J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Original Article

Volume 6, Number 2, April 2014, pages 98-110

Ten Years Experience With Belatacept-Based Immunosuppression After Kidney Transplantation

Figure 1. Development of observational groups up to month 14 post-transplant. CyA: cyclosporine A; Tac: tacrolimus; CNI: calcineurin inhibitor; MMF: mycophenolate mofetil.

**Table 1.** Data of Patients Primarily Enrolled Into the Phase II Trial With and Developed Third Observational Group Due to Switch From Belatacept-Based to CNI-Based Immunosuppression (Switched Patients)
Pat. No.	Age (years)	Gender	BMI (kg/m²)	No. of CRF	Tye of organ	Donor age (years)	CIT (min)	MM	Underlaying disease
BMI: body mass index; CRF: cardiovascular risk factors; CIT: cold ischemia time; MM: mismatch. *: switched patients.
Patients initially receiving belatacept (*switched patients)
1*	53	M	29.8	3	LRD	57	222	2	Nephrosklerosis
2	44	M	19.4	3	DOD	23	844	2	Unknown
3*	46	M	23.6	1	LNRD	45	226	5	Chronic glomerulonephritis
4*	32	M	23.1	1	DOD	58	980	0	IgA nephropathy
5*	41	M	21	2	DOD	46	1,273	1	IgA nephropathy
6	53	M	25.1	3	DOD	38	849	2	Polycystic kidney disease
7	40	M	30	2	LRD	64	205	3	IgA nephropathy
8	27	M	18.9	1	DOD	37	717	2	Obstructive nephropathy
9*	45	M	27.5	2	DOD	29	1,430	2	Nephrosklerosis
10	41	M	19.5	2	DOD	58	821	4	Unknown
11*	25	M	25.6	2	DOD	58	559	0	IgA nephropathy
12*	70	M	24.2	2	DOD	36	820	1	Nephrosklerosis
13	32	M	22.3	3	DOD	53	1,233	3	Obstructive nephropathy
14*	42	F	20.7	2	DOD	58	856	0	Post-streptococcal glomerulonephritis
15	32	F	18.1	2	DOD	54	786	0	Hereditary nephritis
Patients initially receiving CyA
16	60	M	22.4	2	DOD	17	841	1	Chronic pyelonephritis
17	36	M	22.7	1	DOD	49	784	2	Chronic glomerulonephritis
18	24	M	20.2	1	DOD	48	1,179	3	Cystinosis
19	41	M	23.5	2	DOD	58	1,118	0	IgA nephropathy
20	58	F	27.8	1	DOD	38	1,154	2	Chronic pyelonephritis

Table 1. Data of Patients Primarily Enrolled Into the Phase II Trial With and Developed Third Observational Group Due to Switch From Belatacept-Based to CNI-Based Immunosuppression (Switched Patients)

Pat. No.

Age (years)

Gender

BMI (kg/m²)

No. of CRF

Tye of organ

Donor age (years)

CIT (min)

Underlaying disease

BMI: body mass index; CRF: cardiovascular risk factors; CIT: cold ischemia time; MM: mismatch. *: switched patients.

Patients initially receiving belatacept (*switched patients)

29.8

LRD

222

Nephrosklerosis

19.4

DOD

844

Unknown

23.6

LNRD

226

Chronic glomerulonephritis

23.1

DOD

980

IgA nephropathy

DOD

1,273

IgA nephropathy

25.1

DOD

849

Polycystic kidney disease

LRD

205

IgA nephropathy

18.9

DOD

717

Obstructive nephropathy

27.5

DOD

1,430

Nephrosklerosis

19.5

DOD

821

Unknown

11*

25.6

DOD

559

IgA nephropathy

12*

24.2

DOD

820

Nephrosklerosis

22.3

DOD

1,233

Obstructive nephropathy

14*

20.7

DOD

856

Post-streptococcal glomerulonephritis

18.1

DOD

786

Hereditary nephritis

Patients initially receiving CyA

22.4

DOD

841

Chronic pyelonephritis

22.7

DOD

784

Chronic glomerulonephritis

20.2

DOD

1,179

Cystinosis

23.5

DOD

1,118

IgA nephropathy

27.8

DOD

1,154

Chronic pyelonephritis

**Table 2.** CMV IgG Status and Post-Transplant Infections/Malignancies
Pat. No.	CMV donor	CMV recipient	Viral infection	Bacterial infection	malignancies
CMV: cytomegalovirus; CIN: cervical intraepithelial neoplasia; CNI: calcineurin inhibitor.
Patients initial treated with belatacept
2	pos	pos	-	-	-
6	neg	pos	-	-	2× basalioma (year 5)
					Bronchial carcinoma (year 8)
7	pos	neg	CMV (month 5)	-	-
8	neg	neg	-	-	-
10	neg	pos	Herpes zoster (month 2)	-	-
13	neg	pos	-	Endocarditis, pleural empyema	-
15	pos	neg	CMV (month 8)	Urosepsis (month 6)	CIN cervix (year 7)
Patients switched from belatacept to CNI
1	pos	neg	3× CMV (month 5, 6, 7)	-	-
3	pos	neg	Herpes zoster (year 2)	-	-
4	neg	neg	-	-	-
5	neg	pos	-	-	-
9	neg	pos	-	-	-
11	neg	pos	-	-	-
12	pos	pos	CMV (month 1, 3)	Urosepsis (month 3)	Bronchial carcinoma (year 2)
14	pos	pos	-	-	-
CNI-treated patients
16	pos	neg	-	-	Basalioma (year 8)
17	pos	neg	CMV (month 6)	Urosepsis (year 6)-	-
18	pos	neg	CMV (month 2)	-	-
19	pos	neg	CMV (month 4)	-	2× basalioma (year 6, 9)
20	pos	pos	-	Pseudomembraneous colitis (month 2)	-

Table 2. CMV IgG Status and Post-Transplant Infections/Malignancies

Pat. No.

CMV donor

CMV recipient

Viral infection

Bacterial infection

malignancies

CMV: cytomegalovirus; CIN: cervical intraepithelial neoplasia; CNI: calcineurin inhibitor.

Patients initial treated with belatacept

pos

neg

pos

2× basalioma (year 5)

Bronchial carcinoma (year 8)

pos

neg

CMV (month 5)

neg

pos

Herpes zoster (month 2)

neg

pos

Endocarditis, pleural empyema

pos

neg

CMV (month 8)

Urosepsis (month 6)

CIN cervix (year 7)

Patients switched from belatacept to CNI

pos

neg

3× CMV (month 5, 6, 7)

pos

neg

Herpes zoster (year 2)

neg

pos

neg

pos

neg

pos

CMV (month 1, 3)

Urosepsis (month 3)

Bronchial carcinoma (year 2)

pos

CNI-treated patients

pos

neg

Basalioma (year 8)

pos

neg

CMV (month 6)

Urosepsis (year 6)-

pos

neg

CMV (month 2)

pos

neg

CMV (month 4)

2× basalioma (year 6, 9)

pos

Pseudomembraneous colitis (month 2)

**Table 3.** 10-Year Follow-Up of Serum-Creatinine and Immunosuppression
Pat. No.		14	2 yrs	3 yrs	4 yrs	5 yrs	6 yrs	7 yrs	8 yrs	9 yrs	10 yrs
Bela: belatacept; TAC: tacrolimus; CyA: ciclosporine A; Aza: azathioprine.
CNI-free patients treated with belatacept (1)
2	Immunosup	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela
Creatinine, μmol/L	70	71	73	66	77	72	66	68	76	76
6		Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Patient died
86	86	96	91	-	82	-	75
7		Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela
146	143	151	132	-	139	-	-	-	128
8		Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela
117	101	113	107	94	109	95	90	98	97
10		Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela
113	112	116	116	134	118	108	108	115	118
13		Bela	Patient died
156
15		Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela	Bela
76	93	89	103	112	98	92	98	99	91
Median	113	103	105	105	103	104	94	90	99	97
Patients switched from belatacept to CNI (2)
1		TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC
134	149	149	131	149	165	182	147	181	194
3		TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC
237	251	250	202	219	182	214	196	194	219
4		TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC
189	184	220	180	189	207	206	199	211	197
5		CyA	CyA	CyA	CyA	CyA	CyA	CyA	CyA	CyA	CyA
122	118	126	121	127	116	117	107	102	116
9		Bela	Switch month 14 to CyA; patient died at month 20
115
11		TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	Tx failure
149	149	127	182	190	192	262	379	674
12		CyA	CyA	Patient died
180	161
14		TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC
118	130	119	130	110	160	129	125	143	123
Median	142	149	138	156	169	174	194	172	188	194
CNI-treated patients (3)
16		TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	Patient died
201	250	219	273	266	274	313	362
17		CyA	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC	TAC
200	207	182	199	195	189	179	196	207	194
18		TAC	TAC	TAC	TAC	TAC	+Aza	+Aza	+Aza	+Aza	+Aza
130	170	180	183	237	266	248	189	179	179
19		CyA	CyA	CyA	CyA	CyA	CyA	CyA	CyA	CyA	CyA
95	138	127	129	113	124	108	122	113	120
20		CyA	CyA	CyA	CyA	CyA	+Aza	+Aza	+Aza	+Aza	+Aza
95	107	104	106	126	118	106	102	102	109
Median	130	170	180	183	195	189	179	189	146	150
Mann-Whitney U test; P	1 vs. 2	0.04	0.005	0.026	0.015	0.067	0.009	0.009	0.009	0.019	0.056
1 vs. 3	0.268	0.03	0.052	0.052	0.063	0.017	0.032	0.016	0.114	0.111
1 vs. 2+3	0.046	0.002	0.01	0.007	0.026	0.002	0.003	0.002	0.014	0.029

Table 3. 10-Year Follow-Up of Serum-Creatinine and Immunosuppression

Pat. No.

2 yrs

3 yrs

4 yrs

5 yrs

6 yrs

7 yrs

8 yrs

9 yrs

10 yrs

mon

Bela: belatacept; TAC: tacrolimus; CyA: ciclosporine A; Aza: azathioprine.

CNI-free patients treated with belatacept (1)

Immunosup

Bela

Creatinine, μmol/L

Bela

Patient died

Bela

146

143

151

132

139

128

Bela

117

101

113

107

109

Bela

113

112

116

134

118

108

115

118

Bela

Patient died

156

Bela

103

112

Median

113

103

105

103

104

Patients switched from belatacept to CNI (2)

TAC

134

149

131

149

165

182

147

181

194

TAC

237

251

250

202

219

182

214

196

194

219

TAC

189

184

220

180

189

207

206

199

211

197

CyA

122

118

126

121

127

116

117

107

102

116

Bela

Switch month 14 to CyA; patient died at month 20

115

TAC

Tx failure

149

127

182

190

192

262

379

674

CyA

Patient died

180

161

TAC

118

130

119

130

110

160

129

125

143

123

Median

142

149

138

156

169

174

194

172

188

194

CNI-treated patients (3)

TAC

Patient died

201

250

219

273

266

274

313

362

CyA

TAC

200

207

182

199

195

189

179

196

207

194

TAC

+Aza

130

170

180

183

237

266

248

189

179

CyA

138

127

129

113

124

108

122

113

120

CyA

+Aza

107

104

106

126

118

106

102

109

Median

130

170

180

183

195

189

179

189

146

150

Mann-Whitney U test; P

1 vs. 2

0.04

0.005

0.026

0.015

0.067

0.009

0.019

0.056

1 vs. 3

0.268

0.03

0.052

0.063

0.017

0.032

0.016

0.114

0.111

1 vs. 2+3

0.046

0.002

0.01

0.007

0.026

0.002

0.003

0.002

0.014

0.029

**Table 4.** Cardiovascular Events
Pat. No.	Group	Cardiovascular event
13	Belatacept	Mitral and aortal valve insufficiency (month 4 and 12)
1	Switch	Abdominal aortic aneurism (year 3); stroke (arteria cerebri media; year 8)
5	Switch	Stenosis of right external iliac artery (month 11);
Stenosis of left and right common iliac artery (year 4)
9	Switch	Sudden heart death (month 20)
11	Switch	Stenosis of right coronary artery (year 7)
14	Switch	Stenosis of transplant artery (month 7)
16	CNI	Aortic valve stenosis with decompensation (year 9)
18	CNI	Stroke (arteria cerebri media; year 4)

Table 4. Cardiovascular Events

Pat. No.

Group

Cardiovascular event

Belatacept

Mitral and aortal valve insufficiency (month 4 and 12)

Switch

Abdominal aortic aneurism (year 3); stroke (arteria cerebri media; year 8)

Switch

Stenosis of right external iliac artery (month 11);

Stenosis of left and right common iliac artery (year 4)

Switch

Sudden heart death (month 20)

Switch

Stenosis of right coronary artery (year 7)

Switch

Stenosis of transplant artery (month 7)

CNI

Aortic valve stenosis with decompensation (year 9)

CNI

Stroke (arteria cerebri media; year 4)

**Table 5.** Cardiovascular Risk Factors and Medical Treatment
Parameter	14 mon	3 yrs	5 yrs	8 yrs	10 yrs
BP: blood pressure; mon: months.
Systolic BP median
Belatacept	120	130	132	122	120
Switch	126	123	130	125	120
CNI	135	126	128	139	122
Diastolic BP (mmHg; median)
Belatacept	74	75	77	75	68
Switch	79	80	80	79	80
CNI	82	76	85	83	74
No. of BPM (median; (range))
Belatacept	3 (2-5)	3 (2-5)	3 (1-5)	2 (1-5)	2 (1-4)
Switch	3 (2-4)	3 (2-6)	4 (2-6)	4 (2-4)	4 (2-4)
CNI	4 (2-4)	3 (3-4)	3 (2-4)	3 (3-4)	4 (3-5)
Cholesterol (mg/dL; median)/triglycerides
Belatacept	193/171	233/165	186/112	226/143	232/118
Switch	174/343	195/508	162/259	176/238	197/334
CNI	209/175	186/187	205/188	255/145	231/166
Pat. with lipid lowering medication
Belatacept	4 (57%)	3 (50%)	4 (67%)	4 (67%)	3 (60%)
Switch	4 (50%)	4 (67%)	5 (83%)	4 (67%)	4 (80%)
CNI	2 (40%)	3 (60%)	2 (40%)	2 (40%)	1 (25%)
NODAT (n (%))
Belatacept	0	0	0	0	0
Switch	1 (14%)	1 (17%)	1	1	1 (20%)
CNI	0	0	0	0	0
Number of patients
Belatacept	7	6	6	6	5
Switch	8	6	6	6	5
CNI	5	5	5	5	4

Table 5. Cardiovascular Risk Factors and Medical Treatment

Parameter

14 mon

3 yrs

5 yrs

8 yrs

10 yrs

BP: blood pressure; mon: months.

Systolic BP median

Belatacept

120

130

132

122

120

Switch

126

123

130

125

120

CNI

135

126

128

139

122

Diastolic BP (mmHg; median)

Belatacept

Switch

CNI

No. of BPM (median; (range))

Belatacept

3 (2-5)

3 (1-5)

2 (1-5)

2 (1-4)

Switch

3 (2-4)

3 (2-6)

4 (2-6)

4 (2-4)

CNI

4 (2-4)

3 (3-4)

3 (2-4)

3 (3-4)

4 (3-5)

Cholesterol (mg/dL; median)/triglycerides

Belatacept

193/171

233/165

186/112

226/143

232/118

Switch

174/343

195/508

162/259

176/238

197/334

CNI

209/175

186/187

205/188

255/145

231/166

Pat. with lipid lowering medication

Belatacept

4 (57%)

3 (50%)

4 (67%)

3 (60%)

Switch

4 (50%)

4 (67%)

5 (83%)

4 (67%)

4 (80%)

CNI

2 (40%)

3 (60%)

2 (40%)

1 (25%)

NODAT (n (%))

Belatacept

Switch

1 (14%)

1 (17%)

1 (20%)

CNI

Number of patients

Belatacept

Switch

CNI

**Table 6.** Patient and Graft Survival
Belatacept group	Deaths: 2	- Sepsis due to pleural empyema after valve replacement (year 2)
		- Bronchial cancer (year 8)
	Graft loss: 0
Switch group	Deaths: 2	- Sudden heart failure (month 20)
		- Bronchial cancer (year 3)
	Graft loss: 1	-Recurrence of IgA nephropathy (year 9)
CNI group	Deaths: 1	- Decompensation of aortic valve stenosis (year 9)
	Graft loss: 0

Table 6. Patient and Graft Survival

Belatacept group

Deaths: 2

- Sepsis due to pleural empyema after valve replacement (year 2)

- Bronchial cancer (year 8)

Graft loss: 0

Switch group

Deaths: 2

- Sudden heart failure (month 20)

- Bronchial cancer (year 3)

Graft loss: 1

-Recurrence of IgA nephropathy (year 9)

CNI group

Deaths: 1

- Decompensation of aortic valve stenosis (year 9)

Graft loss: 0