Low-dose cyclosporine in treatment of membranous nephropathy with nephrotic syndrome: effectiveness and renal safety

Figures & data

Figure 1. Patients recruitment flowsheet.

Figure 2. (a) The eGFR change in patients with Non-CsA-RI, CsA-ARI and CsA-CRI during the first four years of follow-up. (b) The SCr change in patients with Non-CsA-RI, CsA-ARI and CsA-CRI during the first four years of follow-up.

Table 1. Comparison on demographic data and general data among non-CsA-RI, CsA-ARI and CsA-CRI groups.

	Non-CsA-RI (n = 38)	CsA-ARI (n = 14)	CsA-CRI (n = 16)	p Value
Baseline data at CsA commencement
Age (years)	51 ± 15	57 ± 12	59 ± 10	.07
Male, n (%)	24 (63)	7 (50)	7 (44)	.37
Mean blood pressure (mmHg)	93 ± 10	92 ± 7	96 ± 11	.60
Serum creatinine (µmol/L)	72.5 ± 15.2	67.0 ± 14.3	8.3 ± 14.5	.05
eGFR (ml/min/1.73 m^2)	105.8 ± 21.8	113.7 ± 34.2	87.4 ± 16.80	.008
CKD stage 1:stage 2 (n)	30:8	11:3	6:10	.012
Serum albumin (g/L)	27.9 ± 6.1	25.8 ± 5.3	28.7 ± 5.6	.38
Proteinuria (g/d)	6.1 ± 3.9	7.10 ± 3.4	6.0 ± 2.6	.39
Hypertension, n (%)	11 (29)	5 (36)	7 (44)	.73
Diabetes mellitus, n (%)	5 (13)	3 (21)	2 (12)	.81
Renal pathology
Stage of IMN (I:II + III) (n)	27:11	5:9	4:12	.003
Tubule/interstitial acute index	1.2 ± .8	1.1 ± .7	1.3 ± .7	.73
Tubule/interstitial chronic index	1.3 ± .8	1.4 ± .7	1.2 ± .8	.82
Artery/arteriole lesions, %(n/n)
Intimal sclerosis of small artery	50 (19/38)	50(7/14)	57 (8/14)	.89
Hyalinosis of arteriole	27 (10/37)	50 (7/14)	38 (6/16)	.30
Treatment
RAS inhibition, n (%)	35 (92)	11 (79)	11 (69)	.071
Initial prednisone dose (mg/kg/d)	.4 ± .2	.3 ± .2	.3 ± .1	.28
Initial CsA dose (mg/kg/d)	1.6 ± .5	1.6 ± .4	1.6 ± .3	.88
Maximum CsA dose in first 3 m (mg/kg/d)	2.0 ± .3	2.0 ± .4	2.1 ± .4	.72
Peak serum CsA level in first 3 m (ng/ml)	99.8 ± 39.9	129.5 ± 6.5	111.8 ± 54.5	.22
By the end of first year
Serum creatinine (µmol/L)	86.0 ± 18.4	92.2 ± 18.6	106.1 ± 17.2	.003
eGFR (ml/min/1.73 m^2)	86.0 ± 19.8	76.7 ± 21.2	62.3 ± 14.5	.001
ΔeGFR (ml/min/1.73 m^2)	16.1 ± 16.1	42.3 ± 19.7	29.5 ± 16.6	<.001
Serum albumin (g/L)	37.2 ± 5.7	34.9 ± 7.1	36.8 ± 6.9	.519
Proteinuria (g/d)	1.92 ± 2.31	4.84 ± 4.43	2.48 ± 3.82	.017
By the end of follow-up
Follow-up time (months)	52 ± 18	44 ± 15	47 ± 19	.32
Overall remission rate, n (%)	37 (97)	12 (86)	13 (81)	.073
Remission rate by the end, n (%)	34 (89)	11 (79)	11 (69)	.17
Proteinuria (g/d)	1.70 ± 2.69	2.91 ± 3.62	3.13 ± 4.41	.028
Time-average proteinuria (g/d)	2.15 ± 1.69	3.84 ± 2.70	3.46 ± 3.19	.026
Reaching renal end point, n (%)	6 (16)	5 (36)	5 (31)	.23

Non-CsA-RI: no cyclosporine related renal injury; CsA-ARI: cyclosporine related acute renal injury; CsA-CRI: cyclosporine related chronic renal injury; CsA: cyclosporine; eGFR: estimated glomerular filtration rate; CKD: chronic kidney disease; IMN: idiopathic membranous nephropathy; RAS: renin angiotensin aldosterone system.

Figure 3. The cumulative renal survival percentage of all 68 patients, patients with CsA-ARI, patients with CsA-CRI and patients in Non-CsA-RI group.

Table 2. Univariate and multivariate analysis for renal endpoint.

		95% CI
	HR	Lower	Upper	p-Value
Univariate analysis
Baseline data at CsA commencement
Age (years)	1.035	0.994	1.078	.092
Gender (male vs. female)	0.740	0.268	2.039	.56
Serum creatinine (per µmol/L)	1.010	0.977	1.044	.56
eGFR (per ml/min/1.73 m^2)	0.996	0.975	1.017	.69
CKD stage (per stage)	0.876	0.281	2.724	.82
Proteinuria (per g/d)	0.984	0.854	1.133	.82
Serum albumin (per g/L)	0.873	0.789	0.967	.009
Hypertension (yes vs. no)	1.499	0.536	4.191	.44
Diabetes mellitus (yes vs. no)	1.247	0.355	4.386	.73
Use of RAS inhibitors (yes vs. no)	0.196	0.071	0.544	.002
Renal pathology
Tubule/interstitial acute index (per)	0.901	0.461	1.762	.76
Tubule/interstitial chronic index (per)	0.975	0.525	1.812	.94
Artery/arteriole lesions (yes vs. no)
Intimal sclerosis of small artery	5.895	1.306	26.611	.021
Hyalinosis of arteriole	1.838	0.664	5.090	.24
Data during follow up
Occurrence of CsA-ARI (yes vs. no)	2.171	0.744	6.330	.16
Occurrence of CsA-CRI (yes vs. no)	1.902	0.657	5.509	.24
Complete/partial remission (yes vs. no)	0.104	0.026	0.422	.002
Time average proteinuria (per g/d)	1.775	1.414	2.229	<.001
Duration of cyclosporine use (per month)	0.945	0.909	0.983	.005
Culmulative cyclosporine dose (per 100g)	0.422	0.148	1.205	.11
Multivariate analysis
Age (per year)	1.031	0.975	1.090	.28
Gender (male vs. female)	2.864	0.638	12.856	.17
Baseline serum albumin (per g/L)	0.895	0.755	1.060	.20
Intimal sclerosis of small artery (yes vs. no)	5.178	1.011	26.532	.049
Use of RAS inhibitors (yes vs. no)	0.164	0.032	0.850	.031
Complete/partial remission (yes vs. no)	0.581	0.028	12.145	.73
Time average proteinuria (per g/d)	1.594	1.060	2.396	.025
Duration of cyclosporine use (per month)	0.993	0.949	1.039	.76

CsA: cyclosporine; eGFR: estimated glomerular filtration rate; CKD: chronic kidney disease; RAS: renin angiotensin aldosterone system; Non-CsA-RI: no cyclosporine related renal injury; CsA-ARI: cyclosporine related acute renal injury; CsA-CRI: cyclosporine related chronic renal injury.

Table 3. Comparison on baseline and overtime clinical-pathological data among patients with different time-average proteinuria.

	<1.0 g/d (n = 18)	1.0 ∼ 3.5 g/d (n = 30)	>3.5 g/d (n = 20)	p Value
Baseline data at CsA commencement
Age (years)	52 ± 16	52 ± 12	56 ± 13	.54
Male, n (%)	8 (44)	18 (60)	12 (60)	.52
Mean blood pressure (mmHg)	90 ± 10	94 ± 9	96 ± 11	.35
Serum creatinine (µmol/L)	74.4 ± 13.9	7.6 ± 1.4	76.4 ± 22.2	.63
eGFR (ml/min/1.73 m^2)	98.7 ± 22.3	106.5 ± 16.5	104.6 ± 36.6	.30
CKD stage 1:stage 2 (n)	10:8	26:4	11:9	.021
Serum albumin (g/L)	29.5 ± 5.6	28.2 ± 5.4	24.9 ± 6.5	.046
Proteinuria (g/d)	4.90 ± 2.63	6.37 ± 3.76	7.81 ± 3.90	.047
Hypertension, n (%)	7 (39)	9 (30)	7 (35)	.81
Diabetes mellitus, n (%)	4 (22)	1 (3)	5 (25)	.042
Renal pathology
Stage of IMN (I:II + III) (n)	14:4	16:14	6:14	.013
Tubule/interstitial acute index	1.2 ± .8	1.2 ± .8	1.2 ± .6	1.00
Tubule/interstitial chronic index	1.3 ± .8	1.2 ± .8	1.4 ± .7	.72
Artery/arteriole lesions, %(n/n)
Intimal fibrosis of small artery	35 (6/17)	57(17/30)	58 (11/19)	.30
Hyalinosis of arteriole	39 (7/18)	38 (11/29)	25 (5/20)	.58
Treatment
RAS inhibition, n (%)	16(89)	27 (90)	14 (70)	.17
Initial prednisone dose (mg/kg/d)	0.3 ± 0.2	0.3 ± 0.2	0.3 ± 0.2	.90
Initial CsA dose (mg/kg/d)	1.4 ± 0.4	1.6 ± 0.4	1.7 ± 0.5	.15
Maximum CsA dose in first 3 m (mg/kg/d)	1.8 ± 0.5	2.1 ± 0.5	2.2 ± 0.6	.095
Peak serum CsA level in first 3 m (ng/ml)	87.04 ± 45.20	11.36 ± 43.63	112.48 ± 51.03	.075
Data at 3rd month
Serum creatinine (µmol/L)	77.2 ± 21.4	78.0 ± 17.6	9.6 ± 18.4	.046
eGFR (ml/min/1.73 m^2)	99.4 ± 34.7	96.7 ± 22.0	8.9 ± 21.7	.056
ΔeGFR (ml/min/1.73 m^2)	1.4 ± 29.6	13.6 ± 27.4	23.5 ± 24.8	.292
Serum albumin (g/L)	36.5 ± 3.8	32.3 ± 5.5	29.34 ± 6.8	.002
Proteinuria (g/d)	1.81 ± 1.50	3.98 ± 2.58	6.18 ± 3.12	<.001
Remission rate, n (%)	14 (78)	12 (40)	3 (15)	<.001
Data at the end of follow up
Follow-up time (months)	57 ± 15	53 ± 15	38 ± 19	.001
Duration of cyclosporine treatment (months)	33 ± 17	36 ± 15	22 ± 18	.018
Serum creatinine (µmol/L)	89.7 ± 15.9	102.1 ± 32.2	168.5 ± 132.4	.013
eGFR (ml/min/1.73 m^2)	8.29 ± 17.80	72.08 ± 19.76	54.81 ± 26.51	.002
ΔeGFR (ml/min/1.73 m^2)	18.4 ± 15.3	34.4 ± 19.4	51.5 ± 32.2	.001
CKD stage 1:stage 2:stage 3:stage 4 (n)	7:7:4:0:0	7:15:7:1:0	2:8:6:1:3	.39
Serum albumin (g/L)	41.59 ± 4.00	37.49 ± 8.79	32.73 ± 7.78	.001
Proteinuria (g/d)	0.30 ± .48	1.50 ± 2.06	4.30 ± 4.22	<.001
Remission rate, n (%)	18 (100)	25 (83)	13 (65)	.017
Reaching renal endpoint, n (%)	0 (0)	7 (23)	9 (45)	.002
Follow up overtime data
Patients with CsA-ARI, n (%)	2 (11)	3 (10)	9 (45)	.009
Patients with CsA-CRI, n (%)	3 (17)	7 (23)	6 (30)	.67
Overall remission rate, n (%)	18 (100)	30(100)	14 (70)	.001
Time-average proteinuria (g/d)	0.60 ± .24	1.95 ± .66	5.38 ± 1.93	<.001

CsA: cyclosporine; eGFR: estimated glomerular filtration rate; CKD: chronic kidney disease; IMN: idiopathic membranous nephropathy; RAS: renin angiotensin aldosterone system; CsA-ARI: cyclosporine related acute renal injury; CsA-CRI: cyclosporine related chronic renal injury.