Tacrolimus Versus Intravenous Pulse CyclophosphamideTherapy in Chinese Adults With Steroid-Resistant IdiopathicMinimal Change Nephropathy: A Multicenter, Open-Label,Nonrandomized Cohort Trial
1Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou,hina; 2Department of Nephrology, Huzhou Central Hospital, Huzhou, China; and 3Department of
Nephrology, Taizhou Hospital, Taizhou, China
4msg
ABSTRACTBackground: The treatment of steroid-resistant mini-
mal change nephropathy (SR-MCN) in adults remains achallenge to nephrologists. Although immunosuppres-sants such as cyclophosphamide (CTX), chlorambucil,and cyclosporin A have been used in these patients, theiruse has been limited by low remission rates and severeadverse effects. Alternative immunosuppressive treat-ments for SR-MCN are therefore needed.
Objective: The aim of this study was to compare thefficacy of tacrolimus (TAC) with that of intravenousIV) pulse CTX therapy in the management of SR-
CN and to assess the tolerability of those treatments.Methods: This was a nonrandomized, case-matched
trial in Chinese adults with SR-MCN. Patients wereself-assigned to either: (1) combination therapy withprednisone and oral TAC; or (2) combination therapywith prednisone and IV CTX. TAC was initiated at0.05 mg/kg/d and was adjusted to maintain a troughblood level of 5 to 10 ng/mL for 1 year. CTX wasinitiated at 1 g/1.73 m2 for a total dosage of 10 g/.73 m2 over 1 year. In both groups, oral prednisoneas initiated at 0.5 mg/kg/d for 3 months but was
apered off to complete cessation by 6 months.Results: A total of 37 patients were enrolled (21 in the
AC group; 16 in the CTX group), of whom 33 (19 in theAC group; 14 in the CTX group) completed the study.here were no significant difference in baseline demo-raphic characteristics between the two treatment groupsThe TAC group-mean age at onset, 28.8 [11.3]; meange at trial, 29.6 [11.0]; male, 63.16%; The CTX group-ean age at onset, 34.4 [12.7]; mean age at trial, 35.9
12.7]; male, 57.14%). The remission rates were 57.9%,
3.7%, and 78.9% in the TAC group and 14.3%,
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2.9%, and 50.0% in the CTX group after 2, 4, and 6onths, respectively. The remission rate at 2 months was
ignificantly higher in the TAC group than in the CTXroup (P � 0.05). The remission rates during the 1-year
therapy and the 1-year follow-up were higher in the TACgroup than in the CTX group (Kaplan-Meier curve,log-rank test, P � 0.001). For patients who achievedremission, the mean (SD) time needed for remissionwas 48.7 (36.0) days in the TAC group and 85.3 (40.6)days in the CTX group (P � 0.05). During the 1-yeartherapy and 1-year follow-up periods, 6 of the 15TAC-treated patients and 1 of the 7 CTX-treated pa-tients relapsed (P � 0.35).
change nephropathy (MCN) and nephrotic syndrome,6% to 25% of adult patients are resistant to steroidtherapy.1,2 Persistent proteinuria in these patients re-sults in severe hypoalbuminemia, edema, hyperlipid-emia, recurrent infections, cardiovascular disease, andprogression to renal failure.3 Patients with steroid-re-sistant MCN (SR-MCN) can be treated with immuno-suppressive agents such as cyclophosphamide (CTX),chlorambucil, or cyclosporin A (CYA). However,treatment of SR-MCN with alkylating agents is asso-ciated with a remission rate �30% and the risk ofmarrow suppression, infections, and malignancy.4,5
CYA is reportedly effective for treating patients withSR-MCN, but its use has been limited by the potentialfor nephrotoxicity and the high relapse rate associatedwith this drug.6 Thus, alternative immunosuppressivereatments for SR-MCN are needed.
Tacrolimus (TAC) is a calcineurin inhibitor that ist least 100 times more potent than CYA at inhibitinguman mixed lymphocyte reactions in vitro and has areater cytokine-suppressing activity.7,8 Another ad-
vantage of TAC is that it is less nephrotoxic than CYA.Since 1993, successful treatment of steroid- andCYA-resistant patients with TAC has been reportedin single cases and in small studies of groups of pa-tients but not in comparative trials.9 –13 Our depart-ment has used TAC to treat adults with steroid-de-pendent and steroid-resistant nephrotic syndromesince the 1990s. We have found that TAC in combi-nation with prednisone (0.3– 0.5 mg/kg/d) is usefulin patients with steroid-dependent nephrotic syn-dromes, steroid- and CTX-resistant nephrotic syn-dromes, and membranous nephropathy.14 –16
Intravenous (IV) pulse CTX in combination withsteroids is relatively inexpensive, commonly used totreat SR-MCN patients in south China, and seems su-perior to oral CTX treatment in children.17,18
This trial was conducted in Chinese adults with SR-MCN to compare the efficacy of TAC with that of IVCTX for the management of SR-MCN and to assessthe tolerability of those treatments.
PATIENTS AND METHODSStudy Design
This was an open-label, prospective, nonrandom-ized cohort study conducted in 3 centers. The scientificand ethics committees of The First Affiliated Hospital(the College of Medicine, Zhejiang University), Hu-
zhou Central Hospital, and Taizhou Hospital ap-
May 2012
proved the study. The patients were informed of thepotential risks associated with the therapies beforewritten informed consent was obtained, and each pa-tient was allowed the option of treatment with oralTAC or IV CTX.
Inclusion and Exclusion CriteriaChinese adults (aged �18 years) with biopsy-
proven idiopathic SR-MCN were eligible for the study.Patients with initial and late resistance were also in-cluded. Initial steroid resistance was defined as the fail-ure to respond to either complete or partial remissionafter a course of daily steroids for at least 3 months(prednisone 1 mg/kg/d). Those who responded initiallybut failed to respond to daily treatment during a sub-sequent relapse were defined as having late resistance.The diagnosis of MCN was made on the basis of lightmicroscopic, immunofluorescence, and electron micro-scopic findings. Renal biopsy tissue samples from allpatients were reviewed before they enrolled in thestudy for confirmation of the diagnosis of MCN. Pa-tients with initial resistance underwent a second renalbiopsy before enrollment to confirm the diagnosis ofMCN.
Exclusion criteria were as follows: (1) age �70ears; (2) serum creatinine �133 �mol/L or glomeru-ar filtration rate �70 mL/min/1.73 m2; (3) active in-fection and peptic ulcer disease; (4) abnormal glucosetolerance test result; (5) abnormal liver function testresult (serum alanine aminotransferase �50 U/L); and(6) previous therapy with alkylating agents, levami-sole, mycophenolate mofetil, CYA, or TAC (other thancorticosteroids).
Drug AdministrationPatients were assigned to 1 of 2 groups: the TAC
group (oral TAC in combination with oral prednisone)or the CTX group (IV pulse CTX in combination withoral prednisone). In both groups, oral prednisone wasstarted at a dose of 0.5 mg/kg/d (maximum daily dose,40 mg) for 3 months; this dose was tapered off tocomplete cessation by 6 months. In the TAC group,TAC treatment was initiated at 0.05 mg/kg/d, dividedinto 2 doses over 12-hour intervals, and the dose wasadjusted to maintain a target trough blood level of 5 to10 ng/mL for 12 months. The trough TAC level wasmeasured by using the PRO-Trac II TAC ELISA kit(DiaSorin Inc., Stillwater, Minnesota) every 2 weeks
until it was stable, after which it was measured
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Clinical Therapeutics
monthly. In the CTX group, CTX was administeredintravenously at 1 g/1.73 m2 body surface area
onthly for 6 months and then every 2 months for andditional 6 months, with a total dosage of 10 g/.73 m2. IV physiologic saline (1000 mL) was given
immediately after each CTX treatment. Patients inboth groups who were resistant to the treatment for 6months were encouraged to withdraw from the study.Patients who were receiving angiotensin-convertingenzyme inhibitor or angiotensin receptor blocker ther-apy were maintained at the same dose of those drugsfor the duration of their therapy. Other antihyperten-sive drugs were added to the treatment regimen whennecessary to achieve accurate control of blood pres-sure. Hyperlipidemia was treated with simvastatin(20–40 mg/d) or atorvastatin (10–20 mg/d).
Efficacy and Tolerability AssessmentsFollow-up visits were performed weekly for the
first 4 weeks and then monthly thereafter. Duringeach visit, complete blood counts, urinary proteinlevels, blood glucose levels, and serum creatinine,albumin, alanine aminotransferase, and aspartateaminotransferase levels were determined. The esti-
1 lost to follow-up1 withdrew because ofadverse effect*
19 Patients completed the trial
Figure 1. Flow chart of patient enrollment. SR-MCNfocal segmental glomerulosclerosis; TAC �TAC group withdrew from the study becadecrease in oxygen saturation (�80 mm Hsuppressant therapy and treatment with an
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mated glomerular filtration rate (eGFR) was calcu-lated by using the 4-variable modification of diet inrenal disease formula.19
The primary end point was the number of patientsin complete or partial remission. Patients who did notrespond to the 6-month therapy were considered to beresistant to therapy and were withdrawn from the trial.The secondary end points were renal survival, severeadverse effects, resistance, relapse, and compliancewith therapy. Renal survival was estimated on the basisof twice the baseline serum creatinine concentration.Functional factors, such as excessive angiotensin-con-verting enzyme inhibitor/angiotensin receptor blockerand diuretic doses, were carefully excluded before theend point was defined.
Complete remission was defined as a protein level�0.3 g/d. Partial remission was defined as a urinaryprotein excretion �2.0 g/d and �0.3 g/d. Relapse ofproteinuria was defined as a urinary protein excretion�3.5 g/d confirmed in 2 consecutive analyses or therecurrence of nephrotic syndrome. The time requiredfor complete or partial remission was defined as thetime from the start of therapy to the first day on whichremission was observed. Acute renal injury was defined
2 lost to follow-up
ients completed the trial
group= 16)
7 left our hospital7 refused to be enrolled2 were excluded for age >70 years2 were excluded because second biopsyresults revealed FSGS
roid-resistant minimal change nephropathy; FSGS �limus; CTX � cyclophosphamide. *One patient in theof a severe pulmonary infection, as evidenced by ahis patient recovered after the cessation of immuno-tics.
14 Pat
CTX(n
� stetacrouseg). Ttibio
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H. Li et al.
as an increase in serum creatinine �26 �mol/L within48 hours or a urine volume �0.5 mL/kg/h for �6hours.
Statistical AnalysisAll statistical analyses were performed by using
SPSS version 15.0 (SPSS Inc., Chicago, Illinois). Dataare expressed as mean (SD). Comparisons betweengroups were conducted using the Fisher exact test forproportions. For normally distributed continuous vari-ables, the data for the 2 groups were compared usingthe 2-tailed independent-samples Student t test.20 Sur-vival analysis was performed with Kaplan-Meiercurves, and differences were estimated by using thelog-rank test.21 A P value of �0.05 was considered tobe statistically significant.
RESULTSPatient recruitment began in 2005, and follow-up wascompleted in 2010. A total of 37 adult Chinese patientswith biopsy-proven MCN and who fulfilled the enroll-ment criteria were self-assigned to receive TAC treat-ment (TAC group; n � 21) or CTX treatment (CTXgroup; n � 16) (Figure 1). One patient from the TACgroup and 2 patients from the CTX group were lost to
Table I. Baseline characteristics of patients. Unless o
Characteristic
Sex (male/female), no.Age at onset, yAge at trial, yInitial resistance, no.Duration of steroid resistance, moACE inhibitor/ARB therapy, no.Statin therapy, no.Mean arterial pressure, mm HgUrine protein, g/24 hSerum albumin, g/LSerum creatinine, �mol/LeGFR (4-variable MDRD), mL/min/1.73 m2
follow-up. One patient in the TAC group discontinuedtreatment at month 1 because of a severe pulmonaryinfection. Nineteen patients in the TAC group and 14patients in the CTX group were included in the statis-tical analysis. The demographic and laboratory char-acteristics at baseline are shown in Table I. There wereno significant differences in these data between the 2groups. In the TAC group, the mean dose of TAC was2.61 (0.89) mg/d (95% CI, 2.18–3.03), which corre-sponded to a dose of 0.044 (0.014) mg/kg/d (95% CI,0.037–0.051); the mean trough blood level of TACduring the 1-year treatment period was 7.40 (5.97)ng/mL (95% CI, 5.79–9.01).
The cumulative remission and complete remissionrates are shown in Figure 2. The remission rates were57.9% and 14.3% at 2 months (P � 0.05), 73.7% and42.9% at 4 months, and 78.9% and 50.0% at 6months for the TAC and CTX groups, respectively.The remission rates during therapy and during fol-low-up were higher in the TAC group than in the CTXgroup (Kaplan-Meier curve, log-rank test, P � 0.001).For patients who achieved remission, the mean timeneeded for remission was 48.7 (36.0) days (95% CI,28.7–68.6) in the TAC group and 85.3 (40.6) days(95% CI, 47.7–122.8) in the CTX group (P � 0.05).
n-converting enzyme; ARB � angiotensin receptor blocker;on of diet in renal disease.
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The mean serum creatinine and eGFR values of pa-tients in the TAC and CTX groups, including thosewho were responsive or unresponsive to the therapies,are shown in Figure 3. Acute renal injuries were ob-served in 2 TAC-treated patients and 1 CTX-treatedpatient and were resolved by administering dextran 40and albumin solution. No patient in either group wasobserved to have a doubling of the baseline serum cre-atinine concentration. There was no significant differ-ence in serum creatinine or eGFR between the TACand CTX groups at any time point.
The relapses observed in the TAC and CTX groupsare shown Table II. During therapy and follow-up, 6TAC-treated patients experienced 10 relapses and 1CTX-treated patient relapsed (P � 0.35). For the pa-tient in the TAC group who relapsed during treatment,the trough blood level of TAC was measured immedi-ately to avoid the possibility of an insufficient TACdose. For the patients in the TAC group who relapsedduring the follow-up period, prednisone (0.5 mg/kg/d)and TAC (trough blood level, 5–10 ng/mL) were ad-ministered for another 3 months and then tapered offto complete cessation after an additional 3 months.One TAC-treated patient who relapsed during therapy
0T2
4 5
6
11
4
10
3
3
12
3 2
5
13
2 2
5 135
1
1
P = 0.027
P = 0.015
Months2 4 6 12 24
C T C T C T C T C T C
20
40
60
80
100
% R
emis
sion
Figure 2. Probability of complete (grey) and par-tial (white) remissions in the tacrolimus(T) and cyclophosphamide (C) groups.The numbers within the columns indi-cate the total number of patients in com-plete remission or partial remission. Theremission rates in the T group during thetherapy and follow-up periods werehigher than those in the C group(Kaplan-Meier curve, log-rank test, P �0.001).
was found to have a low TAC trough blood level (2.3
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ng/mL) and achieved partial remission soon after theTAC dosage was increased. Another TAC-treated pa-tient frequently relapsed after the cessation of TACtreatment and then became resistant to TAC. One pa-tient in the TAC group relapsed twice during the 1-yearfollow-up period and achieved remission after TACtreatment was resumed; the patient then remained inpartial remission without TAC treatment for �6months.
Table III provides a list of the adverse effects ob-served in the TAC and CTX groups. The most commonadverse effects experienced were pulmonary infectionand gastrointestinal symptoms. The only patient in the
Figure 3. Mean (SD) (A) serum creatinine and (B)estimated glomerular filtration rate(eGFR) (4-variable modification of dietin renal disease) levels in patients in thetacrolimus (TAC) and cyclophospha-mide (CTX) groups. No significant differ-ences were observed between the groupsduring the 2 years of treatment and fol-low-up.
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TAC group who withdrew from the trial did so becauseof a severe pulmonary infection, as evidenced by a de-crease in oxygen saturation (�80 mm Hg). This patientrecovered after treatment with antibiotics and the ces-sation of immunosuppressive therapy. Pulmonary in-fections also occurred in 2 other patients in the TACgroup and 3 patients in the CTX group, but all infec-tions were mild and resolved after antibiotic treatment.A 37-year-old man in the TAC group exhibited glucoseintolerance after 4 months of therapy and required in-sulin therapy. A 24-year-old man in the TAC groupdeveloped hepatotoxicity, defined as an elevated ala-nine aminotransferase level (20–90 U/L), at the end ofthe first month of TAC therapy; this adverse effect re-solved after a reduction in the dose of TAC and treat-ment with diammonium glycyrrhizinate, a componentof the traditional Chinese medicine Gan Cao.22 Gas-trointestinal symptoms such as nausea, vomiting, anddiarrhea occurred in 2 patients in the TAC group andin 6 patients in the CTX group; all of these episodeswere mild, short-lived, and tolerated by the patients.
During the treatment period, the average monthlypersonal therapeutic expenditure in the TAC groupwas 1356 Chinese Yuan (CNY) (range, 156–4350CNY), which was significantly more than that in theCTX group (262 CNY; range, 0–590 CNY) (P �
Table II. Relapses in patients from the tacrolimus(TAC) and cyclophosphamide (CTX) groupswith complete or partial remission.
Case
No. of Cases/Total
PTAC
GroupCTX
Group
Relapse under treatment 1/15 0/7 0.99Immediate relapse(�1 month) aftertreatment 1/15 0/7 0.99Relapse cases during thefirst year of follow-up 5/15 1/7 0.62Total relapse casesduring therapy andfollow-up 6/15 1/7 0.35
.001).
May 2012
DISCUSSIONIn this multicenter, prospective, nonrandomized co-hort trial, the efficacy of TAC therapy was comparedwith that of IV CTX therapy in 33 patients with SR-MCN. Tolerability of those treatments was alsoassessed.
SR-MCN is responsible for 6% to 25% of cases ofidiopathic MCN in adults.1,2 Most reports on thetreatment of these patients are case reports or retro-spective analyses.15,23–26 Competitive trials concerninghe treatment of this small proportion of MCN pa-ients have rarely been conducted.27 Although this trial
was limited by its nonrandomized format, limited pa-tient numbers, and short follow-up time, we believethat these results are still important because they camefrom a competitive trial focused on the treatment ofadults with SR-MCN.
Our results revealed that 78.9% of the patients inthe TAC group improved after 6 months of therapy,with a complete remission rate of 63.2%. Comparedwith remission rates observed with CYA and other im-munosuppressive therapies, this remission rate wassurprisingly high.27–29 TAC therapies also showed
ore rapid effects than did CTX therapies in thistudy. Half of the patients in the TAC group achievedemission within the first 2 months of therapy, whereasost patients in the CTX group achieved remissionuring months 2 to 4 of therapy.
Table III. Adverse events in patients of the tacroli-mus (TAC) and cyclophosphamide (CTX)groups.
*Including 1 patient who withdrew from the trial becauseof a severe pulmonary infection.
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Clinical Therapeutics
The basis of TAC’s mechanism of action in SR-MCN is unknown, but its immunosuppressive effectsare considered to be very important. Another possiblemechanism of action is a potent suppressive effect onthe release of cytokines. Maruyama et al30,31 showedhat CYA and TAC significantly inhibited the produc-ion of vascular permeability factor in T lymphocytesultured from patients with MCN. Some data suggesthat the effects of TAC on proteinuria in nephroticyndrome are different from those of CYA. TAC haseen reported to be effective in some patients withYA-resistant nephrotic syndrome.10,32 The biologi-
cal mechanism remains unknown but may be due tothe suppressive effects of TAC on cytokines. Based onthese results, some researchers have concluded thatTAC is superior to CYA in treating proteinuria. Addi-tional comparative and crossover trials are needed tocompare the effects of TAC and CYA on proteinuria.
In this study, 6 of the 15 patients in the TAC group,but only 1 of the 7 patients in the CTX group, relapsedduring the therapy and the 1-year follow-up. The re-lapse rate in the TAC group seemed to be higher thanthat in the CTX group, although this apparent differ-ence was not statistically significant (P � 0.35). Re-ports on the relapse rate of patients undergoing TACtherapy are controversial. Duncan et al33 reported thatnone of the 6 patients treated with TAC for nephroticsyndrome in their study relapsed during a mean fol-low-up period of 12.8 months. However, most otherresearchers reported a high relapse rate (�70%) afterthe cessation of TAC treatment.20,32,34 The high re-lapse rate observed in the TAC group in the presenttrial may have resulted from an insufficient treatmentperiod or the sudden cessation of TAC treatment after1 year of treatment. Strategies such as prolonging thetreatment period, tapering off the TAC dose beforetotal cessation, and/or the use of another immunosup-pressive agent as a maintenance therapy should be im-plemented to reduce the relapse rate after the cessationof TAC therapy.
Although some adverse effects were reported in theTAC group, all were treatable. No significant renaltoxicity was observed in the TAC group. The low dosesof TAC administered in this study, which are consid-erably lower than the doses used for immunosuppres-sion in patients undergoing solid organ transplanta-tion,35 may explain the low incidence of adverse
effects.
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This trial was limited by its low number of patients,nonrandomized format, and the potential bias associ-ated with the ability of some self-pay patients to choosetheir treatment.
CONCLUSIONSOur study suggests that in this select group of Chinesepatients, TAC was an effective immunosuppressiveagent compared with IV pulse CTX for the treatmentof SR-MCN. Both agents were well tolerated. How-ever, some patients tended to relapse after the cessationof TAC treatment. Additional trials are required todetermine the optimal duration of TAC treatment andstrategies that can effectively reduce the relapse rateafter the cessation of TAC therapy.
ACKNOWLEDGMENTThis study was sponsored and financially supported bystate-owned Zhejiang University.
The authors thank their colleagues, who partici-pated in the study: Dr. Qun Li, Dr. Xuelin He, Dr.Xiaohui Zhang, Dr. Yilun Chen, Dr. Suya Wang, Dr.Fei Han, and Dr. Jianyong Wu, Dr. Chen, X. Li, HengLi, Shi, and Shen contributed to the conception anddesign of the study. Drs. Heng Li, X. Li, Hongmei Li,and Xu contributed to the data collection. Dr. Wangcontributed to the pathologic diagnosis of all patientsenrolled in this study. Dr. Heng Li provided statisticalanalysis and drafted the manuscript. Analysis, anddata interpretation were undertaken by all of the au-thors. The overall responsibility for the manuscript be-longed to Dr. Chen.
CONFLICTS OF INTERESTThe authors have indicated that they have no conflictsof interest regarding the content of this article.
REFERENCES1. Waldman M, Crew RJ, Valeri A, et al. Adult minimal-change
disease: clinical characteristics, treatment and outcomes.Clin J Am Soc Nephrol. 2007;2:445–453.
2. Huang JJ, Hsu SC, Chen FF, et al. Adult-onset minimalchange disease among Taiwanese: clinical features, thera-peutic response, and prognosis. Am J Nephrol. 2001;21:28–34.
3. Bonilla-Felix M, Parra C, Dajani T, et al. Changing patternsin the histopathology of idiopathic nephrotic syndrome in
children. Kidney Int. 1999;55:1885–1890.
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1
1
1
1
1
1
1
1
2
2
2
2
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2
2
2
2
2
3
3
H. Li et al.
4. Baipai A, Bagga A, Hari P, et al.Intravenous cyclophosphamide insteroid-resistant nephrotic syn-drome. Pediatr Nephrol. 2003;18:351–356.
5. Plank C, Kalb V, Hinkes B, et al.Cyclosporin A is superior to cyclo-phosphamide in children with ste-roid-resistant nephrotic syn-drome—a randomized controlledmulticentre trial by the Arbeitsge-meinschaft fur Padiatrische Neph-rologie. Pediatr Nephrol. 2008;23:1483–1493.
7. Henderson DJ, Naya I, Bundick RV,et al. Comparison of the effects ofFK-506, cyclosporin A and rapamy-cin on IL-2 production. Immunology.1991;73:316–321.
8. Jordan ML, Shapiro R, Vivas CA, etal. FK-506 “rescue” for resistant re-jection of renal allografts under pri-mary cyclosporine immunosuppres-sion. Transplantation. 1994;57:860–865.
9. McCauley J, Shapiro R, Ellis D, et al.Pilot trial of FK 506 in the manage-ment of steroid-resistant nephroticsyndrome. Nephrol Dial Transplant.1993;8:1286–1290.
3. Loeffler K, Gowrishankar M, Yiu V.Tacrolimus therapy in pediatric pa-tients with treatment-resistant ne-phrotic syndrome. Pediatr Nephrol.2004;19:281–287.
4. Li X, Li H, Chen J, et al. Tacrolimus asa steroid-sparing agent for adultswith steroid-dependent minimalchange nephrotic syndrome. NephrolDial Transplant. 2008;23:1919 –1925.
5. Li X, Li H, Ye H, et al. Tacrolimustherapy in adults with steroid- andcyclophosphamide-resistant ne-phrotic syndrome and normal ormildly reduced GFR. Am J Kidney Dis.2009;54:51–58.
6. Li X, Lv R, He Q, et al. Early initiationof tacrolimus or cyclophosphamidetherapy for idiopathic membranousnephropathy with severe protein-uria. J Nephrol. 2008;21:584–591.
7. Elhence R, Gulati S, Kher V, et al.Intravenous pulse cyclophospha-mide—a new regime for steroid-resistant minimal change nephroticsyndrome. Pediatr Nephrol. 1994;8:1–3.
8. Bajpai A, Bagga A, Hari P, et al.Intravenous cyclophosphamide insteroid-resistant nephrotic syn-drome. Pediatr Nephrol. 2003;18:351–356.
9. Levey AS, Bosch JP, Lewis JB, et al. Amore accurate method to estimateglomerular filtration rate from se-rum creatinine: a new predictionequation. Modification of Diet inRenal Disease Study Group. AnnIntern Med. 1999;130:461–470.
0. Sinha MD, Macleod R, Rigby E, etal. Treatment of severe steroid-dependent nephrotic syndrome(SDNS) in children with tacrolimus.Nephrol Dial Transplant. 2006;21:1848–1854.
1. Praga M, Barrio V, Fernandez JuarezG, et al. Tacrolimus monotherapy inmembranous nephropathy: A ran-domized controlled trial. Kidney Int.2007;71:924–930.
2. Orlent H, Hansen BE, Willems M, et
al. Biochemical and histological ef-
fects of 26 weeks of glycyrrhizintreatment in chronic hepatitis C: arandomized phase II trial. J Hepatol.2006;45:539–546.
4. Tang S, Tang AW, Tam MK, Ho YW.Use of tacrolimus in steroid- andcyclophosphamide-resistant mini-mal change nephrotic syndrome.Am J Kidney Dis. 2003;42:E13–E15.
5. Mogyorosi A, Lippman HR, Feld-man GM. Successful treatment ofsteroid-resistant minimal changedisease with mycophenolate mofetil.Am J Nephrol. 2002;22:569–572.
6. Lee HY, Kim HS, Kang CM, et al. Theefficacy of cyclosporine A in adultnephrotic syndrome with minimalchange disease and focal-segmentalglomerulosclerosis: a multicenterstudy in Korea. Clin Nephrol. 1995;43:375–381.
7. Ponticelli C, Rizzoni G, Edefonti A,et al. A randomized trial of cyclospo-rine in steroid-resistant idiopathicnephrotic syndrome. Kidney Int.1993;43:1377–1384.
9. Niaudet P, French Society of Pediat-ric Nephrology. Treatment of child-hood steroid-resistant idiopathic ne-phrosis with a combination ofcyclosporine and prednisone. J Pedi-atr. 1994;125:981–986.
0. Maruyama K, Tomizawa S, Seki Y, etal. Inhibition of vascular permeabil-ity factor production by ciclosporinin minimal change nephrotic syn-drome. Nephron. 1992;62:27–30.
1. Maruyama K, Tomizawa S, Seki Y, etal. FK 506 for vascular permeability
32. Segarra A, Vila J, Pou L, et al. Com-bined therapy of tacrolimus andcorticosteroids in cyclosporin-resis-tant or -dependent idiopathic focalglomerulosclerosis: a preliminary un-controlled study with prospectivefollow-up. Nephrol Dial Transplant.2002;17:655–662.
33. Duncan N, Dhaygude A, Owen J, etal. Treatment of focal and segmen-tal glomerulosclerosis in adults withtacrolimus monotherapy. NephrolDial Transplant. 2004;19:3062–3067.
4. Ballarin J, Poveda R, Ara J, et al.Treatment of idiopathic membra-nous nephropathy with the combi-nation of steroids, tacrolimus andmycophenolate mofetil: results of apilot study. Nephrol Dial Transplant.2007;22:3196–3201.
5. Kokado Y, Takahara S, Kyo M, et al.Low-dose tacrolimus (FK506)-basedimmunosuppressive protocol in liv-ing donor renal transplantation.Transpl Int. 1998;11(Suppl 1):S60–S64.
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Address correspondence to: Jianghua Chen, MD, Kidney Disease Center,The First Affiliated Hospital, College of Medicine, Zhejiang University,#79 Qingchun Road, Hangzhou, Zhejiang Province, P.R.China, 310003.
