1820 Volume 5 . Number 10 ‘ 1995

Aggressive, Long-Term Cyclosporine Therapy forSteroid-Resistant Focal Segmental �2

Elizabeth Ingulli, Anup Singh, Noosha Baqi, Hadi Ahmad, Shohreh Moazami, and Amir Tejani3

E. Ingulli. University of Minnesota. Minneapolis. MN

A. Singh. N. Baqi. H. Ahmad. S. Moazami. A. Tejani.SUNY Health Science Center. Brooklyn. NY

(J. Am. Soc. Nephrol. 1995; 5:1820-1825)

ABSTRACTShort-term cyclosporine (CsA) has been shown toreduce the proteinuria in refractory nephrotic syn-drome, but the effect on disease progression has not

been evaluated. This study was undertaken to evalu-ate whether maintenance C5A therapy in steroid-resistant focal segmental glomerulosclerosis (FSGS)will prevent progression to ESRD. Twenty-one blackand Hispanic children (mean age, 8.4 ± 4.5 yr) withbiopsy-proven, steroid/cyclophosphamide-resistantFSGS were treated with CsA (initiated at 6 mg/kg perday and titrated to the serum cholesterol level toachieve a response). The mean CsA dose was 7 (4 to20) mg/kg per day, the duration of CsA therapy was27.5 (3 to 97) months, and the duration of follow-upwas 8.5 ± 4.7 yr. At the end of CsA therapy, the mean(± SE) proteinuria fell from 6.2 ± 0.2 to 2.0 ± 0.1 g/24

h (P < 0.001), the mean albumin rose from 1.95 ± 0.04

to 3.41 ± 0.04 g/dL (P < 0.001), the mean cholesteroldecreased from 472 ± 12.7 to 257 ± 5.3 mg/dL (P <

0.005), and the mean creatinine rose from 0.79 ± 0.02to 1.16 ± 0.03 mg/dL (P < 0.005). Seven childrencontinue to receive maintenance CsA therapy, and14 patients have had CsA stopped: 6 for an increase

in serum creatinine and/or continued proteinuria, 5

for sustained remission, 2 for noncompliance, and 1

for pregnancy. Five (24%) of the 21 patients pro-gressed to ESRD. This ESRD rate was compared with ahistorical population with a similar age and follow-up,

and fewer patients were found to have progressed toESRD using long-term CsA therapy (5 of 21 (24%)versus 42 of 54 (78%); P < 0.05). Long-term CsA ther-apy reduces the proteinuria and blunts the progres-sion of FSGS to ESRD in black and Hispanic children.

Key Words: Cyclosporine. nephrotic syndrome. focal sclerosis

1 Received August 4. 1994. Accepted December 20, 1994.

2 Presented in part at the APS-5PR Meeting, seattle, May 1994.

3 correspondence to Dr. A. Tejani, Renal Division, SUNY Health Science center,Pediatrics, Box 49, 450 clarkson Ave., Brooklyn. NY 11203-2098.

104&6673/051 0-1 820$03.00/0Journal of the American Society of Nephroiogycopyright c 1995 by the American Society of Nephrology

F ocal segmental gbomemubosclerosis (FSGS) is the

most common acquired renal disease leading to

either dialysis or transplantation among North Amer-

ican children ( 1 ). We have previously reported thatblack and Hispanic children demonstrate a more vir-

ulent form of FSGS, resulting in a more rapid progres-sion to ESRD compared with white children (2). It has

been suggested that the protelnuria contributes to the

progression of disease and, when massive, can accel-erate the disease process (3). The treatment of protein-uria in patients with FSGS Is difficult because many

are resistant to corticosteroid and alkylating therapy

(4,5). Short-term cycbosporine (CsA), a potent immu-

nosuppressive, has been shown to reduce the massive

protelnuria in instances where corticosteroids and

alkylating agents have failed; however, dlscontinua-

tion of the drug often leads to a relapse of proteinuria(6-1 1 ). We have shown improved remission rates in

resistant patients using an alternative dosing regimenof CsA ( 1 2). To date, there are no studies addressingwhether a reduction in the proteinuria induced withCsA in this lesion affects the devolution of renal

function. In this study, we test the hypothesis that

maintenance CsA therapy will reduce the proteinuria

and blunt the progression to ESRD among black and

Hispanic patients with FSGS.

MATERIALS AND METHODS

Patients were included in this study if they (1 ) had biopsy-proven FSGS and proteinurla �40 mg/m2 per hour or 3g/day; (2) were younger than 18 yr of age; (3) were black orHispanic; (4 ) were corticosteroid resistant, which was de-fined as a failure to respond to the International Study ofKidney Disease in Children protocol of prednisone. 60mg/rn2 per day, for the first 4 wk, followed by 40 mg/m2every other day for 4 wk; and (5) received at least one courseof cyclophosphamide (2.5 to 3 mg/kg per day for 60 days).Additionally, parents and patients were required to consentto percutaneous renal biopsies at 12- to 18-month intervalsafter the initiation of CsA therapy.

The protocol for treating patients with CsA has variedthrough the years. Previously, patients received CsA at aninitial daily dose of 7 mg/kg. The dose was titrated tomaintain a whole blood trough level measured by high-pressure liquid chromatography between 100 and 200 ng/mL. The dose was reduced if the bevel was more than 200ng/mL. but the dose was not increased above 7 mg/kg perday if the level was below 100 ng/mL (1 1). More recently, Inthe setting of severe hypercholesterolemla, the dose of CsA istitrated to the serum cholesterol level to achieve a response,regardless of blood level. Patients are started with 10 mg/kgof CsA, and the dose is gradually increased in a stepwisemanner every 2 wk. In the presence of severe hypercholes-terolemia, this stepwise Increase In CsA dose is carried on upto a maximum of32 mg/kg unless signs ofnephrotoxicity areseen. Nephrotoxicity was defined as a rise of serum creati-

Ingulli et al

Journal of the American Society of Nephrology 1821

TABLE 1 . The mean (± SD) proteinuria, serumalbumin, serum cholesterol, and serum creatinine inthe 21 patients before the initiation of CsA (PRE) andat the end of CsA therapy (POST)

Parameter PRE CSA POST CSA P Value

Proteinuria (g/24 h) 6.2 ± 4.6 2.0 ± 2.5 <0.001Albumin (g/dL) 1 .95 ± 0.73 3.41 ± 0.75 <0.001Cholesterol (mg/dL) 472 ± 241 257 ± 107 <0.005

Creatinine (mg/dL) 0.79 ± 0.34 1.16 ± 0.63 <0.005

nine equal to or greater than 0.5 mg on two consecutive days.When clinical evidence of nephrotoxlclty was present, thedose of CsA was reduced by one-third and then graduallyincreased If the clinical signs of nephrotoxicity disappeared.Because CsA dosing Is titrated to cholesterol level, whenserum cholesterol is below 400 mg/dL, a stepwise reductionin CsA dose Is carried out so that patients with cholesterollevels of 200 or less are generally maintained on 10 mg/kg orless of CsA.

After a reduction in the proteinurla below 500 mg/day, thedose of CsA is gradually tapered and withdrawn over a 2- to3-month period. Recurrence of the proteinuria during thetaper or after the withdrawal of the drug resulted in reinsti-tution of the drug according to the protocol previously dis-cussed. In patients in whom a reduction of proteinurla doesnot occur within 3 months, the drug is discontinued. In anypatient exhibiting two consecutive rises in serum creatinineof 0.5 mg or more, despite CsA dose reduction, the drug waswithdrawn.

All patients received low-dose prednisone at the InitiationofCsA therapy. Children younger than 6 yr ofage were begunon 5 mg daily. those 6 to 12 years ofage were begun on 10 mgdaily, and those 12 to 18 yr ofage were begun on 15 mg daily.Two obese children received 20 mg of prednisone daily. Instable patients, prednisone was eventually discontinued. Inedematous patients, furosemide was administered. No pa-tients were given an angiotensin-converting enzyme inhibitorto treat their hypertension.

Patients were monitored In the clinic weekly where serumelectrolytes, BUN, creatinine, albumin, cholesterol, liverfunction tests, and 24-h urine protein excretion were mea-sured. Percutaneous renal biopsies were performed at 1 2- to18-month intervals to look for evidence of CsA-inducednephrotoxIclty. CsA nephrotoxlclty was diagnosed with the

presence of vacuolization of tubules, arteriolopathy, disrup-tion of tubular architecture, and stripe interstitial fibrosis.

Statistical analysis was carried out by the use of a pairedtest to compare individual values between groups. A f testwas used to compare groups. Actuarial renal survival rateswere calculated with product-limit estimates of survival cbs-tributions (13). A P value <0.05 was considered significant.Values are reported as means ± standard deviations unlessindicated.

RESULTS

Twenty-one children ( 1 3 boys) met inclusion criteriaand formed the study population. Thirteen patients

were black, and eight were Hispanic. All patients hadbiopsy-proven FSGS, and their proteinuria was resis-tant to both corticosteroid and cycbophospha.midetherapy. The mean age of the patients at the time ofdiagnosis was 8.4 ± 4.5 yr. The mean duration offollow-up was 8.5 ± 4.7 yr.

The mean duration of CsA therapy was 27.5 ± 22

months, and it ranged from 3 to 97 months. Table 1shows the mean pretherapy and posttherapy labora-tory values for all patients at the end of CsA therapy.There was a significant reduction in the mean 24-hproteinuria, serum albumin, and serum cholesterol atthe end of the study period. There was also a signifi-cant elevation in the serum creatinine bevel at the endof the study period.

At the most recent follow-up (April 1 994), 7 of the 21patients continue on maintenance CsA therapy. The

current status of these patients is shown in Table 2.CsA was discontinued in the remaining 14 patients, in5 because of sustained remission, in 5 because ofrising creatinine, and in 2 because of noncompliance.Persistent proteinuria (N = 1) and pregnancy (N = 1)necessitated withdrawal in two cases. Table 3 depictsthe current status of the five patients who continue tobe in remission without CsA or prednisone therapy. Intwo patients, the drug was discontinued because thepatients did not comply with the frequent clinic visitsand blood tests required. Both patients were in apartial remission of their nephrotlc syndrome (normal

serum albumin, no edema, and proteinuria of 1 . 1 and

TABLE 2. The proteinuria, serum albumin, and serum creatinine before CsA treatment (PRE) and at most recentfollow-up (POST), the serum cholesterol at the most recent follow-up, the duration of CSA therapy in months,and the most recent dose for the patients continuing on CSA

PatientNo.

Proteinuria(g/24 h)

PRE POST

Albumin

(g/dL)

PRE POST

Creatinine (mg/dL)Cholesterol

(mg/dL)

Durati on of CsA Dose

PRE POST CsA (months) Dose (mg/kg per day)

1 7.2 0.2 2.0 4.3 0.5 0.7 191 101 112 2.5 0.2 4.2 4.3 1.0 1.6 196 15 103 3.0 0 1.4 4.0 1.0 1.7 150 56 44 3.0 0.4 2.4 4.4 0.9 0.7 200 44 105 3.0 0 1.3 4.0 1.0 1.0 140 43 36 5.1 1.0 2.5 3.9 0.9 1.2 240 10 127 8.0 0.1 1.9 3.3 0.5 0.5 290 15 20

a,E

C.)

U)

2

0

START CSA

D/C CSA

CsA Therapy for FSGS

1822 Volume 5 . Number 10 . 1995

TABLE 3. The proteinuria, serum albumin, and serum creatinine before CSA treatment (PRE) and at most recentfollow-up (POST), the duration of CSA therapy in months, and the duration since the discontinuation of CSA inmonths in the patients with sustained remission

PatientNo.

Prote

(gI

PRE

inuria24 h)

POST

Albumi

PRE

n (g/dL)

POST

Creatinine(mg/dL)

PRE POST

Duration (months)

On CSA Off CSA

1 5.4 0.1 1.2 4.0 0.7 1.0 65 362 1.5 0.4 3.4 3.6 1.5 1.7 8 83 4.5 0.3 2.0 3.9 0.4 0.6 14 1054 3.4 0.5 1.9 3.1 0.4 0.9 25 855 12.0 0.1 1.8 4.3 0.4 0.5 21 18

1 .0 g/ 24 h) at the time CsA was stopped. The patientswere treated with CsA for 28 and 30 months, respec-tively. In one of the patients, CsA was discontinued at

6.5 yr of age (serum creatinine, 0.8 mg/dL). After CsAwas stopped, a relapse of the nephrotic syndromeresulted In massive proteinuria, and in 8 months, thepatient progressed to ESRD. The course of this pa-

tient, plotted as 1 /cr, is shown in Figure 1 . For theother patient, no follow-up was available. CsA wasdiscontinued in one patient because of pregnancy. Atthe time CsA was stopped, she was in a partial remis-sion of her nephrotic syndrome.

In six patients, CsA was discontinued because ofcontinued proteinuria and/or a rise In serum creati-nine. Three of the six patients had a significant reduc-

tion (�50%) in their proteinuria, and one patient was

in complete remission of the proteinurla ( 100 mg/24h) at the time CsA was stopped. After the discontinu-ation ofCsA, massive proteinuria and edema resulted.

Four of the six patients progressed to ESRD within 2,

4, 6, and 24 months after CsA was discontinued. Arepresentative course of one of the patients, plotted as1 /cr, Is shown in Figure 2. This patient was begun onCsA at 1 2 yr of age with a serum creatinine of 1.5mg/dL. She was treated with CsA for 25 months witha significant reduction but continued proteinuria.Over that period of time, her serum creatinine had

J.M.

4 8 2 6 20 24 28 32 36 40

MONTHS

Figure 1 . The course of renal function, plotted as 1/cr, inPatientJ.M. during CsA therapy and after the discontinuatIon(D/C) of CsA.

risen to 2.0 mg/dL and the drug was stopped. Massiveproteinuria resulted, and the patient reached ESRD in4 months.

Five (24%) of the 21 patients have reached ESRD

over the study period. The time to reach ESRD fromthe time of the diagnosis of FSGS in the 5 patients was30, 43, 44, 47, and 63 months. We reviewed histologyto determine if globally prominent collapse of the

glomerula tuft ( 14) could identify progression toESRD. Of our 2 1 patients, only 4 had the collapsingvariant ofFSGS. One ofthese patients has a sustainedremission, one went into ESRD, one dropped out

because of noncompliance, and one continues to re-celve maintenance CsA. In order to determine whetherprolonged maintenance CsA therapy prevents the pro-gression to ESRD, we compared the renal outcome of

this study group with our historical controls prey-

ousby reported (2). Despite similar racial distributionsof patients In the two groups, the mean age at diagno-515, and the duration of follow-up, the renal outcomewas significantly better in CsA-treated patients (5 of2 1 124%] versus 42 of 54 [78%]; P < 0.05; Table 4). An

actuarial renal survival comparing this CsA-treatedpopulation with our historical controls Is depicted inFigure 3.

There was no clear histologic evidence for CsA neph-rotoxicity in any of the biopsy specimens; however, in

all of the biopsy specimens, the lesion of FSGS per-

sisted. Side effects Included gingival hyperplasia (N =

6), hypertrlchosis (N = 8), coarse facies (N = 4), andhypertension (N = 2 1 ); however, they did not necessi-tate the discontinuation of CsA.

DISCUSSION

On the basis of clinical correlations and in vitro

studies, it has been suggested that the proteinuria of

the nephrotic syndrome Is the result of a circulatingsubstance produced from an abnormal cellular im-mune response ( 15-20). With the Improved under-standing of the mechanisms of the immune response,

it is now believed that the circulating substance is a

cytokine, produced by T lymphocytes, that injures theglomerular basement membrane and/or the epithelialcell, resulting in the leakage of protein in the urine(2 1-23). Administration of interleukln-2 (IL-2) to hu-

.80

.60

csA

D/C CSA

0

YEARS

Historical ControlCurrent Study

10 20 30 40 60 80

MONTHS

Ingulli et al

Journal of the American Society of Nephrology 1823

�0

a,

E

C)Cl)

AK.

Figure 2. The course of renal function, plotted as 1/cr, in Patient AK. during CsA therapy and after the discontinuation (D/C) ofCsA.

TABLE 4. Comparison of this study with our historicalcontrols (2)

ParameterHistoricalControls

This Study

Black, N (%) 38/57 (70) 13/21 (62)Age at diagnosis (yr) 7.3 ± 4.6 8.4 ± 4.5Follow-up (yr) 8.3 ± 4.3 8.5 ± 4.7ESRD, N (%) 42/54 (78) 5/21 (24)�

a p < 0.05.

100

80

-J�60

>

U)

�40

20

ACTUARIAL RENAL SURVIVAL

Figure 3. ActuarIal renal survival for patients with steroid/cyclophosphamide-reslstant FSGS treated with CsA in thisstudy (doffed line) and historical controls (solid line).

mans has been associated with the development of

nephrotic syndrome (24). StudIes have shown a cor-relation between elevated IL-2 levels in vitro and its

receptor, IL-2R, in vivo in nephrotic syndrome pa-

tients ( 1 1 ,25-28). CsA, a potent immunosuppressive

agent, has been shown to inhibit the production of

various cytokines, especially IL-2 (29). Remission of

the proteinuria in patients with the nephrotic syn-drome after the addition of CsA correlates with a

decrease in IL-2 levels (11,25,28).In patients with FSGS, an inverse relationship with

the degree of proteinurla and time to renal failure has

been reported (3). Thus, shutting off the protelnurla

and remitting the nephrotic state should, theoreti-

cally, prevent renal insufficiency. Our population ofpredominantly black and Hispanic patients with

FSGS usually demonstrated a virulent course of dis-

ease, with halfpredlcted to reach ESRD within 3 yr (2).

This time course is three to six times faster than the

time course reported in the literature for predomi-

nantly white populations (30-32). The North Amen-

can Pediatric Renal Cooperative Study supports the

notion that the disease is more severe among black

and Hispanic children and has reported that black

and Hispanic children comprise 44% of renal trans-

plants for FSGS but only 32% of the entire transplant

population (33). On the basis of this, we feel that

intervention in our population to prevent or slow the

development of ESRD is necessary.Many uncontrolled studies have shown CsA to be

highly effective in reducing the proteinuria in steroid-

dependent or frequently relapsing nephrotic syn-

drome (33-40). The ability of CsA to completely remit

the protelnuria in cases of steroid resistance is van-

able (7,8,10-12,35-37,41-43). Recently, two con-

trolbed studies have shown a significant reduction inproteinuria associated with a 6-month course of CsA

in steroid-resistant patients (44,45). Our current dos-ing of CsA is unconventional and is based on our

previous observations that, in the setting of severe

hypercholestenolemia, higher doses of CsA are neces-

sary to achieve a clinical response in both idiopathic

FSGS and recurrent proteinunia after renal transplan-

tation ( 1 2,46). The need for higher doses is thought tobe based on the erratic absorption of CsA, the in-

CsA Therapy for FSGS

1824 Volume 5 . Number 10 ‘ 1995

creased metabolism of the drug in children, and theamount of drug bound to serum lipids (47).

Alter the discontinuation of CsA, a sustained remis-sion is variable, often necessitating the reinstitution of

CsA ( 1 1 ,4 1 ). We, therefore, have treated patients withlong-term CsA therapy to maintain the reduction inproteinuria. For this study, we evaluated the efficacyof maintenance CsA therapy in a group of patientswith a high likelihood of a poor outcome due to theirpersistent proteinuria. The comparison of the out-come of these patients with a historical control groupis not ideal, but a controlled trial using a conventionalor supportive therapy am for comparison would beredundant, because this patient group was refractoryto conventional modes of therapy.

Despite similar demographics and duration of fob-low-up, the renal outcome between these two popula-tions Is significantly different. Fewer patients In thisstudy have progressed to ESRD than in our historical

population (2). With our aggressive dosing of CsA, wewere abbe to maintain a sustained reduction in pro-teinuria in seven patients (33%) continuIng on CsAand in five patients (24%) remaining off CsA for 8 to105 months. In the remaining patients, CsA wasdiscontinued for various reasons and more than half

(five of nine) have progressed to ESRD.

It has been suggested that the antiproteinunic effect

of CsA is due to its vasoconstrictive properties (47).

Zeitse and colleagues have shown that CsA reduces

proteinuria, independent of its effect on GFR (48).

Long-term treatment with CsA is cautioned by its

nephrotoxic effect. We have not been abbe to differen-

tiate the histologic makers of CsA toxicity from the

lesion of FSGS, despite surveillance renal biopsies in

patients in remission maintained on CsA. Renal biop-

sles in these patients were difficult to interpret be-cause many of the patients had interstitial changes at

baseline. The persistence of the histologic lesion while

in remission on CsA Is concerning but not surprising

because it is unlikely that the drug will reverse the

damage already done. Because the incidence of ESRD

is reduced and the time to reach ESRD is prolonged in

these patients compared with our historical popula-

tion, It appears that the nephrotoxic effect of CsA did

not accelerate the disease process. Longer follow-up ofthese patients in remission will be necessary to see if

the lesion progresses even though the proteinuria has

remitted.

In summary, long-term CsA therapy successfully

reduces the proteinuria in black and Hispanic chib-

dren with steroid-resistant FSGS and blunts the pro-

gression to renal failure. Close monitoring of thesepatients is essential.

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