Follow-up study of children with nephrotic syndrome treated with a long-term moderate dose of cyclosporine

Because of its potential for chronic nephrotoxicity, the long-term use of cyclosporine A (CsA) as treatment for nephrotic syndrome (NS) is controversial. The clinical outcome of patients with NS treated with CsA is unclear. We retrospectively evaluated 35 children with idiopathic NS, 24 with steroid-dependent NS (SDNS), and 11 with steroid-resistant NS (SRNS), who received CsA therapy for more than 12 months (median, 23 months) at the dosage maintaining 50 to 120 ng/mL in trough level. For SDNS patients, CsA was added to prednisolone after complete remission was achieved. For SRNS patients, CsA was used in combination with alternate-day prednisolone. Initial renal histology showed minimal changes (MC) in 28 patients (including all of the patients with SDNS) and focal segmental glomerulosclerosis (FSGS) in seven patients. The patients were followed up for 2 to 10.5 years (median, 6.5 years) after the termination of the CsA therapy. In SDNS patients, the relapse rate, dosage of prednisolone, standard deviation score for height, and body mass index significantly improved during CsA treatment. The follow-up study showed the proportion of SDNS decreased to 13 of 24 (54%) patients. In SRNS patients, CsA therapy induced remission in 8 of 11 patients (73%) (complete remission in seven and incomplete remission in one). Six of 11 patients (55%) then became steroid sensitive. Post-therapy biopsies, performed in 13 patients (10 with SDNS and three with SRNS), showed mild stripped interstitial fibrosis in two SDNS patients (15%). Long-term CsA therapy in moderate doses was effective to the patients with SDNS and SRNS and low in incidence of nephrotoxicity. The long-term use of CsA appears to result in a decrease in the proportion of SDNS and acquisition of subsequent steroid responsiveness in SRNS.     

Switch from cyclosporine A to mycophenolate mofetil in nephrotic children

Nephrotoxicity is a well-known adverse effect of cyclosporine A (CyA) treatment in children with steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome (NS). We analyzed nine children (age: 3.3–15.7 years, two girls) with SD or SR NS who experienced a significant decrease in their GFR under CyA treatment as measured by inulin clearance (C_IN). Mycophenolate mofetil (MMF) was introduced progressively until doses of 1 g/1.73 m² twice daily were reached. CyA treatment was stopped after introduction of MMF and oral steroids were reduced if possible. After a median follow up of 261 days, no adverse effects of MMF such as diarrhea or hematological anomalies occurred in our patients. After switching from CyA to MMF, those children with SD NS remained in remission without proteinuria and those with SR NS did not show any significant changes in their residual proteinuria. The serum protein level did not change significantly in any of the children analyzed. GFR increased from a mean of 76.9±4.8 to 119.9±5.9 mL/1.73 m² per min (P<0.001). Oral steroid treatment could be reduced from a median [range] prednisone dose of 0.85 [0.26–2.94] mg/kg/d pre-MMF to 0.29 [0–1.1] mg/kg per day (P=0.026), and blood pressure decreased moderately after CyA withdrawal, but the difference did not reach statistical significance. We conclude that a switch from CyA to MMF seems to be safe for children with SDNS and SRNS in terms of side effects as well as disease control, at least in the short term. Interruption of CyA treatment lead to rapid amelioration of kidney function in these children, often associated with steroid sparing, which may lead to additional benefit for growth velocity, blood pressure and physical appearance.     

A prospective study on the use of mycophenolate mofetil in children with cyclosporine-dependent nephrotic syndrome

Cyclosporine A (CsA) has relieved children with steroid-dependent nephrotic syndrome (NS) from steroid toxicity. However, most patients frequently relapse again when CsA is withdrawn, resulting in the development of CsA nephropathy for its long-term use. In order to assess the efficacy of mycophenolate mofetil (MMF) therapy, we prospectively analyzed 12 children with idiopathic steroid-dependent NS requiring long-term CsA therapy with MMF for at least 6 months. Mean follow-up after starting MMF was 11 months (range 6–42). The mean MMF dose required was 610±95 mg/m²/12 h, which maintained mean predose mycophenolic acid (C0-MPA) levels of 2.4±1.1 mcg/ml. Treatment with MMF resulted in CsA and/or prednisolone (PSL) sparing, with a reduction in mean CsA dose from 3.5±1.3 to 1.5±2.4 mg/kg/day (p<0.01), and mean PSL dose from 0.29±0.16 to 0.21±0.11 mg/kg/day (p<0.05). Nine of 12 patients (75%) were finally able to be weaned off CsA. Mean relapse rates decreased from 2.7±1.6 to 0.6±0.9 episodes/year (p<0.01). Relapse-free ratio on MMF therapy was lower in patients whose average C0-MPA levels were less than 2 mcg/ml (p<0.05). Our experience demonstrates that MMF therapy results in significant CsA and/or steroid sparing and reduction in relapse rates in children with CsA-dependent NS.     

Novel multidrug therapy for children with cyclosporine-resistant or -intolerant nephrotic syndrome

An effective treatment for children with refractory nephrotic syndrome (NS), especially in those with cyclosporine (CsA)-resistant or CsA-intolerant NS, has yet to be established. Recently, the efficacy of multidrug therapy consisting of tacrolimus (Tac), mycophenolate mofetil (MMF) in combination with prednisolone (PDN) in adult patients with refractory NS has been reported. We successfully treated 14 consecutive children with refractory CsA-resistant or CsA-intolerant NS using combination therapy consisting of relatively low-dose Tac, mizoribine (MZR), which has a mechanism of action very similar to that of MMF, and PDN. There were no serious clinical toxicities. Of the 14 children, 9 with a mean age of 13.0 years had steroid-dependent NS (SDNS) and 5 with a mean age of 9.6 years had steroid-resistant NS (SRNS). All SDNS patients had minimal change disease (MCD), 4 with SRNS had focal segmental glomerulosclerosis (FSGS), and the remaining child had MCD on renal biopsy. All patients were in a prospective cohort, but were evaluated retrospectively. The mean follow-up from the initiation of multidrug therapy was 18.4 months in SDNS and 18.6 months in SRNS patients. At the last observation point, the calculated relapse rate and minimum dose of PDN required for maintenance of clinical remission after the start of multidrug therapy were significantly decreased compared with those prior to this therapy, while on CsA, in SDNS patients (0.4?±?0.5 times/year vs 2.9?±?1.5 times/year, P?=?0.0077, and 0.3?±?0.2 mg/kg on alternate days vs 0.5?±?0.2 mg/kg on alternate days, P?=?0.0184 respectively). All SDNS and two SRNS patients (40%) achieved complete remission, allowing further decreases in the minimal doses of PDN required for maintenance of clinical remission in most our patients. However, one patient with FSGS remained refractory to multidrug therapy and subsequently developed end-stage renal disease. These clinical observations, although preliminary and involving a small number of patients, suggest that multidrug therapy consisting of relatively low-dose Tac, MZR, and PDN might be effective and safe for treating children with refractory CsA-resistant or CsA-intolerant NS. However, further studies involving larger numbers of patients are needed.     

Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: current status and future directions

Clinicians are often faced with therapeutic dilemmas and challenges while treating children with frequently relapsing steroid-dependent nephrotic syndrome (SDNS) and steroid-resistant nephrotic syndrome (SRNS). In the past, children with SDNS have been treated with long-term alternate day steroids cyclophosphamide, cyclosporine (CSA), chlorambucil, levamisole, and azathioprine. The essential aim of these therapies is to maintain remission while limiting exposure to steroids. These medications have variable efficacy and undesirable toxicity profiles. Recently, mycophenolate mofetil (MMF) has emerged as a new therapeutic option for the management of SDNS in a few uncontrolled clinical trials. Preliminary data are encouraging. MMF was found to be useful in maintaining remission and has a steroid-sparing effect. Clearly, more data are needed to further characterize the safety and efficacy of MMF, define adequate length of treatment, and optimize drug exposure and monitoring. The management of SRNS is primarily aimed at decreasing proteinuria and inducing remission, if possible. By doing so, one would aim to preserve renal function. CSA therapy is known to be useful in this regard but has undesirable side effects, the most concerning being nephrotoxicity. MMF in combination with steroids and angiotensin-converting enzyme-inhibitor drugs is known to have some efficacy in the management of SRNS. These preliminary data have prompted the National Institutes of Health to sponsor a multicentric controlled trial to compare the safety and efficacy of MMF with that of CSA in the treatment of steroid-resistant focal segmental glomerulosclerosis (FSGS). If MMF therapy is found to be efficacious, it would help obviate the need for CSA and its associated nephrotoxicity. Clearly, MMF has emerged as an important new therapeutic option for the treatment of childhood nephrotic syndrome and FSGS. Further data are required to assess those conditions most likely to respond.     

Growth in boys with idiopathic nephrotic syndrome on long-term cyclosporin and steroid treatment

Although steroid-free remission can usually be achieved with cyclosporin A (CsA) in patients with steroid-dependent nephrotic syndrome (SDNS), some CsA-treated patients require long-term steroid therapy. Data on growth in these patients are scarce. Sixty-four boys with SDNS receiving long-term CsA and steroid therapy were retrospectively analyzed. During the 10-year follow-up period, height standard deviation score (HSDS) remained in the normal range in 47 patients but was below −2 SD in 17 patients. The occurrence of growth retardation was influenced by height at diagnosis and the number of relapses. Thirty patients were followed for at least 3 years before and after age 12. The decrease in HSDS per year of disease in patients older than 12 years was twice that observed in children younger than 12. However, adult height was ≤ −2 SD in only two of the 14 patients reaching adult height, reflecting potential catch-up growth during late puberty. Careful monitoring of growth is recommended, given than up to 25% of patients experienced severe growth retardation during the course of their disease.     

Glycosaminoglycan excretion in children with nephrotic syndrome

Although most childhood nephrotic syndromes respond to steroid treatment, steroid resistant nephrotic syndrome (SRNS) is also common and is particularly difficult to treat. This study investigated the role of glycosaminoglycans (GAG) in the pathogenesis and clinical course of nephrotic syndrome in children. Thirty-four children (21 males and 13 females, mean age 3.7±1.6 years) with steroid-sensitive nephrotic syndrome and 20 children with steroid-resistant nephrotic syndrome (12 males and 8 females, mean age 10.9±3.8 years; of the twenty, four had primary SRNS (FSGS) and the others had secondary SRNS) were included the study. Mean urine levels of GAG relative to creatinine (U_GAG/U_Cr) in patients with SRNS (n=20, 113.01±78.46 mg g^–1 Cr) and in patients experiencing the nephrotic period of steroid-sensitive nephrotic syndrome (n=34, 132.15±101.55 mg g^–1 Cr) were both significantly higher than mean U_GAG/U_Cr for control subjects (n=30, 51.83±47.66 mg g^–1 Cr) (P<0.01 for both). Patients excreted significantly more GAG during the nephrotic period of steroid-sensitive nephrotic syndrome than during remission (132.15±101.55 vs 39.11±42.73 mg g^–1 Cr, respectively; P<0.01). There was, however, no significant difference between U_GAG/U_Cr for patients with steroid-resistant nephrotic syndrome and U_GAG/U_Cr in the nephrotic period of steroid-sensitive nephrotic syndrome. Urine GAG excretion correlated significantly with the severity of proteinuria. The results suggest that GAG play a significant role in the pathogenesis of nephrotic syndrome but that GAG excretion is not a marker for response to steroid treatment in pediatric patients with this condition.     

Mutational analysis of <Emphasis Type="Italic">NPHS2</Emphasis> and <Emphasis Type="Italic">WT1</Emphasis> in frequently relapsing and steroid-dependent nephrotic syndrome

Idiopathic nephrotic syndrome is a common pediatric kidney disease, 80% of all cases are steroid sensitive (SSNS). A significant proportion of children with SSNS will have a frequently relapsing or steroid-dependent course (FRNS/SDNS) that is associated with significant treatment-related morbidity. Mutations in NPHS2 account for more than 28% of all cases of steroid-resistant nephrotic syndrome (SRNS) and dominant mutations in WT1 for 5%; while mutations are absent from children with uncomplicated SSNS. Since FRNS/SDNS is phenotypically positioned within a spectrum between SSNS and SRNS, we hypothesized that heterozygous mutations of NPHS2 may be causing FRNS/SDNS. Mutational analysis of NPHS2 and WT1 was carried out in a single-center cohort of 20 children with FRNS/SDNS, ten children with uncomplicated SSNS (control), and 22 children with SRNS (control). Renal biopsy findings were available in 15/20 children with FRNS/SDNS and revealed IgM nephropathy, MCNS, and FSGS in six, five, and four children, respectively. Children with FRNS/SDNS were significantly younger at first presentation than those with SSNS and SRNS (median age: 3.0 years in FRNS/SDNS patients, 7.0 years in SSNS patients, and 5.0 in SRNS patients; p < 0.001). No NPHS2 or WT1 mutations were found in patients with FRNS/SDNS and uncomplicated SSNS. The hypothesis that FRNS/SDNS may be associated with heterozygous mutations in NPHS2 or WT1 was not confirmed.     

Quantitative morphometry of renal biopsies prior to cyclosporine in nephrotic syndrome

Use of cyclosporine (CsA) in the management of children with steroid-resistant (SRNS) and steroid-dependent (SDNS) nephrotic syndrome has become increasingly popular in recent years. Although most children receive a renal biopsy prior to initiation of CsA, the relationship between initial renal histology and the subsequent clinical response to CsA is not known. We analyzed the correlation between pre-CsA segmental and global glomerular scarring and interstitial fibrosis and the subsequent response to CsA in 23 children (5.6±1.0 years, Mean±SEM) with SDNS (n=8) and SRNS (n=15) treated with CsA for 24.2±3.8 months and followed for 28.0±4.1 months. Complete remission was obtained in 78% of patients within 67.6±16 days, while 18% had a partial response and 4% no response. Quantitative histological analysis revealed a trend toward partial rather than complete response with increasing segmental glomerular (P=0.13), global glomerular (P=0.05), and interstitial (P=0.08) scarring, and among patients with minimal change nephrotic syndrome versus IgM nephropathy versus focal segmental glomerulosclerosis. Among complete responders, linear regression analyses revealed no correlation between time to response and pre-CsA glomerular or interstitial scarring. We conclude that increased glomerular or interstitial scarring on a pre-CsA renal biopsy tends to correlate with a partial, rather than complete, response to CsA in childhood nephrotic syndrome. Received June 9, 1997; received in revised form October 14, 1997; accepted January 13, 1998     

Long-term outcome of children treated with the ISKDC regimen for the first episode of INS

We retrospectively analyzed the long-term outcome of 82 children (SRNS group, 10; SDNS group, 35; IRNS group, 37) who were initially treated with the ISKDC regimen at the Saitama Children's Medical Center. The ISKDC regimen consisted of PSL 60 mg/m2/day for 4 weeks, followed by 40 mg/m2 on alternate days for another 4 weeks. The aims of our study were to identify factors at onset that could predict the relapse pattern after using the initial ISKDC regimen, and to assess the prognosis and renal histology after long-term CsA therapy in 31 children. All of six asymptomatic children without edema and identified by chance proteinuria on a urinary screening program had an extremely favorable clinical course. Initial remission time of 9 or more days and the time interval from the initial therapy to the first relapse were significant predictors of steroid dependency. The sensitivity and specificity of these findings were 100% and 90%, respectively, with a positive predictive value of 95% and a negative predictive value of 100%. In addition, after the introduction of CsA therapy, termination of steroid therapy was achieved in 56% of patients with SRNS, and 64% of SDNS, respectively. However, after CsA therapy was tapered or stopped, most patients (21/20: 95%) developed relapses of NS. Of these, 76% (16/21) returned to SDNS, resulting in the reintroduction of CsA. Ten of 22 patients taking CsA (mean duration 31.3 months) had chronic nephrotoxicity. In conclusion, the initial ISKDC regimen is useful for the early prediction of whether or not the patient will develop SDNS. When pediatric nephrologists introduce CsA therapy in children with SDNS, an alternative strategy after long-term use of the agent should be considered.     

Urine proteomic profiling of pediatric nephrotic syndrome

The prognosis of pediatric nephrotic syndrome (NS) correlates with the responsiveness to glucocorticoid therapy. Steroid-resistant NS (SRNS) patients progress to end-stage renal disease, while steroid-sensitive NS (SSNS) and steroid-dependent (SDNS) patients do not. We have performed proteomic profiling of urine samples from a cross section of pediatric and adolescent subjects with SSNS, SRNS, and orthostatic proteinuria (OP) to identify urinary biomarkers of steroid resistance. We performed surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) on urine from 19 subjects with SSNS/SDNS in remission, 14 with SSNS/SDNS in relapse, 5 with SRNS in relapse, and 6 with OP. Genetic algorithm search of principal component space revealed a group of five peaks distinguishing SRNS subjects, with mass/charge (m/z) values of 3,917.07, 4,155.53, 6,329.68, 7,036.96, and 11,117.4. Our analyses identified the peak at m/z 11,117.4 with an accuracy of 95% for classifying SRNS. Multidimensional protein fractionation and mass spectrometric analysis of SRNS urine samples combined with immunodepletion identified the 11,117.4 protein as β₂-microglobulin (B2M). Using an unbiased protein profiling approach, we have validated previously reported findings of B2M as a biomarker associated with SRNS. Prospective studies are warranted to establish additional biomarkers that would be predictive of SRNS.MK and AZT contributed equally to this work.     

Long-term effects of cyclosporine in children with idiopathic nephrotic syndrome: a single-centre experience

Background. Because of its potential nephrotoxicity, the long-termuse of cyclosporine (CsA) as treatment for nephrotic syndrome(NS) is controversial. The clinical outcome of the patientswith NS treated with CsA is unclear. Methods. This study reports the results of long-term CsA treatmentin 117 children with idiopathic NS, who received CsA therapyfor more than 2 years (median, 34 months). The mean age of childrenat initiation of CsA therapy was 11±4 years. The startingdose of CsA was 5 mg/kg/day, adjusted to maintain a trough levelof 100–150 ng/ml in the first 2 months, 50–100 ng/mlthereafter. Later, a level as low as 30 ng/ml was accepted solong as it maintained remission. All patients received CsA between1993 and 2003. Indications for treatment included steroid-dependentnephrotic syndrome (SDNS) in 74 patients and steroid-resistantnephrotic syndrome (SRNS) in 43 patients. Initial renal histologyshowed minimal change disease (MCD) in 38 patients and focalsegmental glomerulosclerosis (FSGS) in 79 patients. Most patientswere receiving moderate doses of prednisone. Sixty patientsreceived cyclophosphamide prior to CsA. The observation periodswere 5.8±3 years and 6.1±1.9 years before andafter CsA treatment, respectively. Results. Complete remission [proteinuria <4 mg/h/m²/bodysurface area (BSA)], partial remission (proteinuria between4.1 and 40 mg/h/m²/BSA) and resistance to CsA (proteinuria 45mg/h/m²/BSA) were observed in 82.1, 5.1 and 12.8%, respectively.Hypertension, renal impairment (>30% rise of serum creatinine),gingival hyperplasia and hypertrichosis occurred in 10.3, 6.0,32.5 and 70.1%, respectively. Steroids were stopped in 102 patients,of which 31 relapsed. Out of 29 patients for whom CsA was intentionallydiscontinued while in remission, 22 relapsed. Of these, sixpatients were resistant to a second course of CsA. Post-therapybiopsies, performed in 45 patients (33 with SDNS and 12 withSRNS), showed mild stripped interstitial fibrosis and tubularatrophy in two SDNS patients (4.4%). At the last follow-up,one child had developed end-stage renal failure and two hadchronic renal insufficiency. Conclusions. Long-term CsA therapy in low doses is effectivein the treatment of children with idiopathic NS, but the rateof relapse is high after drug withdrawal. Hypertension developedin 10% of patients and renal insufficiency in 6% (most patientswith FSGS).     

Hearing status in children with frequently relapsing and steroid resistant nephrotic syndrome

Background

Children with idiopathic nephrotic syndrome (INS) are at risk of hearing impairment due to nephrotoxic drugs and biochemical impairments.

Methods

Forty children with INS aged 5–16 years [20 patients with frequently relapsing nephrotic syndrome (FRNS)/steroid dependent nephrotic syndrome (SDNS) and 20 with steroid resistant nephrotic syndrome (SRNS)] and 20 normal healthy controls were enrolled in this study. Pure tone audiometry was done using the ALPS AD 2000 audiometer. Sensorineural hearing loss was diagnosed when the bone conduction level was >20 dB and the difference in air to bone gap was ≤15 dB. Based on the air conduction (AC) threshold, deafness was graded into the following categories: mild (26–40 dB), moderate (41–55 dB), moderately severe (56-70 dB), severe (71–91 dB) and profound (>91 dB).

Results

Children with FRNS/SDNS had a higher threshold for hearing at frequencies of 250 and 500 Hz, respectively, than the controls. Of the children in the FRNS/SDNS category, three (15 %) had mild sensorineural hearing impairment. These children had a low serum calcium level (P?<?0.03) and received higher cumulative doses of furosemide (P?<?0.04). Children with SRNS had a higher threshold for hearing at frequencies of 250, 500, 1,000, and 2,000 Hz, respectively, than the controls. Of the 20 children with SRNS, ten (50 %) had sensoineural hearing impairment (8 mild, 2 moderate). Children with SRNS with a hearing defect had received a higher cumulative dose of furosemide (P?<?0.03).

Conclusions

Children with FRNS/SDNS and SRNS are at risk of sensorineural hearing impairment. The risk factors associated with this impairment were higher cumulative doses of furosemide and hypocalcemia. Larger prospective cohort studies are required to evaluate this association.     

Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome

Background

Rituximab (RTX) is a promising option for treating childhood-onset steroid-dependent (SDNS), frequently relapsing (FRNS), and steroid-resistant (SRNS) nephrotic syndrome.

Methods

We retrospectively surveyed RTX treatment for these conditions to evaluate its indications, efficacy and adverse events. Questionnaires were sent to 141 hospitals in Japan.

Results

Seventy-four patients (52 SDNS; 3 FRNS; 19 SRNS) were treated with RTX because of resistance to various immunosuppressive agents. Most patients received a single administration of RTX (85%). Forty-one of 53 SDNS/FRNS (77%) and 5 of 17 SRNS (29%) patients successfully discontinued prednisolone (16 SDNS/FRNS and 6 SRNS achieved their first discontinuation since onset), and 17 out of 53 SDNS/FRNS patients (31%) discontinued cyclosporine. However, 28 of the 53 patients (51%) relapsed. Although immunosuppressive agents did not extend B cell depletion, relapses were significantly less if immunosuppressive agents were continued after RTX (P?=?0.006; hazard ratio?=?0.2). Among the SRNS patients, complete (n?=?6) and partial remission (n?=?6) were achieved. No life-threatening adverse events were experienced.

Conclusions

Although this was a multi-center survey where treatment of nephrotic syndrome varied between centers, the steroid-sparing effect of RTX in SDNS/FRNS was excellent. If single administration of RTX is chosen, continuation of immunosuppressive agents is recommended for prevention of relapse.     

Mycophenolate Mofetil versus Cyclosporin A in Children with Frequently Relapsing Nephrotic Syndrome

The severe side effects of long-term corticosteroid or cyclosporin A (CsA) therapy complicate the treatment of children with frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). We conducted a randomized, multicenter, open-label, crossover study comparing the efficacy and safety of a 1-year treatment with mycophenolate mofetil (MMF; target plasma mycophenolic acid trough level of 1.5–2.5 µg/ml) or CsA (target trough level of 80–100 ng/ml) in 60 pediatric patients with FR-SSNS. We assessed the frequency of relapse as the primary endpoint and evaluated pharmacokinetic profiles (area under the curve [AUC]) after 3 and 6 months of treatment. More relapses per patient per year occurred with MMF than with CsA during the first year (P=0.03), but not during the second year (P=0.14). No relapses occurred in 85% of patients during CsA therapy and in 64% of patients during MMF therapy (P=0.06). However, the time without relapse was significantly longer with CsA than with MMF during the first year (P<0.05), but not during the second year (P=0.36). In post hoc analysis, patients with low mycophenolic acid exposure (AUC <50 µg⋅h/ml) experienced 1.4 relapses per year compared with 0.27 relapses per year in those with high exposure (AUC>50 µg⋅h/ml; P<0.05). There were no significant differences between groups with respect to BP, growth, lipid levels, or adverse events. However, cystatin clearance, estimated GFR, and hemoglobin levels increased significantly with MMF compared with CsA. These results indicate that MMF is inferior to CsA in preventing relapses in pediatric patients with FR-SSNS, but may be a less nephrotoxic treatment option.Idiopathic nephrotic syndrome, the most common form of childhood nephrotic syndrome, is most often associated with renal biopsy findings of minimal glomerular and tubulointerstitial changes (minimal change disease). Most patients respond to therapy with corticosteroids,¹ but about 70% experience a relapsing course.² Approximately 30% develop frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS), defined as ≥4 relapses per year.³Although corticosteroids are the mainstay of therapy in pediatric patients with minimal change disease, their repeated use in FR-SSNS results in severe side effects, and other therapeutic options are needed to prevent steroid toxicity.⁴ A 2- to 3-month course of cyclophosphamide or chlorambucil has been shown to produce a longer remission period in many patients⁵; however, these drugs may have serious side effects and their long-term efficacy is limited.^6,7 Levamisole has been shown to reduce the risk of relapse in several small studies, but information is limited regarding long-term efficacy and adverse effects, and the drug is currently not available in most countries. Treatment with cyclosporin A (CsA) is highly effective in maintaining remission in patients with FR-SSNS allowing withdrawal of corticosteroids, but most patients relapse after withdrawal of CsA.⁸ Importantly, prolonged CsA therapy is accompanied by time- and dose-dependent nephrotoxicity.⁹Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a non-nephrotoxic immunosuppressive drug with inhibitory effects on T and B lymphocytes, cell-surface markers, and cytokine gene expression¹⁰ and has proven efficacy and tolerability in renal allograft recipients. Several small studies with limited statistical power have shown that MMF has steroid-sparing effects and reduces relapse rates in patients with FR-SSNS, albeit with varying efficacy.^11–18We studied efficacy and safety of MMF in patients with FR-SSNS in comparison with CsA in a prospective randomized multicenter open-label crossover trial.     

Fifteen-year remission of a steroid-resistant nephrotic syndrome sustained by cyclosporine A

Many children with a late steroid-resistant nephrotic syndrome (SRNS) and focal glomerulosclerosis have a poor prognosis and enter end-stage renal failure (ESRF) within five years. Reports are scarce on the long-term follow-up of patients entering remission while receiving immunosuppressive therapy after steroids have failed. A two-year-old boy with focal and segmental glomerulosclerosis having both late steroid and cyclophosphamide resistance entered complete remission of the SRNS almost two years after starting induction therapy with cyclosporine A (CSA). During the 15-year follow-up, the patient experienced five relapses during CSA maintenance therapy. All relapses were successfully treated within 10 days by intravenous methylprednisolone pulses in addition to CSA. The relapses were accompanied by a drop in the glomerular filtration rate (GFR). At the age of 18 years, the patient had grade II chronic kidney disease (GFR=61 ml/min/1.73 m²). At the age of 14 years, mycophenolate mofetil (MMF) was added to the maintenance therapy and the CSA dosage was reduced. Two renal biopsies at the ages of 10 and 18 years failed to detect CSA nephrotoxicity. We conclude that children with SRNS may have long-term benefit from a combination therapy using intravenous methylprednisolone pulses and CSA.     

Treatment with mycophenolate mofetil and prednisolone for steroid-dependent nephrotic syndrome

The management of patients with steroid-dependent nephrotic syndrome (SDNS) refractory to treatment with long-term steroids, levamisole and cyclophosphamide is difficult. We report our experience on long-term treatment with mycophenolate mofetil (MMF) and alternate-day prednisolone in 42 patients with SDNS previously treated with levamisole (n = 35) and/or cyclophosphamide (n = 37). The mean age (range) at onset of nephrotic syndrome was 37 (13–92) months and at treatment with MMF 104.7 (32–187) months. MMF was administered at a mean daily dose of 26.5 (16.6–31.3) mg/kg for 14.3 (6–45) months. The mean 6-monthly relapse rates decreased from 3.0 episodes before therapy to 0.9 episodes in the first 6 months, 0.7 in next 6 months, and 0.3 in those treated longer than 12 months (P < 0.0001). While on therapy, 32 (76.2%) patients showed 50% or more reduction in relapse rates, and nine (21.4%) had sustained remission. The cumulative dose of prednisolone declined significantly from 0.6 mg/kg per day before to 0.3 mg/kg per day while receiving MMF. Prednisolone requirement was reduced by 50% or more in 16 patients and between 40% and 50% in eight patients. Treatment continuation beyond 12 months resulted in sustained steroid sparing and reduced need for alternative treatments while maintaining low relapse rates. No patients had diarrhea, hematological abnormalities, or impaired renal function. This data confirms the efficacy and safety of treatment with MMF and tapering doses of alternate-day prednisolone in patients with SDNS and supports its use for longer than 12 months.     

Association of steroid and cyclosporin resistance in focal segmental glomerulosclerosis

Given the variable response of steroid-resistant nephrotic syndrome (SRNS) to treatment with cyclosporin (CsA), it may be inappropriate to expose all SR patients to additional immunosuppression. How to determine from which patients to withhold CsA is unclear. We tested the hypothesis that in patients with primary focal segmental glomerulosclerosis (FSGS), steroid resistance predicts CsA resistance. We studied 16 children with steroid-dependent (SD) or steroid-resistant (SR) histologically confirmed primary FSGS treated with CsA with no prior exposure to other immunosuppressive medications. All had received at least 4 weeks of daily prednisone, followed by addition of CsA aiming at trough levels of 200 ng/ml. Of the 16 patients, nine (56%) were SR, of whom seven (78%) were CsA resistant and two (22%) were CsA responsive. Seven patients (44%) were SD; all of them (100%) were CsA responsive (P = 0.003, Fisher’s exact test). SR patients had faster deterioration of glomerular filtration rate (GFR) over a median follow-up of 21 months (P = 0.06). These data demonstrate that in primary FSGS, steroid resistance may predict CsA resistance. Genetic testing for known mutations associated with resistance to immunosuppression may be advisable before treatment of SR-FSGS patients with cyclosporin. Prospective studies should be conducted to explore this hypothesis.     

Unfavorable response to cyclophosphamide in steroid-dependent nephrotic syndrome

Development of steroid dependency represents a significant therapeutic challenge in steroid-sensitive nephrotic syndrome. Previous studies have shown conflicting results concerning the benefit of a 12-week treatment with cyclophosphamide (CPO), with 24%–67% of patients achieving long-term remission. We therefore analyzed the clinical response of 20 consecutive children with steroid-dependent nephrotic syndrome (SDNS) (12 male, median age at start of treatment 5.9 years, range 3.2–14.7 years) treated at our institution with CPO (2 mg/kg per day) for 12 weeks since 1989. Median duration of follow-up was 5.8 (range 1.1–9.25) years. Only 6 of 20 children (30%) showed a long-term remission of >2 years, while 14 of 20 (70%) developed relapses again. Of these, 12 patients (86%) again developed steroid dependency, requiring further alternative treatment. Our data show that a 12-week course of CPO leads to unfavorable results in the majority of patients with SDNS. We therefore conclude that there is a need for further optimization of therapy in SDNS. Received: 16 August 1999 / Revised: 21 October 1999 / Accepted: 25 October 1999     

Follow-up of steroid-resistant nephrotic syndrome: tubular proteinuria and enzymuria

The aim of this study was to examine the compromise of proximal tubule cells in steroid-resistant nephrotic syndrome patients with a histologic diagnosis of focal segmental glomerulosclerosis (FSGS) through assessment of the urinary levels of β₂-microglobulin (β₂M) and N-acetyl-β-d-glucosaminidase (NAG) during active disease and remission over a follow-up period of 3 years. We studied 34 children with nephrotic syndrome: 12 with steroid-resistant nephrotic syndrome (SRNS) and massive proteinuria, 7 with steroid-dependent nephrotic syndrome (SDNS) and 15 with steroid-sensitive nephrotic syndrome (SSNS). Of the SSNS patients, 8 children were in remission (RM) and 7 were in relapse (RL). Seven healthy children were included as controls. Urinary β₂M, measured by enzyme-linked immunosorbent assay, was significantly increased in the SRNS group as compared to the SDNS group (P<0.01), SSNS in remission (P<0.01), and controls (P<0.01). There were no differences between the SRNS group and SSNS in relapse. Analysis of urinary N-acetyl-β-d-glucosaminidase (U-NAG) by colorimetric assay showed significantly higher values in the SRNS group of patients than in SDNS, SSNS, and control groups. A positive correlation between U-NAG and proteinuria was demonstrated (r=0. 73, P<0.01). The SRNS group of patients (n=12, 11 with a histologic diagnosis of FSGS and one with diffuse mesangial proliferation) was treated with the same protocol of i.v. methylprednisone and oral cyclophosphamide. Long-term follow-up showed a progressive decrease in U-β₂M and U-NAG excretion to control values in the 3rd year, except in one patient who did not respond to the treatment. In the FSGS patients, evaluation of the contribution of structural interstitial histological abnormalities, including each of the histological parameters considered in interstitial scarring to the functional tubule abnormalities assessed by β₂M and NAG excretion, was performed by multiple regression analysis. The r ² values for β₂M and NAG were 53.99%, P=0.19, and 57.90%, P=0.14, respectively; neither was significant. We conclude that: (1) proximal tubule cell dysfunction, partially affected by massive albuminuria, may account for the higher values of β₂M and NAG excretion in the SRNS patients and (2) urine β₂M and NAG levels are not helpful in identifying histological evidence of structural tubulointerstitial damage in children with steroid-resistant nephrotic syndrome. Received: 28 December 1999 / Revised: 20 July 2000 / Accepted: 21 July 2000