Abstract
Background
Idiopathic nephrotic syndrome (NS) in children is classified as steroid sensitive or steroid resistant. Steroid sensitivity typically portends a low risk of permanent renal failure. However, some initially steroid-sensitive patients later develop steroid resistance. These patients with late steroid resistance (LSR) are often treated with immunosuppressant medications, but the effect of these additional drugs on the long-term prognosis of LSR is still unknown.
Methods
A retrospective chart review was performed on patients diagnosed with idiopathic NS and subsequent LSR during the 8-year study period from 2002 up to and including 2009, with a minimum of 2 years of follow-up. Primary outcome measures were proteinuria and renal function.
Results
A total of 29 patients were classified as having LSRNS. The majority of patients received treatment with calcineurin inhibitors and/or mycophenolate mofetil. Seven patients received three or more non-steroid immunosuppressant medications. Sustained complete or partial remission was achieved in 69 % of patients. Three developed end-stage renal disease, and all others maintained normal renal function. There were 13 episodes of serious adverse events, none of which were fatal or irreversible.
Conclusion
Most patients with LSRNS responded to immunosuppressive therapy by reduction or resolution of proteinuria and preservation of renal function. The results suggest that immunosuppressive treatment is a viable option in NS patients who develop LSR.
Keywords: Steroid-resistant nephrotic syndrome, Late steroid-resistant nephrotic syndrome, Outcome of nephrotic syndrome, Immunosuppressant therapy, Adverse events of immunosuppression
Introduction
Idiopathic nephrotic syndrome (NS) in children is classified as steroid sensitive or steroid resistant [1, 2]. Steroid sensitivity is most often associated with minimal change histology and a more favorable long-term prognosis, whereas steroid resistance is frequently associated with focal segmental glomerulosclerosis (FSGS) histology and carries a high risk of progression to end-stage renal disease (ESRD) [2–4]. Some initially steroid-sensitive patients later develop steroid resistance, sometimes with histologic progression to FSGS. In our previously published series of 163 patients with new-onset idiopathic NS, 115 (63 %) patients were initially steroid sensitive, but 19 (17 %) of this cohort later became steroid resistant, usually within the first year [5]. Patients who develop late steroid resistance (LSR) are often treated with additional, potentially toxic immunosuppressant medications [6]. Very little information is available on the long-term outcome of these children. Intensified immunosuppressant regimens using alkylating agents [7], calcineurin inhibitors (CNIs) [8], mycophenolate mofetil (MMF) [9, 10] and rituximab (RTX) [10, 11] variably achieve remission in patients with primary steroid resistance, with remission induced with these agents possibly being temporary, sustained only during therapy, or permanent. Exposure to multiple drugs in series or concurrently increases the risk of side effects [12]. Moreover, the impact of intensified immunosuppression on long-term prognosis is unknown.
The goal of our multi-center retrospective observational study was to assess the renal outcome of patients with LSR, along with the risks and benefits of additional immunosuppressant therapy. We hypothesized that patients with LSR frequently respond to other immunosuppressant medications. The main outcome measures were proteinuria and renal function. Additional objectives were to determine the role of age, gender, and ethnicity on the response and incidence of serious adverse effects associated with use of non-steroid immunosuppressant drugs.
Subjects and methods
This study was conducted in collaboration with eight participating centers from the Midwest Pediatric Nephrology Consortium (MWPNC): Louisiana State University Health Sciences Center, Nationwide Children’s Hospital, Duke University, University of Michigan, University of Minnesota Amplatz Children’s Hospital, Children’s Mercy Hospital, University of North Carolina, and Emory University. Each center obtained Institutional Review Board approval prior to commencing the study. A retrospective chart review was performed on all patients diagnosed with idiopathic NS and subsequent LSR during the 8-year study period from 2002 up to and including 2009, with a minimum of 2 years of follow-up. In an effort to avoid selection bias, charts of all new-onset nephrotic patients aged ≤18 years during the study period were reviewed at each participating center. LSR was defined as: (1) initial complete remission of proteinuria in response to steroids and (2) subsequent resistance or partial response (persistence of proteinuria) to a minimum of 4 weeks of full-dose (2 mg/kg/day, maximum of 60 mg/day) steroid treatment. Patients with steroid dependence and those with frequent relapses (if steroid-sensitive) were excluded. There was no exclusion based on gender, race, or ethnicity.
Demographic and anthropometric variables, blood pressure, and laboratory data serum creatinine, serum albumin, random urine protein:creatinine ratio [Up/c (mg/mg) or urine dipstick] were reported at the time of initial diagnosis of NS and during the follow-up. Estimated glomerular filtration rate (eGFR, ml/min/1.73 m2) was calculated using the original Schwartz formula (k=0.55) based on Jaffe’s method or by the enzymatic method of plasma creatinine measurement used during the study period [13–15]. Time to remission during the initial steroid treatment and time to development of LSR after the diagnosis of NS were reported. For each non-steroid immunosupressive drug used, the duration of use as well as laboratory results at initiation and end of therapy were reported. If multiple drugs were used in sequence, the order was recorded. Although renal biopsy was not an inclusion requirement, all biopsy results were also reported. The biopsies were read by the renal pathologist at each center.
Response to individual drugs was defined by nadir Up/c during the treatment period with each drug as follows: complete remission (CR; Up/c <0.2 mg/mg or urine dipstick negative or trace), partial remission (PR; Up/c decreased by >50 % and <2.0 mg/mg or urine dipstick 1+ to 2+), or no response (NR; Up/c >2.0 mg/mg or urine dipstick 3+ to 4+). Dipstick readings were only used when Up/c was not available. The same criteria were used for assessing the final outcome at the most recent visit. Concomitant steroid use during each treatment period was reported as continuous (>50 % of the time), partial (<50 % of the time), or none.
Serious adverse events with each individual drug, specified as death, sepsis, peritonitis, cellulitis, or any condition requiring hospitalization, were recorded. Progression to ESRD and renal transplant, if applicable, were reported.
Statistical analysis was performed using GraphPad Prism ver. 4.0 (GraphPad Software, San Diego, CA). One-way analysis of variance and the Kruskal–Wallis test were used to compare means and medians, respectively. Means ± standard deviation and medians with range are reported.
Results
Characteristics of LSR population
A total of 29 patients developed LSR during the study period. All 29 patients had documentation of CR in response to an initial course of empiric steroid therapy, with a median time to initial remission of 14 days (range 4–56 days). The pediatric patient cohort comprised 19 males (66 %) and ten females (34 %) with a mean age at diagnosis of NS of 4.3±3.4 years. Mean eGFR, serum albumin, and Up/c at initial diagnosis of NS were 123.0±33.3 ml/min/1.73 m2, 1.9±0.7 g/dL, and 14.1±17.1 mg/mg, respectively. One patient had decreased eGFR at onset (38 ml/min/1.73 m2). Median time from the diagnosis of NS to the development of LSR was 19 months (range 2–170 months). Patient characteristics at initial diagnosis of NS are presented in Table 1.
Table 1.
Patient characteristics
| Patient characteristics | Caucasian | African American | Hispanic/other |
|---|---|---|---|
| N (% of total patients) | 12 (41) | 12 (41) | 5 (17) |
| Male:female | 9:3 | 7:5 | 3:2 |
| Age at diagnosis of NS (years) | 5.3±3.9 | 4.1±3.3 | 2.7±1.0 |
| Casual BP>90th percentilea (% of patients) | 30 % | 50 % | 50 % |
| Initial eGFR (ml/min/1.73 m2) | 124.2±31.5 (n=9) | 117.9±41.2 (n=6) | 132.8±29.9 (n=2) |
| Initial serum albumin (g/dL) | 2.0±0.8 (n=9) | 1.9±0.8 (n=9) | 1.7±0.1 (n=2) |
| Initial Up/c (mg/mg) | 17.7±18.6 (n=8) | N/A | N/A |
| Time to first remission (days) | 10 (4–56) (n=9) | 13 (5–37) | 15 (15–30) (n=3) |
NS, Nephrotic syndrome; BP, blood pressure; eGFR, estimated glomerular filtration rate; Up/c, urine protein:creatinine ratio; N/A, not available or n<2
Results are expressed as mean ± standard deviation (SD) or as the median with the range in parenthesis
Based on age, gender and height
Immunosuppressant treatment and response
Of the 29 patients with LSR 28 received a total of 59 courses of intensified immunosuppressant regimens with non-steroid medications over the study period. Table 2 shows the length of each treatment period as well as the immediate response to each individual treatment course. Overall, CR or PR was achieved in 67–87 %, with a numerically higher rate in CNI-treated patients compared to alkylating agents or MMF, but the difference did not reach statistical significance. There was no difference in the response rate between cyclosporine (CsA) and tacrolimus (Tac). One patient received supportive treatment with angiotensin-converting enzyme inhibitor (ACE-I) only and remained in PR.
Table 2.
Immunosuppressant drugs: exposure and response
| Drug | N | Total exposure (days) | CR | PR | NR | Remissionb with drug (%) | Number of adverse events (%) |
|---|---|---|---|---|---|---|---|
| Alkylating agents | 9 | 90±42 | 2 | 4 | 3 | 67 | 2 (22) |
| Cyclosporine | 15 | 961±1,054 | 6 | 7 | 2 | 87 | 4 (27) |
| Tacrolimus | 13 | 612±363 | 6 | 5 | 2 | 85 | 5 (38) |
| Mycophenolate mofetil | 18 | 486±305 | 4 | 8 | 6 | 67 | 2 (11) |
| Rituximab | 4 | 1–2 (doses) | 1 | 2 | 1 | 75 | 0 |
| Nonea | 1 | – | – | 1 | – | 100 | 0 |
CR, complete remission (Up/c <0.2 mg/mg or urine dipstick negative or trace); PR, partial remission (Up/c decreased by >50 % and <2.0 mg/mg or urine dipstick 1+ to 2+); NR, no response (Up/c >2.0 mg/mg or urine dipstick 3+ to 4+)
Data are presented as the mean ± SD where appropriate
No additional immunosuppressant therapy: angiotensin-converting enzyme inhibitor (ACE-I) treatment only
CR or PR at the end of treatment course with individual drug
Ten patients (34 %) received only a single non-steroid immunosuppressant drug with either an alkylating agent (2 patients), CNI (6), or MMF (2). Of these ten patients eight had either a CR or PR. Four of six patients treated with CNIs alone achieved CR—two with CsA and two with Tac.
Eighteen patients (62 %) received two or more immunosuppressant medications over the study period because they were unable to achieve CR with a single drug or had a relapse of the disease. Eleven patients received two immunosuppressant medications. The most frequent sequential combination treatment was CNI and MMF which was successful in achieving CR or PR in four of nine treated patients. Five patients received three immunosuppressant drugs, and three of these patients achieved CR or PR. Two patients received four immunosuppressant medications over the study period. Five patients received combinations of immunosuppressive drugs concurrently instead of sequentially.
Data on concomitant steroid use was missing for two patients. The majority of patients (25/27) received steroids with the immunosuppressive drugs, despite being categorized as LSR. Of these 25 patients, 18 received steroids for >50 % of the total treatment time, and seven received steroids for <50 % of the total treatment time; there was no significant difference in response rate between these two groups.
Adverse events
Thirteen episodes of serious adverse events were reported, as presented in Table 2. Adverse events associated with alkylating agents were viral encephalitis and peritonitis. Adverse effects of CNIs included rhabdomyolysis, bacteremia, posterior reversible encephalopathy syndrome and status epilepticus associated with CsA, as well as nephrotoxicity (2 patients), acute kidney injury (2), and peritonitis associated with Tac. The use of MMF was associated with one episode each of sepsis and peritonitis.
Final outcome
Table 3 illustrates the outcome after a mean follow-up period of 85±47 months from the initial diagnosis of NS. There were no statistically significant differences between the racial/ethnic groups. At most recent follow-up, 14 of the 29 patients (48 %) were in CR and six (21 %) were in PR. Six patients had nephrotic-range proteinuria (Up/c >2.0 mg/mg), and three patients had reached ESRD. Mean age at ESRD was 13.7± 4.8 years, and median time from development of LSR to ESRD was 7.3 years (range 4.3–8.9 years). Two patients underwent renal transplantation and one had FSGS recurrence in the allograft. No additional patients had an eGFR of <60/ml/min/1.73 m2.
Table 3.
Latest follow-up of late steroid-resistant nephrotic syndrome
| Patient characteristics | CR | PR | NR | ESRD |
|---|---|---|---|---|
| N (% of total patients) | 14 (48) | 6 (21) | 6 (21) | 3 (10) |
| Ethnicity (C:AA:O) | 7:5:2 | 3:2:1 | 1:3:2 | 1:2:0 |
| Sex (M:F) | 8:6 | 3:3 | 6:0 | 2:1 |
| Age (years) | 9.8±3.9 | 14.2±3.9 | 10.3±3.0 | 15.1±4.6 |
| Median time to LSR (months)а | 11.5 (2–84) | 21 (6–152) | 38.5 (6–112) | 58 (18–170) |
| Duration of follow-up (months) | 64.5 (24–160) | 72 (49–184) | 89 (48–126) | 134 (90–227) |
| eGFR (ml/min/1.73 m2) | 128.4±25.3 | 126.9±32.7 | 98.8±19.1 | N/A |
| Serum albumin (g/dL) | 4.2±0.4 | 3.7±0.6 | 1.6±0.6 | 3.0±2.0 (n=2) |
| Up/c (mg/mg) | 0.09±0.07 | 1.1±0.9 | 6.5±4.1 | N/A |
C:AA:O, Caucasian:African American:Other; LSR, late steroid resistance; ESRD, end-stage renal disease; N/A, not available or n<2
Data are presented as the mean ± SD or as the median with the range in parenthesis
p=0.07 median time to LSR vs. final outcome
There were no significant differences in final outcome based on the mean age at diagnosis of NS, or on the time from initial diagnosis to development of LSR. Patients who had no response to therapy or reached ESRD trended towards a significantly longer time to development of LSR after initial diagnosis of NS (p=0.07).
Table 4 shows the final outcome according to the total immunosuppression received. Of the 19 patients who had good long-term outcome (CR or PR), eight needed only a single drug to achieve it. However, CR or PR was also achieved by the majority (11/18) of those requiring two or more drugs. Three of four patients responded to RTX after their disease was not controlled by other immunosuppression.
Table 4.
Drug combinations versus final outcome
| Drug regimen | CR | PR | NR | ESRD |
|---|---|---|---|---|
| ACE-I only | – | 1 | – | – |
| Alkyl only | 1 | 1 | – | – |
| CNI only | 4 | – | 2 | – |
| MMF only | 2 | – | – | – |
| Alkyl + CNI | 1 | – | – | – |
| Alkyl + MMF | 1 | – | – | – |
| CNI + MMF | 2 | 2 | 3 | 2 |
| Alkyl + CNI + MMF | 2 | – | – | 1 |
| CNI + MMF + RTX | – | 1 | 1 | – |
| Alkyl + CNI + MMF + RTX | 1 | 1 | – | – |
ACE-I, Angiotensin-converting enzyme inhibitor; CNI, calcineurin inhibitor; MMF, mycophenolate mofetil; Alkyl, alkylating agent; RTX, rituximab
Histopathology
All study patients underwent a renal biopsy after LSR was diagnosed. The biopsy demonstrated minimal change disease (MCD) in 19 patients (66 %, 1 with positive C1Q by immunofluorescence), FSGS in seven patients (24 %), mesangial hypercellularity (MH) in two patients, and focal global glomerulosclerosis in one patient.
Eleven patients had one or more repeat biopsies later during their follow-up period. The most recent biopsy showed MCD in two patients (1 with positive immunoglobulin M staining by immunofluorescence), FSGS in seven patients, and MH in two patients. Six of nine patients with an initial diagnosis of MCD or MH demonstrated FSGS on repeat biopsy. One of the three patients who developed ESRD had MCD on the first biopsy and FSGS on a later biopsy; the other two who developed ESRD only had one biopsy each, which showed MCD in one patient and FSGS in the other.
Discussion
To our knowledge, this is the first report to systematically examine treatment results of LSRNS in children. Previous anecdotal evidence has suggested that at least some children respond to escalated immunosuppression and consequently, as shown by our results, additional immunosuppressive drugs are commonly used. However, long-term outcomes and risk of complications of such treatments are not well-defined.
The present study of 29 patients with LSR has two main clinically relevant findings. First, 69 % of the patients responded to the immunosuppressive drugs by achieving either CR or PR by the end of the follow-up period (Table 4). Individual drugs resulted in immediate CR or PR in 78 % of the 59 treatment courses given (Table 2); however, in many cases the effect was not sustained, requiring additional treatment (Table 4). Patients receiving CNIs had the highest percentage of remission, with nearly equivalent remission rates for CsA and Tac. Alkylating agents and MMF more frequently resulted in a PR versus CR, and patients receiving MMF had the highest frequency of NR (39 %). The duration of use of concomitant steroids did not affect final response. Almost all patients who were not in CR also received ACE-I or angiotensin receptor blocker treatment, thereby preventing separate evaluation of the efficacy of these drugs.
We were surprised to find that only three patients progressed to ESRD and that most maintained a normal eGFR. Although we did not have an untreated control group, reduction of proteinuria in FSGS and renal disease in general is believed to improve long-term outcome and reduce the risk of ESRD [16–18]. Therefore, our results suggest that the escalation of immunosuppression was beneficial in this cohort.
The second major finding is that the escalated immunosuppression was relatively safe in this high-risk population. Six patients remained in nephrotic state, which by itself carries a risk of serious complications. Although several serious adverse effects occurred, there were no deaths and no irreversible complications. With the possible exception of mild nephrotoxicity, we do not believe that serious side effects were missed because the participating centers were specifically instructed to report all hospitalizations in addition to specific diagnoses such as sepsis, pneumonia, cellulitis, and peritonitis. Therefore, we conclude that these treatments are relatively well tolerated. Very long-term side effects, such as lifetime risk of malignancy, obviously could not be assessed.
Because our cohort consisted of all LSR patients during the defined time period from eight large pediatric nephrology centers, we believe that the use of additional immunosuppressive drugs reflects the national pattern in the USA. With the introduction of newer drugs, including CNIs, MMF, and RTX, the use of conventional alkylating agents has decreased, comprising only 16 % of all treatment courses in the present study. At the time of the study, RTX was still an uncommon treatment in LSR patients. However, emerging evidence suggests that, in contrast to initially steroid-resistant patients, RTX may be effective in LSR [10, 11]; our results do not contradict those findings (Table 4). Only one of 29 patients did not receive any immunosuppressive drugs because he achieved spontaneous PR on ACE-I therapy only.
In contrast to our expectations, we observed no early predictors of LSR. The age of the patients was that of typical childhood NS patients. The time it took to achieve remission with steroids after the initial diagnosis of NS was not unexpectedly long. Long-term outcome was also not predictable by patient age, either at the initial diagnosis of NS or at the time LSR developed. Interestingly, however, a longer time interval to the development of LSR tended to result in poor outcome. We have no readily apparent explanation for this finding.
Our cohort included an equal number of Caucasian and African American children. Although numerically fewer African American children responded to the treatments, the number of subjects is too small to draw firm conclusions. The role of inherited disease was not assessed. However, because all patients initially responded to steroids, it is unlikely that any of the known genetic mutations associated with NS were prevalent in this cohort [19].
Renal histology was not a main objective in the study design, but all biopsy results were requested from the participating centers. Although not performed in a consistent manner, all patients had a biopsy when LSR was first documented, and many had follow-up biopsies. These provide some interesting observations. First, as shown previously by others, early renal biopsy is not always a good indicator of outcome. Of our 29 LSR patients, 20 had the diagnosis of MCD or MH based on histology, which is generally associated with steroid responsiveness and excellent long-term prognosis. Moreover, when 11 of these 20 patients underwent a second biopsy, the histologic diagnosis changed to FSGS in six of them. It is obvious that either the diagnosis based on the initial biopsy was missed due to sampling error or that the disease “progressed” to FSGS in these patients. Importantly, in this cohort of LSR patients, diagnosis based on histologic findings, either in the first or in a later biopsy, did not seem to correlate with outcome. This contrasts with the well-documented association of MCD with good outcome and that of FSGS with poor prognosis in childhood NS in general. We believe that the explanation of our results lies in the fact that the subjects were selected on the basis of LSR. The findings suggest that the emergence of steroid resistance may be a better prognostic indicator than renal histology.
In summary, our data suggest that most patients with LSR have a relatively good long-term outcome, with reduction of proteinuria and preservation of renal function, when treated with immunosuppressive medications. The results are consistent with our hypothesis that patients with LSR frequently respond to non-steroid immunosuppressive therapy. Although serious adverse events were seen, none resulted in permanent morbidity. Therefore, we consider the risk–benefit ratio of these treatments favorable.
The limitations of the study include its retrospective nature and lack of an untreated control group. A randomized trial would be required to assess the value of each drug; however, with the widespread use and presumed efficacy of the immunosuppressive drugs in LSR, a future placebocontrolled trial is unlikely. The source documents did not always have complete data, particularly at the time of initial diagnosis. In some instances, quantitative Up/c levels were not available and had to be substituted by dipstick readings. CNI drug level data were not collected, raising the possibility of inadequate or toxic dosing, and neither was CNI toxicity systematically assessed by repeat biopsies. The degree of adherence to medications could not be assessed in this retrospective study. Finally, a longer follow-up period might have revealed less favorable outcomes in some patients.
Acknowledgments
We are grateful to Corinna Bowers and the MWPNC for their help and participation in this study.
Contributor Information
Caroline Straatmann, Department of Pediatrics, Louisiana State University Health Sciences Center, 200 Henry Clay Avenue, New Orleans, LA 70118, USA.
Rose Ayoob, Nationwide Children’s Hospital, Columbus, OH, USA.
Rasheed Gbadegesin, Department of Pediatrics, Duke University, Durham, NC, USA.
Keisha Gibson, Department of Medicine and Pediatrics, University of North Carolina, Chapel Hill, NC, USA.
Michelle N. Rheault, University of Minnesota Amplatz Children’s Hospital, Minneapolis, MN, USA
Tarak Srivastava, Children’s Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA.
Cheryl L. Tran, Department of Pediatrics, Mayo Clinic, Rochester, MN, USA
Debbie S. Gipson, Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, MI, USA
Larry A. Greenbaum, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA, USA
William E. Smoyer, The Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
V. Matti Vehaskari, Department of Pediatrics, Louisiana State University Health Sciences Center, 200 Henry Clay Avenue, New Orleans, LA 70118, USA.
References
- 1.Gipson D, Massengill S, Yao L, Nagaraj S, Smoyer W, Mahan J, Wigfall D, Miles P, Powell L, Lin J, Trachtman H, Greenbaum L (2009) Management of childhood onset nephrotic syndrome. Pediatrics 124:747–757 [DOI] [PubMed] [Google Scholar]
- 2.International Study of Kidney Disease in Children (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. Report of the International Study of Kidney Disease in Children J Pediatr 98:561–564 [DOI] [PubMed] [Google Scholar]
- 3.Del Rio M, Kaskel F (2008) Evaluation and management of steroid-unresponsive nephrotic syndrome. Curr Opin Pediatr 20:151–156 [DOI] [PubMed] [Google Scholar]
- 4.McBryde K, Kershaw D, Smoyer W (2001) Pediatric steroid-resistant nephrotic syndrome. Curr Probl Pediatr Adolesc Health Care 31:275–307 [DOI] [PubMed] [Google Scholar]
- 5.Kim J, Bellew C, Silverstein D, Aviles D, Boineau F, Vehaskari V (2005) High incidence of initial and late steroid resistance in childhood nephrotic syndrome. Kidney Int 68:1275–1281 [DOI] [PubMed] [Google Scholar]
- 6.Ehrich J, Pape L, Schiffer M (2008) Corticosteroid-resistant nephrotic syndrome with focal and segmental glomerulosclerosis. an update of treatment options for children. Paediatr Drugs 10:9–22 [DOI] [PubMed] [Google Scholar]
- 7.International Study of Kidney Disease in Children (1974) Prospective, controlled trial of cyclophosphamide therapy in children with nephrotic syndrome. Report of the International Study of Kidney Disease in Children Lancet 2:423–427 [PubMed] [Google Scholar]
- 8.Plank C, Kalb V, Hinkes B, Hildebrandt F, Gefeller O, Rascher W, Arbeitsgemeinschaft für Pädiatrische Nephrologie (2008) Cyclosporine A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome - a randomized controlled multicentre trial by the Arbeitsgemeinschaft für Pädiatrische Nephrologie. Pediatr Nephrol 23:1483–1493 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Gipson D, Trachtman H, Kaskel F, Greene T, Radeva M, Gassman J, Moxey-Mims M, Hogg R, Watkins S, Fine R, Hogan S, Middleton J, Vehaskari V, Flynn P, Powell L, Vento S, McMahan J, Siegel N, D’Agati V, Friedman A (2011) Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int 80:868–878 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, Benetti E, Murtas C, Messina G, Massella L, Porcellini M, Montagna M, Regazzi M, Scolari F, Ghiggeri G (2012) Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 23:1117–1124 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Prytula A, Lijima K, Kamei K, Geary D, Gottlich E, Majeed A, Taylor M, Marks S, Tuchman S, Camilla R, Ognjanovic M, Filler G, Smith G, Tullus K (2010) Rituximab in refractory nephrotic syndrome. Pediatr Nephrol 25:461–468 [DOI] [PubMed] [Google Scholar]
- 12.Habashy D, Hodson E, Craig J (2006) Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev 2:CD003594 [DOI] [PubMed] [Google Scholar]
- 13.Srivastava T, Alon U, Althahabi R, Garg U (2009) Impact of standardization of creatinine methodology on the assessment of glomerular filtration rate in children. Pediatr Res 65:113–116 [DOI] [PubMed] [Google Scholar]
- 14.Schwartz G, Haycock G, Edelmann C, Spitzer A (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259–263 [PubMed] [Google Scholar]
- 15.Schwartz G, Muñoz A, Schneider M, Mak R, Warady B, Furth S (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Troyanov S, Wall C, Miller J, Scholey J, Cattran D, Toronto Glomerulonephritis Registry Group (2005) Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J Am Soc Nephrol 16:1061–1068 [DOI] [PubMed] [Google Scholar]
- 17.Gipson D, Chin H, Presler T, Jennette C, Ferris M, Massengill S, Gibson K, Thomas D (2006) Differential risk of remission and ESRD in childhood FSGS. Pediatr Nephrol 21:344–349 [DOI] [PubMed] [Google Scholar]
- 18.Gipson D, Gibson K, Gipson P, Watkins S, Moxey-Mims M (2007) Therapeutic approach to FSGS in children. Pediatr Nephrol 22:28–36 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Büscher A, Kranz B, Büscher R, Hildebrandt F, Dworniczak B, Pennekamp P, Kuwertz-Bröking E, Wingen A, John U, Kemper M, Monnens L, Hoyer P, Weber S, Konrad M (2010) Immunosuppression and renal outcome in congenital and steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 5:2075–2084 [DOI] [PMC free article] [PubMed] [Google Scholar]