ORIGINAL INVESTIGATIONS

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athogenesis and Treatment of Kidney Disease and Hypertension

Cyclosporine A and Chlorambucil in the Treatment of IdiopathicFocal Segmental Glomerulosclerosis

Peter Heering, MD, Prof, Norbert Braun, MD, Reinhard Mullejans, MD, Katrin Ivens, MD,Ingeborg Zauner, MD, Reinhard Funfstuck, MD, Prof, Frieder Keller, MD, Prof,

Bernhard K. Kramer, MD, Prof, Peter Schollmeyer, MD, Prof, Teut Risler, MD, Prof, andBernd Grabensee, MD, Prof, on behalf of the German Collaborative Glomerulonephritis Study Group

Background: The therapy of nephrotic syndrome in focal segmental glomerulosclerosis (FSGS) is still a matter ofontroversy. Methods: We performed a prospective randomized study of the treatment of nephrotic syndrome dueo FSGS. We compared 2 specific treatment protocols to assess the effect of treatment on proteinuria and renalunction. Fifty-seven patients were randomly assigned to 2 groups: group 1 (n � 34) received steroids andyclosporine, and group 2 (n � 23) received steroids and chlorambucil for 6 months. When treatment was refractoryo chlorambucil, the patients in this group were treated with cyclosporine. Creatinine, blood urea nitrogen,roteinuria, lipids, and arterial hypertension were monitored at regular intervals. Results: Patients showed a meanerum creatinine of 1.5 � 0.2 mg/dL (132.6 � 17.7 �mol/L) and proteinuria of 4.8 � 2.8 g/24 h with no differencesetween the groups. At the end of the chlorambucil therapy, patients in group 2 had creatinine levels of 1.8 � 0.6g/dL (159.1 � 53 �mol/L) and proteinuria levels of 3.4 � 1 g/24 h. All patients in this group were given

yclosporine. After 4 years the mean creatinine level in group 1 was 1.7 � 0.4 mg/dL (150.3 � 35.4 �mol/L) and theroteinuria level was 2.5 � 1 g/24 h. In group 2, the mean creatinine level was 1.9 � 0.6 mg/dL (168 � 53 �mol/L) (notignificant [NS]) and the mean proteinuria level was 2.3 � 1.1 g/24 h (NS). Full remission occurred in 23% of theatients in group 1 (n � 8) and 17% of the patients in group 2 (n � 4; NS). Partial remission was observed in 38% ofhe patients in group 1 (n � 13) and 48% in group 2 (n � 11; NS). The number of patients who developed end-stageenal disease was comparable in both groups: 4 of 34 patients in group 1 after 2.5 � 0.8 years, and 5 of 23 patients inroup 2 (NS). Conclusion: Additional treatment with chlorambucil was found to be ineffective in FSGS. Patientsesponded to treatment with steroids or cyclosporine, but additional treatment with chlorambucil did not improvehe patient’s outcome. Future studies must focus on the long-term prognosis of these patients. Am J Kidney Dis 43:0-18.2004 by the National Kidney Foundation, Inc.

NDEX WORDS: Cyclosporine A (CsA); nephrotic syndrome; focal segmental glomerulosclerosis (FSGS).

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DIOPATHIC FOCAL segmental glomerulo-sclerosis (FSGS) is a frequent cause of ne-

hrotic syndrome, which has a poor prognosis.1,2

ight microscopy reveals glomerular segmental

From the Klinik fur Nephrologie und Rheumatologie,einrich Heine Universitat Dusseldorf, Dusseldorf, Ger-any; the Sektion Nieren-und Hochdruckkrankheiten, Uni-

ersitatsklinikum Tubingen, Tubingen, Germany; the Abtei-ung fur Nephrologie, Klinik fur Innere Medizin,niversitatsklinik Jena, Jena, Germany; the Abteilung furephrologie, Universitat Freiburg, Freiburg, Germany; theektion Nephrologie, Medizin Universitatsklinik Ulm, Ulm,ermany; and the Klinik und Poliklinik fur Innere Medizin

I, Regensburg, Regensburg, Germany.Received January 17, 2003; accepted in revised form

eptember 19, 2003.Address reprint requests to Peter Heering, MD, Prof,

epartment of Medicine III, Solingen General Hospital,niversity of Cologne, D-42653 Solingen, Germany. E-mail:eering@klinikumsolingen.de© 2004 by the National Kidney Foundation, Inc.0272-6386/04/4301-0028$30.00/0

mdoi:10.1053/j.ajkd.2003.09.027

American Journal o0

clerosing together with segmental mesenchy-al progression and proliferation as well as

yaline deposits in the sclerosing loop. At theime of diagnosis 30% to 50% of the patientsave elevated serum creatinine values, and 50%evelop end-stage renal disease (ESRD) within0 years.1 Most patients with FSGS receive im-unosuppressive therapy employing steroids or

ytotoxic agents.3-6 A number of authors haveeported a higher remission rate in nephroticyndrome due to FSGS when the steroid treat-ent is given in combination with a cytotoxic

gent over an extended period.6,7 It has beenuggested that the unfavorable prognosis in theseatients is due to insufficient therapy. The firstuccessful results were observed during therapyith chlorambucil3 and cyclophosphamide.4 Cy-

losporine A (CsA) has been employed in thereatment of nephrotic syndrome resulting fromembranous nephropathy8,9 and FSGS.10,11 Nu-

erous mechanisms have been discussed, includ-

f Kidney Diseases, Vol 43, No 1 (January), 2004: pp 10-18

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CYCLOSPORINE A AND FSGS 11

ng the influence on permselectivity, charge selec-ivity, and impairment of glomerular filtrationate.12-14 The impact of CsA-induced nephrotox-city remains a matter of controversy.15-17

A decrease in proteinuria has been observed interoid-sensitive patients during treatment.18-22

he results in patients with steroid-resistant ne-hrotic syndrome have also been the subject ofuch controversy. A few authors have described

mprovements following a combination of CsAnd an alkylating agent, but these studies have aumber of limitations because of the lack ofandomization, mixed age groups, and mixedathology. Clinical benefit has been reported,ith impairment as a result of nephrotoxicity and

elapse after withdrawal.21,23-26 In the presentnvestigation, we compared the effect of CsA inhe therapy of nephrotic syndrome with a combi-ation therapy including chlorambucil.

METHODS

atientsIn a multicenter, prospective, randomized study, 57 pa-

ients with idiopathic FSGS, confirmed by biopsy, weretudied over a period of 4 years. The biopsy was examinedy an experienced nephropathologist (Prof. Dr. U. Helm-hen, Department of Pathology, University of Hamburg,amburg, Germany). The patients presented with protein-ria �3.5g/24 h and serum creatinine concentration of lesshan 2 mg/dL (177 �mol/L). The patients were randomlyssigned to 2 different therapy groups. The treatment withinhe study period lasted 6 months. CsA was continued beyondhis period in some cases to maintain remission. Patients inroup 2 were treated with CsA monotherapy if remission ofhe nephrotic syndrome was not achieved by that time or ifhey relapsed after withdrawal. The treatment was supple-ented by a low-protein diet with 0.6 g protein per kilogram

ody weight per day. Antihypertensive therapy was alsodministered at the discretion of the treating physician.

ntry CriteriaAge at entry was between 18 and 79 years. All patients

ad to have failed to achieve an improvement in proteinuriafter a minimum of 8 weeks of prednisone in a dosage ofver 1 mg/kg/d. Exclusion criteria included women unwill-ng to take effective birth control measures, comorbid condi-ions with expected survival of less than 2 years, seriousystemic infections, and associated disorders requiring dailyonsteroidal anti-inflammatory medication. Patients withiabetes mellitus and conditions known to be associatedith FSGS lesions such as obesity and unilateral renal

genesis were also excluded. No immunosuppressive agents,lasma exchange therapy, or antilymphocyte products werellowed in the 6 months prior to the start of the study

edication period. p

efinitionsNephrotic syndrome was defined as proteinuria in excess

f 3.5 g/24 h for adults. Steroid resistance was defined asersisting nephrotic syndrome following therapy for 6 weeksith steroids (prednisolone 1 mg/kg/d). Partial remissionas considered present when the proteinuria was less than.5 g/24 h after 3 control measurements. Full remission wasonsidered to be present when the proteinuria was less than.2 g/24 h. The reaction time was expressed as the number ofays from the beginning of the therapy until full or partialemission. A relapse of the nephrotic syndrome was consid-red to have taken place when patients with a full or partialemission for at least 2 weeks again deteriorated. ESRD wasonsidered to have developed when patients were perma-ently dialysis-dependent or serum creatinine exceeded 6.0g/dL (530 �mol/L) for more than 1 month. Arterial hyper-

ension was defined as a diastolic blood pressure of over 95m Hg in adults. The histological diagnosis of FSGS was

ased on World Health Organization criteria.Patients were judged to be nonresponsive to treatment if

heir proteinuria did not decline during the course of thetudy. The total improvement in each group was defined ashe sum of those patients who experienced complete orartial remission. An initial dose of 5 mg/kg body weight ofsA was administered with the objective of obtaining a

arget CsA level of 100 to 180 ng/mL. The dose was reducedhen the confirmed CsA level was in excess of 200 ng/mL,

he serum creatinine level was more than 0.3 mg/dL (27mol/L) above the baseline, aspartate aminotransferase

SGOT) and alanine aminotransferase (SGPT) increased, orhe total bilirubin level was �2 mg/dL (34 �mol/L). Bio-hemical serum and urine parameters were determined bytandard laboratory methods. CsA was monitored as trough,hole-blood levels by monoclonal radioimmunoassay. Pro-

einuria was assessed by means of a 24-hour urine collec-ion. The failure to control hypertension with optimal dos-ges of 3 antihypertensive agents was followed by gradualeduction in the study drug dose. Adverse reactions and thencidence of known CsA toxicities were recorded.

andomization and TreatmentPatients were randomly assigned to group 1 or 2 on the

asis of their date of birth. Informed consent was obtainedefore randomization. A full history was recorded and physi-al evaluation, as well as laboratory tests, including serumreatinine, 24-hour urine excretion protein, creatinine, andrea, a lipid profile including cholesterol and triglyceride,nd screening tests to rule out potential secondary causes ofSGS, were performed. The test drugs were continued for 26eeks and then cut back to 0 over 4 weeks.

reatment: FSGS Therapy (Table 1)Group 1. Patients in group 1 were given prednisolone

1.5 mg/kg/d) and acetylsalicylic acid (500 mg/d) for 6eeks. If no remission occurred, they were given CsA (5g/kg/d). The target CsA blood concentration was 130 to

80 ng/mL whole blood. The treatment was administered fort least 6 months. Further treatment was determined by the

hysicians at the treating center.

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Group 2. The patients in group 2 were given pred-isolone 1.5 mg/kg/d for 2 to 6 weeks. If no remission tooklace the patients were given prednisolone (1.5 mg/kg/d)nd chlorambucil (0.1 to 0.4 mg/kg/d) for 6 to 12 weeks. Ifo remission occurred after this treatment, the patients wereransferred to CsA. In this case there was also a minimum of

months’ therapy. A daily whole blood concentration ofetween 130 and 180 mg/mL was also aimed at during thiseriod.

tatistical AnalysisThe Medical Ethical Committee of the Medical Faculty of

he Heinrich Heine University approved the protocol. Thetudy was an open randomized clinical study. The statisticalnalysis was performed on the basis of intention to treat. Thendpoints of the present investigation were partial remis-ion, complete remission, or the development of ESRD. Thehi-square test was used to determine the distribution ofariables such as sex, diagnosis, outcome (full remission,artial remission, no remission), and arterial hypertension.hanges in the variables during the study were comparedith the baseline using the t-test for paired and unpairedata. The results for the 2 groups were compared in the sameay. In order to achieve a normal distribution, the protein-ria, serum creatinine, and creatinine clearance data wereogarithmically transformed. A multifactorial analysis ofariance (ANOVA) was carried out without the centerseing included as factors. The effect of therapy on the timef full or partial remission was analyzed using a Kaplan-eier plot. Statistical analysis was performed using t-test,

hi-square, and multiple regression analysis. All data arexpressed as the mean � SD. Significance was considered at

Table 1. Protocol of the Study Performed in PatientsWith Nephrotic Syndrome Due to FSGS

Group 1* Group 2†

rednisolone(1.5 mg/kg/d)

Prednisolone (1.5 mg/kg/d)

SA (500 mg/d)(2-6 wk)

6 wk)2Prednisolone (1.5 mg/kg/d)

o remissionChlorambucil (0.1-0.4 mg/kg/d)(6-12 wk)

sA (5 mg/kg/d)2

Recommendation atleast 6 mo)

CsA (5 mg/kg/d)

rough levels 130-180 ng/mL

(Recommendation at least 6 mo)Trough levels 130-180 ng/mL

*Patients in group 1 were treated with prednisolone andcetylsalicylic acid. If no remission occurred, they wereiven CsA (5 mg/kg/d).†Patients in group 2 were treated with prednisolone. If

o remission occurred, they were given prednisolone (1.5g/kg/d) and chlorambucil (0.1 to 0.4 mg/kg/d) for 6 to 12eeks. If no remission occurred after this treatment theatients were transferred to CsA.

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RESULTS

atients

Six centers contributed patients to the study.ifty-seven patients were available and partici-ated in the study, 34 being randomly assigned toroup 1, and 23 to group 2 (Fig 1). The serumreatinine did not differ between group 1 (1.5 �.2 mg/dL) (132.6 � 17.7 �mol/L) and group 21.4 � 0.1 mg/dL) (123.8 � 8.8 �mol/L) (Fig 2).he proteinuria levels at the beginning of the

nvestigation were between 5.5 � 2.6 g/24 h inroup 1 and 4.2 � 0.6 g/24 h in group 2 (NS).here were no differences in age, sex, serumreatinine concentration, urine sodium, protein-ria, cholesterol, and triglycerides (Table 2).

enal Survival Following Immunosuppressivereatment

There was no significant difference betweenhe 2 groups within the first 4 years in terms ofenal survival rate, with both groups showing aurvival rate of 83% (Fig 3). Full remissionccurred in 23% of the patients in group 1 (n �) and 17% of the patients in group 2 (n � 4;S). Partial remission was observed in 38% of

he patients in group 1 (n � 13) and 48% (n �1; NS) in group 2. The number of nonre-ponders and those developing terminal renalailure was similar in both groups (Fig 1). ESRDccurred in 5 patients in group 2, and 7 patientschieved remission.

A creatinine concentration of 1.4 � 0.4 mg/dL123.8 � 35.4 �mol/L) and proteinuria of 4.2 �.6 g/24 h were seen at the end of the treatmentith chlorambucil. There was no significant dif-

erence between the 2 patient groups 4 monthsrior to the commencement of therapy and be-ore CsA treatment was initiated.

The number of patients who developed ESRDas comparable in both groups: 4 of 34 patients

fter 2.5 � 0.8 years in group 1, and 5 of 23atients in group 2 (NS). The mean time toSRD was 4.1 � 4.5 years (NS). A statisticalnalysis according to Kaplan-Meier showed noifference in the incidence of renal death inither group of patients. There was no mortalityn either group.

holesterol

Hypercholesteremia was observed in all of the

atients (Fig 4). During the treatment, the choles-

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CYCLOSPORINE A AND FSGS 13

erol level decreased from 347 � 158 mg/dL9 � 4.1 mmol/L) to 265 � 95 mg/dL (6.9 � 2.5mol/L) in group 1 and from 309 � 109 mg/dL

8 � 2.8 mmol/L) to 241 � 27 mg/dL (6.2 � 0.7mol/L) in group 2. These data reflect a signifi-

ant decrease in cholesterol but without a signifi-ant difference between the groups.

roteinuria

Proteinuria decreased from 5.2 � 1.1 g/24 h to.6 � 0.6g/24 h during the 4-year therapy, buthere was no difference between the 2 groupsFig 5). The proteinuria levels at the beginning ofhe investigation were 5.5 � 2.6 g/24 h in group

and 4.2 � 0.6 g/24 h in group 2 (NS). Aignificant increase was observed in plasma albu-in and total protein at 6 and 12 months in both

roups. The significant changes remained

Fig 1. Follow-up of pa-ients included in the studyn the basis of an intentiono treat.

hroughout the investigation. h

rterial Hypertension

At the start of treatment, the mean systoliclood pressure was 145 � 14 mm Hg over 88 �mm Hg. There was no difference between the

roups. The mean number of antihypertensivesas 2.1 � 1.4 in group 1 and 1.6 � 1.7 in group(NS). During the observation period, there waso significant increase in the number of antihyper-ensives in group 1 (2.3 � 1.3 at the end of thebservation period). In group 2 the number ofntihypertensives dropped from 1.6 � 1.7 to.2 � 1.3.

reatment With CsA

Thirty-three patients were treated with CsAgroup 1: n � 23; group 2: n � 10). The meanuration of CsA administration was 23 � 16.5onths. The proteinuria fell from 6.2 � 1.1 g/24

to 3.6 � 0.6 g/24 h. The serum creatinine in

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roup 1 rose from 1.4 � 0.1 mg/dL (123.8 � 8.8mol/L) to 1.6 � 0.2 mg/dL (141.4 � 17.7mol/L) after 4 years; this difference was not

ignificant from that of group 2, where it roserom 1.4 � 0.1 mg/dL (123.8 � 8.8 �mol/L) to.6 � 0.1 mg/dL (141.4 � 8.8 �mol/L).

During the observation period a number offforts to withdraw patients from CsA were un-ertaken. In group 1, an attempt was made with8 of 23 patients. In 14 of these 18 patients webserved relapses. In 7 of the 14 patients aecond attempt was made. Four of 7 patientsgain had a relapse. We were able to withdraw 8

Table 2. Clinical and Biochemical Data of PatientsUnder Investigation

Group 1 Group 2 Significance

atients (n) 34 23 NSge (y) 47 � 15 46 � 15 NSex (M/F) 20/15 15/8 NSreatinine(mg/dL) 1.3 � 0.4 1.5 � 0.5 NS

UN (mg/dL) 47 � 21 49 � 25 NSroteinuria(g/24 h) 5.4 � 5.2 4.6 � 3.1 NSholesterol(mg/dL) 439 � 191 315 � 118 NS

riglycerides(mg/dL) 376 � 164 327 � 148 NS

NOTE. To convert creatinine in mg/dL to �mol/L, multi-ly by 88.4; urea nitrogen in mg/dL to mmol/L, multiply by.357; cholesterol in mg/dL to mmol/L, multiply by 0.02586;

sriglycerides in mg/dL to mmol/L, multiply by 0.01129.

f 18 patients. In group 2 CsA treatment wasiscontinued in 3 of 9 patients. One patient had aelapse, so in 2 of 8 patients CsA was withdrawnuccessfully. The success rate in both groups wasot significantly different. Effective withdrawalf CsA in patients with FSGS was seen as theain problem of treatment.

ide Effects

No significant difference was observed regard-ng serum albumin and calcium levels. Serumagnesium levels decreased under therapy. Liver

unction parameters remained unchanged. ThesA, steroid and chlorambucil therapies wereell tolerated. No acute nephrotoxicity episodesr opportunistic infections were observed.

DISCUSSION

No generally accepted treatment regimen isvailable for patients with nephrotic syndromeue to FSGS, and renal prognosis is poor. Forhis reason, a number of studies have been per-ormed with immunosuppressive interventionss steroids, cyclophosphamide,4,5 chlorambucil,3

yclosporine,18,20,25,27 tacrolimus,28 and immuno-dsorption,29 but there is no clear-cut evidence inavor of any 1 kind of treatment. Treatmentptions have been recommended on the basis ofge, nephrotic syndrome, renal scarring, residualenal function, and response to treatment with aemission of the proteinuria in only 27% of the

4

Fig 2. Creatinine in thelong-term monitoring of the2 groups. There were 34 pa-tients in group 1 and 23 ingroup 2 being analyzed tothe end of the study. To con-vert creatinine in mg/dL to�mol/L, multiply by 88.4.

ubjects. At least 50% of the FSGS patients with

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CYCLOSPORINE A AND FSGS 15

eavy proteinuria progress to ESRD over 7 to 10ears.30 In fact, most FSGS patients are likely toevelop ESRD over the extended course of theirisease.The continued use of immunosuppressive

herapy has been the subject of different studies.minority of patients are steroid-responsive.10

n the only controlled study, both steroids alonend steroids plus cyclophosphamide producedemission of the proteinuria in only 27 % of theubjects.4 Immunosuppressive agents have beenound by some investigators to be beneficial, butcontrolled trial did not show any advantage of

yclophosphamide over corticosteroids in chil-ren with FSGS. It has been claimed that aggres-

Fig 3. Renal survival inhe long-term monitoring ofhe 2 groups. There were 34atients in group 1 and 23 inroup 2 being analyzed tohe end of the study.

ive treatment with methylprednisolone pulsesnd cytotoxic agents improves the outcome foratients with steroid-resistant FSGS. Unfortu-ately, no controlled trial to support this claimas been published. In a retrospective review ofSGS patients, Banfi et al31 state that there wereore remissions in patients receiving a cytotoxic

herapy. Cameron et al1 reported a review of 28atients including 14 adults. Details of treatmentnd response were not provided, but a 5-yearurvival rate of 75% was reported. Ponticelli etl25 described a prospective trial in which 44atients with nephrotic syndrome were random-zed to CsA or standard therapy. Patients werelassified as steroid-resistant if they had no re-

Fig 4. Cholesterol in thelong-term monitoring of the2 groups. There were 34 pa-tients in group 1 and 23 ingroup 2 being analyzed tothe end of the study. To con-vert cholesterol in mg/dL to

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ponse after 6 weeks on prednisone. A number ofapers have appeared in recent years on thereatment of FSGS with CsA.

Although the pathogenesis of nephrotic syn-rome in general and FSGS in particular arenknown, there are 2 potential mechanisms for aeneficial effect of CsA. It has been suggestedhat the altered glomerular permeability in ne-hrotic syndrome is a reflection of changes in-cell function. Also, because CsA is known toause preglomerular vasoconstriction,13,14,17 a re-uction in filtration through a decrease in glomer-lar plasma flow or ultrafiltration pressure couldeduce proteinuria on a purely hemodynamicasis. Previous uncontrolled studies have demon-trated that patients with steroid-resistant, FSGS-elated nephrotic syndrome can achieve full orartial remission following the administration ofsA.22,27 Owing to the fact that CsA is nephro-

oxic it has been suggested that its administrationay lead to a further deterioration in the kidney

unction.17 Relapses are common when CsA isiscontinued. Further open trials of CsA haveeen carried out, but with only very small num-ers of FSGS patients.19,27 Approximately 60%f the patients responded to treatment with CsA.atients who were given additional medicationith chlorambucil showed no further improve-ent. Most studies have reported that the ne-

hrotic syndrome returned a few days after CsAad been abruptly stopped.The object of the present investigation was to

etermine the role of CsA and chlorambucil in

he treatment of nephrotic syndrome. At the time r

hen the study conception was made, neitherngiotensin-converting enzyme inhibitors nor an-iotensin antagonists were included in the con-ept. At randomization, no patient was treatedith this. During the study no angiotensin antag-nist was applied. Angiotensin-converting en-yme inhibitors were added to 5 patients in groupand to 4 patients in group 2. Because of the

mall number of patients treated in this mannero influence was shown with statistical signifi-ance. The side effects attributable to CsA wereelatively mild. No significant changes were ob-erved in the mean arterial blood pressure or theumber of patients requiring antihypertensiverugs. Gingival hypertrophy or hypertrichosisas observed in both patient groups; these side

ffects did not necessitate the discontinuation ofhe medication. In our trial, the drug was taperedff, and some 38% of the responders remained inemission until the twelfth month. It is possiblehat the gradual rather than abrupt reduction ofsA adopted in this protocol may have preventedn early relapse into proteinuria in some patients.o clinical or histological parameter at presenta-

ion was useful for predicting which patientould remain in remission.The data for both patient groups were compa-

able, although the randomization protocol waspen. Possibly as a result of this, there wereewer patients included in group 2 than in group. Future follow-up studies should be random-zed centrally. The present controlled, prospec-ive study showed that CsA led to full/partial

Fig 5. Proteinuria in thelong-term monitoring of the2 groups. There were 34 pa-tients in group 1 and 23 ingroup 2 being analyzed tothe end of the study.

emission in approximately 60% of patients with

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CYCLOSPORINE A AND FSGS 17

teroid-resistant nephrotic syndrome. In the ma-ority of cases, CsA helped to improve bloodressure and the number of antihypertensivegents could be reduced. The duration of theherapy ranged from 2 months to several years.uccess was achieved in 20% to 30% of cases,ainly those suffering from steroid-sensitive

orms of FSGS.These cases of full/partial remission remained

table during CsA medication. By contrast, pa-ients who were given additional medication withhlorambucil showed no further improvement.he problem of recurrence following cessationf CsA medication remained. The majority oftudies report a recurrence of nephrotic syn-rome after discontinuation of the CsA therapy.n the present investigation, the nephrotic syn-rome recurred in 40% of the patients after CsAad been terminated. There were no morphologi-al or clinical parameters to indicate which pa-ients would respond to the therapy, and CsA-nduced nephrotoxicity could not be determinedn the basis of renal biopsy. The difficulty inithdrawing CsA raises the question of totaluration of therapy. There has been significantoncern about the long-term nephrotoxic effectsf CsA, particularly on native kidneys. Datarom patients with autoimmune disorders, suchs uveitis, and non–renal transplant recipientsave indicated that interstitial fibrosis will de-elop in most native kidneys after 2 years of CsAherapy at �5 mg/kg/d. Most patients with FSGSave interstitial fibrosis at diagnosis, and thisrogresses along with their glomerular disease.ecause of this, it is impossible to clearly distin-uish CsA toxicity from disease progression inatients with FSGS. Previous noncontrolled tri-ls have shown that about half of patients withteroid-resistant nephrotic syndrome may obtainomplete or partial remission on CsA. However,ince CsA can cause vascular and tubulointersti-ial lesions and lead to progressive renal dysfunc-ion, there is concern that long-term administra-ion of this drug might accelerate the evolution toenal failure in patients with FSGS. There is littlenformation, however, on the effect of CsA onhe outcome of renal function in patients withteroid-resistant nephrotic syndrome, comparedith untreated patients.In the majority of cases, CsA was beneficial

ut tended to lead to relapse when withdrawn.

n the other hand, there was widespread toler-nce of CsA by the patients in the study. Inddition, this drug produced a manifest clinicalmprovement in the condition of the patients.upplementary medication with chlorambucil didot appear to be more beneficial than steroidedication alone. Since an improvement should

e observed after a few weeks, the treatmenthould be terminated if no significant reductionn proteinuria has occurred within the first 3

onths. CsA can be beneficial over a period ofore than 1 year in patients who are able to

olerate it, but it is still impossible to determinehe precise point at which treatment should beerminated.

Although novel therapeutic approaches, suchs the one described here, can remit the nephroticyndrome, it remains to be shown that theyrevent progression of the underlying glomeru-ar disease. From what we know at present thelinician should probably attempt to remit theephrotic syndrome in patients with steroid-esistant nephrotic syndrome. The combinationf methylprednisolone and CsA outlined hereppears to minimize the side effects of bothgents, while achieving a high initial remissionate with excellent long-term maintenance.

REFERENCES

1. Cameron JS, Turner DR, Ogg CS, Chantler C, WiliamsG, on behalf of the German Collaborative Glomerulonephri-

is Study Group: The long-term prognosis of patients withocal segmental glomerulosclerosis. Clin Nephrol 10:213-18, 19782. Korbet S, Swartz MM, Lewis EJ: Primary focal seg-ental glomerulosclerosis: Clinical course and response to

herapy. Am J Kidney Dis 23:773-783, 19943. Grupe WE, Makker SP, Inglefinger JR: Chlorambucil

reatment of frequently relapsing nephrotic syndrome. N EnglMed 295:746-749, 19764. International Study of Kidney Disease in Children:

yclophosphamide therapy in focal segmental glomerularclerosis: A controlled clinical trial. Eur J Pediatr 140:149-53, 19835. Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr:

yclophosphamide does not benefit patients with focal seg-ental glomerulosclerosis. A report of the Internationaltudy of Kidney Disease in Children. Pediatr Nephrol 10:590-93, 19966. Tune BM, Kirpekar R, Sibley RK, Reznik VM, Gris-

old WR, Mendoza SA: Intravenous methylprednisolonend oral alkylating agent therapy of prednisone-resistantediatric focal segmental glomerulosclerosis: A long-termollow-up. Clin Nephrol 43:84-88, 1995

7. Pei Y, Cattran D, Delmore T, Katz A, Lang A, Rance P:

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vidence suggesting undertreatment in adults with idio-athic focal segmental glomerulosclerosis in adults. Am Jed 82:938-944, 19878. Braun N, Erley C, Benda N, et al: Therapy of membra-

ous glomerulonephritis with a nephrotic syndrome. 5 yearsollow up of a prospective randomized multicenter study.Am Soc Nephrol 6:413, 1995 (abstr)9. DeSanto NG, Capodicasa G, Giordano C: Treatment of

diopathic membranous nephropathy unresponsive to meth-lprednisolone and chlorambucil with cyclosporin. Am Jephrol 7:74-76, 198710. Brodehl J, Brandis M, Helmchen U: Cyclosporin A

reatment in children with minimal nephrotic syndrome andocal segmental glomerulosclerosis. Klin Wochenschrift 66:126-1137, 1988

11. Collaborative Study Group of CsA in Nephrotic Syn-rome: Safety and tolerability of CsA in idiopathic nephroticyndrome. Clin Nephrol 135:48-60, 1991 (suppl 1)

12. Ambavalan S, Fauvel JP, Sibley RK, Myers BD:echanism of the antiproteinuric effect of CsA in membra-

ous nephropathy. J Am Soc Nephrol 7:290-298, 199613. Heering P, Schneider A, Grabensee B, Plum J: Influ-

nce of cyclosporin on renal function in patients with glo-erulonepritis. Deutsche Med Wochenschrift 126:1093-

098, 200114. Zietse R, Wenting GJ, Kramer P, Schalekamp MA,eimar W: Effect of cyclosporin on glomerular barrier

unction in the nephrotic syndrome. Clin Science 82:641-50, 199215. Feutren G, Mihatsch MJ: Risk factors for CsA in-

uced neuropathy in patients with autoimmune diseases.nternational Kidney Biopsy Registry of Cyclosporine inutoimmune Diseases. N Engl J Med 326:1654-1660, 199216. Mihatsch M, Bach JF, Coovadia HM, et al: CsA

ssociated nephropathy in patients with autoimmune dis-ase. Klin Wochenschrift 66:43-47, 1988

17. Myers BD, Sibley R, Newton L, et al: The long termourse of CsA associated chronic nephropathy. Kidney Int3:590-600, 198818. Cattran DC, Appel GB, Hebert LA, et al: A random-

zed trial of cyclosporine in patients with steroid resistantocal segmental glomerulosclerosis. Kidney Int 56:2220-226, 199919. Lee HY, Kim HS, Kang CM, Kim SG, Kim MJ: The

fficacy of cyclosporin A in adult nephrotic syndrome with

inimal change disease and focal-segmental glomeruloscle- N

osis: A multicenter study in Korea. Clin Nephrol 43:375-81, 199520. Meyrier A, Condamin MC, Broneer D: Treatment of

dult idiopathic nephrotic syndrome with cyclosporin A:inimal change disease and focal segmental glomeruloscle-

osis. Clin Nephrol 3:37-40, 199121. Meyrier A, Noel LH, Auriche P, Callard P: Long-term

enal tolerance of cyclosporin A treatment in adult nephroticyndrome. Kidney Int 45:1446-1456, 1994

22. Niaudet P, Habib R: CsA in the treatment of idio-athic nephrosis. J Am Soc Nephrol 5:1049-1056, 199423. Ingulli E, Tejani A: Severe hypercholesteremia inhib-

ts Cyclosporin A efficacy in a dose dependant manner inhildren with nephrotic syndrome. J Am Soc Nephrol 3:254-59, 199224. Ingulli E, Singh A, Baqi N, Ahmad H, Moazami S,

ejani A: Aggressive, long term CsA (CSA) therapy inefractory nephrotic syndrome (NS) blunts the progressionf focal segmental glomerulosclerosis (FSGS) to end stageenal disease (ESRD). J Am Soc Nephrol 5:1820-1826, 1995

25. Ponticelli C, Rizzoni G, Edefonti A, et al: A random-zed trial of CsA in steroid resistant idiopathic nephroticyndrome. Kidney Int 43:1377-1384, 1993

26. Ponticelli C, Villa M, Banfi G, et al: Can prolongedreatment improve the prognosis in adults with focal segmen-al glomerulosclerosis? Am J Kidney Dis 34:618-625, 1999

27. Green A, O’Meara Y, Sheehan Y, Carmody M, Doyle, Donohoe J: The use of cyclosporin A in adult nephrotic

yndrome: Nine cases and literature review. Ir J Med Sci59:178-181, 199028. McCauley J, Shapiro R, Ellis D, Igdal H, Tzakis A,

tarzl TE: Pilot trial of FK 506 in the management ofteroid-resistant nephrotic syndrome. Nephrol Dial Trans-lant 8:1286-1290, 199329. Haas M, Godfrin Y, Oberbauer R, et al: Plasma

mmunadsorption treatment in patients with primary focalnd segmental glomerulosclerosis. Nephrol Dial Transplant3:2013-2016, 199830. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM:

ocal segmental glomerular sclerosis in adults: Presentation,ourse, and response to treatment. Am J Kidney Dis 25:534-42, 199531. Banfi G, Moriggi M, Sabadini E, et al: The impact of

rolonged immunosuppression on the outcome of idiopathicocal-segmental glomerulosclerosis with nephrotic syn-rome in adults. A collaborative retrospective study. Clin

ephrol 36:53-57, 1991