Cyclosporine A induced remission of relapsing nephrotic syndrome in children

Kidney International, Vol. 33 (/988), pp. 729—734

Cyclosporine A induced remission of relapsing nephrotic syndrome in children AMIR TEJANI, KHALID BUTT, HOWARD TRACHTMAN, MANIKKAM SUTHANTHIRAN, CONSTANTINE J. ROSENTHAL, and MOHAMED R. KHAWAR Renal Division, Department of Pediatrics, and the Departments of Surgery and Medicine, State University of New York, Health Science Center at Brooklyn and The Rogosin Institute, New York, New York, USA

Cyclosporine A induced remission of relapsing nephrotic syndrome in

Methods

children. We treated 20, steroid resistant or steroid dependent and

Children between the ages of 3 and 18 years were enrolled in

cyclophosphamide or chlorambucil treated, relapsing nephrotic patients with oral cyclosporine A for eight weeks. Cyclosporine A was started at 7 mg/kg/day and titrated to maintain HPLC level of 100 to 200 ng/ml. Of

the study after an informed consent was obtained from the

20 patients, 14 had a complete remission and the remaining 6 had a reduction in their proteinuria. The mean serum albumin of the 14 responders rose from 2.1 g/dl to 4.1 g/dl (P < 0.00001) after

Criteria for entry into the study were: (1) a frequently relapsing course, defined as two or more relapses in the

parents.

preceding six months or four or more relapses in the preceding

cyclosporine A therapy. The mean serum cholesterol of the 14 respond-

ers decreased from 394 mg/dl to 184 mg/dl (P <

0.0001)

after

year; (2) steroid dependence or resistance; steroid resistance was defined as failure to respond to 60 mg/rn2 of prednisone patients (104 ml/min/l.73 m2) was unchanged (107 ml/min/1.73 m2) after given for eight weeks. Steroid dependence was defined as eight weeks of cyclosporine A. By life table analysis, 40% of the recurrence of proteinuria when the dose of prednisone was responders show a sustained remission of up to a year. Cyclosporine A responders had a higher T3 cell count prior to therapy compared to discontinued or lowered below a critical level. (3) Prior admincyclosporine A therapy. The mean creatinine clearance of the 20

nonresponders (69

5.54% vs. 61

6.4%,

P<

0.02). Pre-therapy

istration of at least one course of cyclophosphamide or

interleukin-2 levels measured in 10 patients were normal or

supranormal in 8, 6 of whom were treatment responders. Two patients chlorambucil. In patients classified as steroid dependent, prednisone was with low interleukin-2 levels were nonresponders. Cyclosporine A can be used to induce a remission in relapsing nephrotic patients, and withdrawn for 14 days prior to starting cyclosporine A therapy. short-term cyclosporine A therapy does not produce nephrotoxicity. Prior to therapy, 24-hour urine protein together with serum albumin, serum cholesterol and liver enzymes were measured. A 24-hour creatinine clearance was obtained in all the patients The proportion of patients who will have a sustained remis- before and at the end of therapy. Additionally, (a) T cell subsets sion of their nephrotic syndrome with the initial course of (N = 20) (b) mitogen stimulated blast transformation (N = 20)

steroid therapy is highly variable. The rates for children re- and (c) interleukin-2 production (N = 10) before and after ported in literature range from 10% in one study [1] to 60% in therapy were determined. T cell determination was done by another [2], and a range of 20 to 70% has been reported for fluorescence microscopy using Ortho-mune Monoclonal Antiadults [31. Among those children who present with minimal body [6]. Mitogen stimulation was measured by determining glomerular changes at initial histological study, 43% will be- uptake of 3H thymidine [7]. come frequent relapsers [4]; the corresponding figure for adults is 39% [3]. Children whose disease is characterized by frequent

Interleukin-2 assay

relapse are treated with repeated courses of steroid therapy. Peripheral blood mononuclear cells, isolated by ficoll-hyWhen steroid toxicity develops or when the nephrotic syn- paque gradient centnfugation of anticoagulated blood, were drome develops resistance to the action of steroids, alternative activated with 2 g/ml of PHA. The cells were cultured for 16 therapy consists of either cyclophosphamide or chlorarnbucil. Based on the evidence suggesting a T cell involvement in the pathogenesis of nephrotic syndrome [5], we have treated a group of children whose nephrotic syndrome was either steroid dependent or had developed steroid resistance, with a course of cyclosporine A.

Received for publication July 22, 1986 and in revised form November 11, 1986 and April 29, 1987

© 1988 by the International Society of Nephrology

hours at 37°C in a 5% of C02-95% air atmosphere and cell free

supernatants were obtained. The supernatants were screened for IL-2 activity using an IL-2 dependent cytotoxic T cell line as previously reported [8]. 3H-thymidine incorporation found dur-

ing 20 to 24 hours of incubation period of CTLL were determined in a liquid scintillation system and the results found with patients cells were expressed as percent of control response (100% = IL-2 activity found in supernatants from normal PBM activated with PHA). Cyclosporine A was started at 7 mg/kg/day orally in a single dose and the dose titrated to maintain a trough HPLC whole

729

730

Tejani ci a!: Cvclosporine A in nephrotic syndrome 1.0

Table 1. Age, sex and duration of illness prior to CY therapy Mean Age at onset Age at the time of study Duration of illness

5.3 years 10.7 years 4.8 years

Range 2—15.5

0

3—18

a) (0

6 mo—14 yrs

E a,

0.8

0.6

C

blood level between 100 to 200 ng/ml. Cyclosporine A dose was reduced when the blood level was higher than 200 ng/ml, but the

dose was not increased over 7 mg/kg/day when the level of cyclosporine A was less than 100 ng/ml. In grossly edematous patients, prednisone was used in the dose of 5 or 10mg per day per patient for the first 10 to 14 days. Older children received 10

mg per day and the younger ones received 5 mg per day. Furosemide, 40 mg p.o. was also administered to edematous patients for the first 7 to 10 days. Cyclosporine A was administered for eight weeks and then abruptly discontinued. Patients were treated in hospital for the first three days when daily serum creatinine was monitored. Subsequently, renal function, liver function, serum albumin and cholesterol were measured weekly along with quantitation of urinary protein excretion. Student's t-test was used for paired comparisons and Fisher exact probability test was used for observations too small to apply a ,2 p valves below 0.05 were considered significant. Duration of remission was calculated by actuarial methods using the Biomedical Statistical software (Univ. of California) series of computer program. Results Twenty children (13 males and 7 females) were enrolled into

the study. Table 1 shows age at onset, age at start of

0 0.4 0 0. 0

0

0.2

0.0 0

1 23 4 56 7 89101112 Time, months

Fig. 1. Actuarial duration of remission in cvclosporine responders after discontinuation of therapy.

administration (P < 0.00001). The mean serum cholesterol of these 14 responders decreased from pre-therapy level of 394 156 mg/dl to 184 86 mg/dl after cyclosporine A administration (P < 0.00003). Six patients (nos. 15-20), Table 2, failed to achieve a remis-

sion, however there was reduction in proteinuria in all six patients following cyclosporine A administration (Table 2). Four of these six patients were steroid resistant at the time of cyclosporine A therapy, while the remaining two were steroid sensitive. (Fisher exact P = 0.078). The four steroid resistant patients were cytotoxic therapy resistant as well. The other two non-responders had responded to cytotoxic therapy in the past with a remission of three and six months, respectively. Of the 10 patients with focal segmental glomerulosclerosis (Table 2), 7 were steroid resistant, and had focal segmental sclerosis documented at the initial biopsy. The remaining three

cyclosporine A treatment and the duration of illness. Given the long history of disease the number of relapses per patient were not calculated, but an approximation of the total steroid dosage received was made which ranged from 1.05 to 46.47 grams. Of the 20 children, 7 were resistant to steroid therapy at the time of patients had evolved from minimal change into focal segmental entry, whereas 13 continued to be steroid sensitive but were sclerosis and continued to be steroid sensitive. All three steroid steroid dependent requiring continuous steroid administration sensitive and three of the seven steroid resistant patients in the dose range between 20 and 40 mg/m2/day to prevent a responded to cyclosporine A therapy. When steroid resistant relapse. None of the patients classified as steroid resistant had patients were separately analyzed three had a remission while four failed to respond. The mean number of days of received bolus methyl-prednisolone therapy. As regards prior cytotoxic therapy, one patient had received cyclosporine A therapy required to produce a remission in the cyclophosphamide eight weeks prior to starting cyclosporine A. responders was 21 with the earliest response being seen at In the remaining 19 cases cytotoxic therapy had been tried at a seven days and the delayed response appearing as late as 49 mean of 2.5 years prior to entry in the current study (range I to days. 8 years). Eight of the 20 patients were classified as cytotoxic Duration of remission therapy sensitive. The seven steroid resistant patients were also Actuarial duration of remission (Fig. 1) calculated using life cytoxic therapy resistant. The mean dose of cyclosporine A per patient was 6 0.5 table and survival function (BMDP program) showed a 40% sustained remission of up to one year after discontinuation of mg/kg/day. Remission is defined as (1) disappearance of edema, (2) urine therapy. Of 14 patients, 7 had a relapse within five months of remaining free of protein on qualatative testing for at least three discontinuation of therapy, the relapse intervals being I month consecutive days, and on quantitative measurement 24 hour (2 patients), 2 months (2 patients), 3, 4 and 5 months (I patient urine protein is less than 150 mg, (3) serum albumin greater than each). The remaining seven patients have been in remission from 3 to 12 months. Five of these seven patients with a 2.5 g/dl, and (4) normalization of serum cholesterol. Of 20 patients, (Nos. 1-14) Table 2, 14 achieved remission. In continuing remission have remained in remission for over nine

addition to disappearance of proteinuria, the mean serum months after discontinuation of therapy. Four of these five albumin for these 14 patients rose from a pre-therapy level of patients were steroid dependent requiring continued prednisone 2.1 0.5 g/dl to 4.1 0.4 g/dl following cyclosporine A therapy prior to entering the cyclosporine protocol. The fifth

731

Tejani et a!: yc/osporine A in nephrotic syndrome Table 2. Pre- and post-therapy display of all patients in the study

Urine

CCR Serum 24 hour Serum choles(ml! S.A. BiliCreatin- mini u. protein albumin terol Pt. no. mm2 protein mgiday gm!dl mg!dISGOT SGPT rubin BUN inea 1.73 m2 36 0.5 125 I Pre 0.6 4+ 1722 2.2 126 31 13 0.3 0.5 Post 4.4 88 33 14 0.3 13 0.5 128 19 Neg 2 Pre 1.0 4+ 11 0.3 25 0.6 114 3598 2.8 404 22 0.8 Post 4.5 164 29 6 0.2 15 0.7 105 129 Neg 3 Pre 0.8 293 27 6 0.1 13 0.5 160 3+ 1335 2.8 0.6

dipstick

Post

4 Pre

0.8

Post

5 Pre

0.8

Post

6 Pre

0.7

Post

7 Pre 1.1 Post

8 Pre

Post 11 Pre

Neg 4+ Neg

4+

Neg 3+

34 42

—

0.2 0.6

22 23

4 7

0.1

6

0.6 0.6 0.6 0.7 0.3 0.6 0.4 0.5 0.6 0.4 0.6 0.7 0.6 0.7 0.8 0.7 0.7 0.9 0.7 0.6 0.7 0.6 0.8 0.9 0.8

0.3

12

0.5

<100

4.7

133

3892

1.2

630

22 22

ISO

4.1

231

1130

2.4

402

37

4.7

128

2876

2.1

279

140

4.2

134

3730

2.5

266

8 7

0.2 0.6

20

8

37

12

0.6 0.2

20 27 18 25

11

6 8 8

0.3 0.9

9 13 14

8 12

35

0.1

9

0.2

17

Neg 2+

150

4.0

198

18

11

0.3

2950

1.6

498

34

7

0.1

12 10

Neg 3+

140

4.4

128

6192

1.7

642

28 27

9

1.5

13

0.1 0.1

10 11

Neg 4+

34

4.3

182

12

5

0.3

9

0.7

1120

2.5

319

35

46

1.1

12

Post 10 Pre

4+

1.0

Post

9 Pre

Neg

Neg 3+

95 1376

4.7

163

1.0

2.5

381

Post 12 Pre 0.6

Neg 3±

120 1201

4.7 2.9

299

169

17

11 13

152

103

170

Glomerular morphology

Neg 4+

6 2436

3.8 1.8

219 340

Post 14 Pre 0.9

Neg 4+

ISO

3.6

6800

1.2

202 638

Post

15 Pre 0.9

Neg 4+

120

3.2 3.7

340 303

32

101

0.3 0.1

14 7

0.5 0.5 0.5

39

27

0.2

6

18

14

0.3

8

0.5 0.6 0.7 0.6

19

13 11

0.2 0.4

11

Clinical

outcome

F.S.G.S.

St. Remission Resistant

F.S.G.S.

St. Remission Sensitive

Mesangial hypercellularity

Remission St. Sensitive

F.S.G.S.

St. Remission Resistant

1gM

St.

166 81

Remission

nephropathy Sensitive 80

73

F.S.G.S.

St.

Remission

Resistant 102 80

F.S.G.S.

St.

Remission

Sensitive

78

110 1gM

St. Remission nephropathy Sensitive

122

135 1gM

St. Remission nephropathy Sensitive

133

126

F.S.G.S.

St.

Remission

Sensitive 127 83

St. Remission nephropathy Sensitive 1gM

92

M.C.N.S.

0.6 Post 13 Pre 0.8

Steroid status

St.

Remission

Sensitive 106

74 1gM 80

100

St. Remission nephropathy Sensitive M.C.N.S.

St.

Remission

Sensitive 100

St. Non-responsive Resistant to Post I 0.2 50 1.7 38 Trace 399 3.9 312 23 cyclosporine 16 Pre 1.7 4+ 10 0.2 10 1.0 101 F.S.G.S. St. 7693 1.8 413 20 Non-responsive 1.3 Resistant to Post 4+ 3.5 250 15 7 0.2 16 0.9 98 4698 cyclosporine St. 17 Pre 0.7 4+ 443 14 6 0.1 9 0.4 134 M.C.N.S. 2450 2.3 Non-responsive to 0.7 Sensitive Post 2+ 7 0.4 135 1031 2.3 446 18 10 0.2 cyclosporine 17 St. 18 Pre 1.0 4+ 7308 1.6 464 24 14 0.1 0.6 124 1gM Non-responsive 0.6 to nephropathy Sensitive Post 24 3+ 969 3.4 391 31 17 0.2 0.6 139 cyclosporine St. 19 Pre 1.5 4+ 2279 3.6 181 18 7 0.7 10 1.3 70 F.S.G.S. Non-responsive to 1.4 Resistant Post 2+ 0.5 11 1.2 76 882 3.7 186 18 6 cyclosporine 20 Pre 1.7 St. 4+ 13320 3.3 228 14 12 0.3 5 0.9 89 F.S.G.S. Non-responsive 1.1 Resistant to Post 4 4+ 5234 3.6 203 29 32 0.1 0.8 95 cyclosporine a Three values of serum creatinine per patient is shown. These are pre-, the highest during therapy and post-therapy. 2072

24

20

1.5

1.7

41

F.S.G.S.

732

Tejani et a!: Gyclosporine A in nephrotic syndrome

Table 3. T cell subsets and blast transformation in responders and non-responders Responders T3 T4 T5 T4/Tg

PHA PWM Con A

69 46

27.75 1.76 29.46 20.6 20.54

5.54 9.14 5.8 0.51 19.4

Non-responders 61 6.4 41 7.2 24.1 3.8 1.72 0.48 27.08 20.8

25.5

16.5

16.2

17.03

13.8 13.2

B

300

P <0.02 NS NS NS NS NS NS

All data expressed as mean SD.

0 200 C

0 C) C

w

C)

0

100

patient had steroid resistance and had been hospitalized six times in the previous one year for albumin and lasix infusions.

Steroid dependent patients who relapsed following cyclosporine therapy and required further steroid therapy, did not

123456 T

SE

1234

SE

achieve any diminution in their steroid dosage, but the quantiPatients tative proteinuria seen was reduced by about 1/3 in 6 of the 7 Fig. 2. IL-2 activity in nephrotic syndrome patients. IL-2 activity patients. found in supernatants obtained from PBM from the responders (A) and nonresponders (B) are shown. Results are expressed as percent control

T cell studies (100% = IL-2 activity in supernatants from normal PBM activated with Table 3 compares T cell subsets and blast transformation in 2 g/ml of PHA). responders and non-responders prior to therapy. Non-responders in general had lower values in all parameters studied, but ones of nausea and vomitting in about half of the patients, for significant differences were only noted in the T3 subset. the first 24 to 48 hours of drug administration. One child developed a viral pneumonia while on cyclosporine Interleukin studies A therapy, and one patient developed varicella one week after Of the ten patients studied, 6 of 10 patients made supranormal initiation of cyclosporine A. Cyclosporine A was discontinued amounts of IL-2, 2 of 10 made normal amounts of IL-2 and 2 of for two weeks until the infection resolved and then was

10 made subnormal amounts of IL-2. Thus, the majority of readministered without further problem. No tremors, convulsions, hypertension or hyperkalemia were noted in any of the patients.

nephrotic syndrome patients (8 of 10) studied lacked evidence for T cell deficiency as assessed by their ability to elaborate IL-2. More importantly, the effectiveness of cyclosporine A appeared to be related to the patients' lL-2 production status

Discussion

prior to initiation of CSA therapy. All six patients who reThe therapeutic modalities presently available for patients sponded to cyclosporine A intervention made normal or with relapsing nephrotic syndrome are unsatisfacsupranormal amounts of IL-2 and both patients who made tory. frequently Those who are steroid responsive are treated with reminimal IL-2 failed to respond to CSA. (Fig. 2). (x2 = 3.75, P> peated course of prednisolone, and prolonged maintenance 0.05 = <1). The mean SE of responders was 186 30% and therapy is necessary for the steroid dependent patients. Comthe non-responders was 73 35% (t:2.02, df 8, P < 0.05, one promise of growth is a well recognized complication of steroid tail). therapy, and children with a frequently relapsing course are at There was no correlation between histological involvement high risk [9]. and response in focal segmental glomerulo sclerosis patients. The pathogenesis of childhood nephrotic syndrome is unWhen biopsy material was reviewed for number of focal seg- known, but evidence suggesting a disorder of T cell function has mental lesions, degree of interstitial involvement and extent of

tubular atrophy, no differences were observed between responders and non-responders. Side effects There were small transient rises in serum creatinine in some of the patients during the therapy (Table 2), but at the end of therapy serum creatinine had returned to pre therapy values in all but one patient who had elevated serum creatinine prior to

therapy. The mean creatinine clearance of all 20 patients

been accumulating [5, 10]. A current postulate is that lymphokines lead to alteration of glomerular anionic sites, resulting in the increased capillary permeability to proteins [lii. A variety of lymphokines have been identified in patients with

the nephrotic syndrome [12—141. Our presumption that cyclosporine A might have a beneficial effect on the nephrotic syndrome was based on the data in vitro and vivo, showing that cyclosporine A acts by interference with lymphokine-mediated signals between accessory cells [15—20]. The response to cyclosporine A therapy obtained in our study can not be construed as evidence of a T cell involvement in this

measured prior to therapy was 104 34 ml/min/1.73 m2. The mean creatinine clearance of all 20 patients measured at the end disorder, since cyclosporine A has varying effects on renal of cyclosporine A administration was 107 33 ml/min/1.73 m2 function. Studies in the animal model using both rats and dogs (P = NS). The only side effects consistently noted were minor has shown cyclosporine A to increase sympathetic nerve activ-

733

Te/ani ci al: Cvclosporine A in nephrotic syndrome

ity, stimulate plasma renin activity and inhibit renal prostaglan-

cyclosporine A to duplicate the efficacy of steroids is probably

din synthesis [21]. Acute and chronic administration of related to the similarities of action between these two drugs cyclosporine A in rats results in increased vascular resistance leading to decrease renal blood flow [22]. Hemodynamic alterations and potential changes in glomerular filtration rates as shown with ace inhibitor captopril can also alter the degree of proteinuria [231. Since creatinine clearances were unaltered following cyclosporine A therapy in our patients, it is unlikely that the reduction in proteinuria was due to decrease in glomerular filtration. Our observation that response to therapy was to some extent related to the amount of interleukin-2 production is

[29]. The duration of remission following cyclosporine A ther-

apy, however, seems to vary in different studies, and cyclosporine A dependence has been suggested by some investigators [30]. The data regarding steroid resistant patients seems conflicting and a controlled trial in steroid-resistant focal seg-

mental glomerulosclerosis patients is necessary to determine the dose and duration which may lead to a remission, if any. Such a controlled trial would be appropriate since the prognosis

in children with focal segmental glomerulosclerosis whose interesting, but further studies in large numbers would be nephrotic syndrome is steroid resistant, is unfavorable [3 1—33]. necessary to document this preliminary observation. The reThe relative absence of the well-known side effects of mission in one of the patients (Table 2, No. 6) occurred on the cyclosporine A in our study is obviously related to the short 49th day of cyclosporine A therapy, raising the question of duration of therapy. Others, however, using the drugs for spontaneous remission. The evidence that this patient did not

longer periods have noted gum hyperplasia, hypertrichosis and

have a spontaneous remission is based on his subsequent hypertension [28]. Hyperkalemia, gingival hyperplasia and course. This patient remained in remission for three months hirsuitism were also noted by Capodicasa et at [26] using the after discontinuation of therapy. He received monthly courses of bolus methyl prednisolone and albumin infusion over the next five months. Subsequently he received a second course of cyclosporine A and went into remission during the course of therapy. Low-dose cyclosporine therapy utilized in this study was based on observations in renal transplant recipients converted to cyclosporine [24]. While this dosage regimen did not lead to

nephrotoxicity in our study patients, the failure of a third of patients to obtain remission of their nephrotic syndrome may be related to inadequate dosage. Despite our inability to induce a

drug for six months. Thus long term tolerance of cyclosporine A

in nephrotic syndrome patients remains to be evaluated, and careful monitoring of both blood levels and clinical markers of toxicity is mandatory in all patients receiving cyclosporine A for their relapsing nephrotic syndrome. Acknowledgment Portions of this work were presented at the Plenary Session of the 18th Annual Meeting of the American Society of Nephrology, New Orleans, Louisiana. USA.

requests to Amnir Tejani, M.D., Renal Division, Department remission in these patients, the reduction in the proteinuria ofReprint Pediatrics, 450 Clarkson Avenue, Box #49, Brooklyn, New York produced by a course of cyclosporine A in these patients is /1203, USA.

beneficial since the injurious nature of heavy proteinuria to the kidney has recently been documented [25].

The use of cyclosporine A for the treatment of nephrotic syndrome in children and adults has been reported in small studies with differing results. Thus, Meyrier et at [Ill in six adult patients obtained a remission in three minimal change nephrotic syndrome patients, but only a partial remission in three, focal-segmental glomerulosclerosis patients. On the basis of their incomplete response in the steroid resistant cases, the authors suggest that minimal change nephrotic syndrome and

focal segmental glomerulosclerosis may be different entities. However, the inability to obtain a complete remission in the focal segmental glomerulosclerosis patients may be related to the initial lower dose employed in their study. Capodicasa et al [26], on the other hand, using a 150 mg/rn2 dose did achieve a remission in two of the four steroid-resistant cases, and overall

5 of their II patients remain in sustained remission after discontinuation of cyclosporine A. Similarly, Brandis et at [271 observed complete remission in four steroid-resistant patients after a short course of cyclosporine A given in the dose of 100

to 300 mg/m2. Niaudet et at [28] treated 10 steroid-resistant children using a 6 mg/kg dose and obtained partial remission in

three, complete remission in one and failure to remit in six. Eight steroid-sensitive patients in the same study had complete remission. The results from these small studies taken together with our uncontrolled study seem to suggest that patients with a steroidresponsive nephrotic syndrome have a reasonable potential for

undergoing a remission with cyclosporine A. The ability of

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