine tumors (Afinitor®); prophylaxis of organ rejection in patients at low-moderate immunologic risk receiving renal transplants (Zortress)	Novartis
Azathioprine	Imuran	Adjunctive therapy in prevention of rejection of kidney transplants; management of active rheumatoid arthritis	Glaxo-Smith-Kline
MMF	Cellcept	Prophylaxis of organ rejection concomitantly with cyclosporine and corticosteroids in patients receiving allogeneic renal cardiac, or hepatic transplants	Genentech
Mycophenolate sodium	Myfortic	Prophylaxis of organ rejection concomitantly with cyclosporine and corticosteroids in patients receiving allogeneic renal transplantation	Novartis
Mizoribine		Not FDA approved	Asahi Kasei Pharma
Sotrastaurin, AEB-071		Not FDA approved	Novartis
Belatacept, BMS224818	Nulojix	Prevention of acute rejection in renal transplant recipients	Bristol-Myers-Squibb
Tolfacitinib, formerly tasocitinib, CP-690550		Not FDA approved	Pfizer
Rituximab	Rituxan	Treatment of CD20-positive non-Hodgkin’s lymphomas; Treatment of moderately- to severely-active rheumatoid arthritis in adult patients with inadequate response to one or more TNF antagonists; Treatment of Wegener’s granulomatosis; Treatment of microscopic polyangiitis	Genentech
Bortezomib	Velcade	Treatment of multiple myeloma; treatment of relapsed or refractory mantle cell lymphoma	Millenium Pharmaceuticals
Eculizumab	Soliris	Treatment of paroxysmal nocturnal hemoglobinuria to reduce hemolysis	Alexion Pharmaceuticals

FDA: Food and drug administration.