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Initial Steroid Sensitivity in Children withSteroid-Resistant Nephrotic Syndrome PredictsPost-Transplant Recurrence

Wen Y. Ding,*† Ania Koziell,‡§ Hugh J. McCarthy,*† Agnieszka Bierzynska,†

Murali K. Bhagavatula,| Jan A. Dudley,* Carol D. Inward,* Richard J. Coward,*†

Jane Tizard,* Christopher Reid,‡ Corinne Antignac,¶ Olivia Boyer,¶ and Moin A. Saleem*†

*Department of Paediatric Nephrology, Bristol Royal Hospital for Children, Bristol, United Kingdom; †Academic RenalUnit, University of Bristol, Southmead Hospital, Bristol, United Kingdom; ‡Department of Paediatric Nephrology,Evelina Children’s Hospital, London, United Kingdom; §Department of Experimental Immunobiology, King’s CollegeLondon, Guy’s Hospital, London, United Kingdom; |Children’s Hospital for Wales, Cardiff, United Kingdom; and ¶PediatricNephrology, French Institute of Health and Medical Research Unit 983, Necker Hospital for Sick Children, Paris, France

ABSTRACTOf children with idiopathic nephrotic syndrome, 10%–20% fail to respond to steroids or develop second-ary steroid resistance (termed initial steroid sensitivity) and the majority progress to transplantation.Although 30%–50% of these patients suffer disease recurrence after transplantation, with poor long-termoutcome, no reliable indicator of recurrence has yet been identified. Notably, the incidence of recurrenceafter transplantation appears reduced in patients with steroid-resistant nephrotic syndrome (SRNS) due tomonogenic disorders. We reviewed 150 transplanted patients with SRNS to identify biomarkers that consis-tently predict outcomeofSRNSafter transplantation. In all, 25 childrenhadgenetic or familial SRNSanddid notexperience post-transplant recurrence. We reviewed phenotypic factors, including initial steroid sensitivity,donor type, age, ethnicity, time to ESRD, and time on dialysis, in the remaining 125 children. Of these patients,57 (45.6%) developed post-transplant recurrence; 26 of 28 (92.9%) patients with initial steroid sensitivity re-curred after transplantation, whereas only 26 of 86 (30.2%) patients resistant from the outset recurred (oddsratio, 30; 95% confidence interval, 6.62 to 135.86; P,0.001). We were unable to determine recurrence in twopatients (onewith initial steroid sensitivity), and ninepatients did not receive initial steroids.Ourdata show thatinitial steroid sensitivity is highly predictive of post-transplant disease recurrence in this pediatric patientpopulation. Because a pathogenic circulating permeability factor in nephrotic syndrome remains to be con-firmed, we propose initial steroid sensitivity as a surrogate marker for post-transplant recurrence.

J Am Soc Nephrol 25: ccc–ccc, 2014. doi: 10.1681/ASN.2013080852

Idiopathic steroid-resistant nephrotic syndrome(SRNS), interchangeably termed by the commonhistologic description of FSGS, is one of the com-monest causes of end stage renal failure (ESRF) inchildhood and children with SRNS are the mostprevalent group in the US dialysis registry (compris-ing 14.4% of all pediatric dialysis patients).1 Approx-imately 50%–60% of children with SRNS eventuallyrequire a renal transplant. Unfortunately, this groupof patients has a high incidence of disease recurrence,with rates as high as 50% reported.2–4 Several studieshave examined possible risk factors for recurrence.To date, non–African-American race, previous

recurrence after transplantation, and time ,3 yearsto ESRF have been proposed to directly correlate withan increased risk of recurrence.5–7

Received August 10, 2013. Accepted October 8, 2013.

W.Y.D. and A.K. contributed equally to this work.

Published online ahead of print. Publication date available atwww.jasn.org.

Correspondence: Dr. Moin Saleem, Academic Renal Unit, Univer-sity of Bristol, Second Floor, Learning and Research, SouthmeadHospital, Bristol BS10 5NB, UK. Email: m.saleem@bristol.ac.uk

Copyright © 2014 by the American Society of Nephrology

J Am Soc Nephrol 25: ccc–ccc, 2014 ISSN : 1046-6673/2506-ccc 1

Recent advances in our knowledge of the genetics of SRNShave highlighted the potential importance of gene mutations inhelpingtopredictriskofdiseaserecurrence, themajorityofwhichcause structural/signaling changes at the filtration barrier.8

Specifically, a number of studies have shown that patients withautosomal recessive SRNS and either homozygous or compoundheterozygous mutations in NPHS2 (which encodes podocin, aslit diaphragm protein) have very low recurrence rates of 0%–

3% after transplantation.6,9,10 On the other hand, haploinsuffi-cient and apparently sporadic individuals with only a singleheterozygous NPHS2 variant (e.g., R229Q) appear to have sim-ilar recurrence rates to those with no genemutation identified.6,10

However, the contribution of genetic background remains in-completely understood, because another study was unable toreplicate these data and showed no recurrences inNPHS2 hap-loinsufficiency.9 Nonetheless, the true genotype may not havebeen recognized with the other pathogenic SRNS mutationremaining unidentified, and additionally, digenic inheritancehas been described in some forms of SRNS.11 Mutations pres-ent in other key podocyte genes such as NPHS1 or WT1 aresimilarly associated with a low risk of disease recurrence. Pa-tients with genetic mutations also appear to have a reducedresponse to immunosuppression (17% versus 68% in onestudy) and progress more quickly to ESRF.12

AT cell–derived circulating factor responsible for nephroticsyndrome was initially proposed in 1974.13 To date, a numberof possible candidates have been identified, including hemo-pexin, cardiotrophin-like cytokine 1, and soluble urokinase-type plasminogen activator receptor.14,15 Subsequent workhas been supportive of this circulating factor being responsiblefor SRNS recurrence after transplantation.16 Because the ma-jority of patients with podocyte gene mutations appear to beresistant to immunosuppression and do not develop recurrentdisease after transplantation, and the evidence suggests thatthe circulating factor is immunologically derived, we hypoth-esized that initial steroid sensitivity is a marker for circulatingfactor/idiopathic nephrotic syndrome, which segregates to ahigher risk of post-transplant recurrence.

For idiopathic SRNS in childhood, we analyzed the followingpotential risk factors: young age at diagnosis, rapid progression toESRF, young age at transplant, positive family history, and ex-trarenal abnormalities thatmight suggest anunderlying syndrome(predictive of genetic mutation) versus initial steroid sensitivity,late-onset disease, lack of family history, no evidence of extrarenalfeatures, and lack of an identified single gene mutation. We thenexamined whether each factor had an increased risk of diseaserecurrence and whether any of these parameters could be reliablyidentified as risk factors for post-transplant recurrence.

RESULTS

We identified 150 patients transplanted for ESRF secondary toSRNS between 1981 and 2012 in three large pediatric renaltransplant centers in the United Kingdom and France. Of

these patients, 57 (38%) had documented post-transplantrecurrence and 91 had no recurrence (60.7%). It was notpossible to determine outcome in two patients because onebecame anuric after transplantation and died 1 month later,and the second patient developed irrecoverable graft throm-bosis within 24 hours and required transplant nephrectomy.The first patient was initially steroid sensitive, whereas thesedata were unavailable for the second patient.

Patient characteristics in the recurring and nonrecurringgroups are shown in Table 1. In brief, participants were clas-sified by race as follows: 115 patients were Caucasian, 17 wereNorth African, 6 were Afro-Caribbean, 5 were East African, 4were Indian or Pakistani, 1 was of other Asian race, 1 was ofmixed race (white and black Caribbean), and 1 was of un-known race. The median age of patients at diagnosis was 4.0years (range, 0.3–15.5), median time to ESRF was 3.0 years(range, 0–17), andmedian age at first transplant was 11.5 years(range, 2.5–23.5).

The 57 patients with post-transplant recurrence had almostdouble the rate of complications, graft loss, and subsequentretransplantation compared with patients who did not haverecurrence (28% versus 16.5%). One patient underwent threetransplants; graft losswas attributed to rejection in thefirst two(with primary nonfunction) and recurrence in the third graft.Anadditional 10patientshad two transplants.Twopatients hadthrombosis or renal vein occlusionwith thefirst graft, followedby disease recurrence in the second graft. The histopathologicreports of the removed grafts showed extensive necrosis in thefirst patient and hemorrhagic infarction in the second patient,with no evidence of recurrence in either. In eight patients, graftloss was due to disease recurrence in both transplants. Fivepatients lost their first graft due to recurrence and were notretransplanted. Of the 91 patients without recurrence, 15patients lost their grafts. One patient had four transplants and11 had two transplants; the remaining 3 patients did not haveretransplants.

Genetic Mutations and Family HistoryGenetic testing (either by conventional Sanger sequencing oran extended gene panel by Next Generation Sequencing17) in62 of 150 patients revealed 18 pathogenic mutations. Of the 62tested patients, 7 had pathogenic NPHS2 mutations, 4 hadWT1 splicing mutations (2 with Frasier syndrome and 2with Denys–Drash syndrome), 1 had a pathogenic NPHS1mutation, 1 had an unbalanced chromosomal translocationbetween chromosomes 2 and 6, 1 had a COQ2 mutation, 1had a PLCE1mutation, 1 had a SMARCAL1mutation, 1 had aTRPC6 mutation, and 1 was heterozygous for NPHS1 andheterozygous for NPHS2 mutations. None developed post-transplant recurrence. Of 62 patients, 3 carried heterozygouschanges in NPHS2, but data mining using variant predictiontools and the human mutation database indicated that thesewere nonpathogenic. All three patients had recurrence of dis-ease. Another patient with recurrence had a NPHS1 heterozy-gous variant of unknown significance.

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Of 150 children (without extrarenal abnormalities/knowngenetic mutations), 3 had positive family histories of a first-degree relative with isolated SRNS. Two patients were siblings.An additional four children had extrarenal abnormalities withpositive family histories. Two patients were siblings withSchimke’s immune-osseous dysplasia, one had features of Gal-loway Mowat syndrome, and one was dysmorphic with car-diomegaly, cataracts, and learning disabilities. None of thesepatients had recurrence. One patient had a distant cousin withsteroid-sensitive nephrotic syndrome (SSNS) who recovered;therefore, this is more likely a chance association, rather than apositive family history, because SSNS has an increased inci-dence in this particular ethnic group. One patient had abrother who died at age 2 years, but the cause was unknown.There were four children with extrarenal abnormalitieswithout a positive family history or mutation. One patienthad pulmonary stenosis with infertility, one had developmentaldelay with epilepsy and hearing impairment, one had learningdisabilities, and one had sensorineural hearing loss, primaryT-cell immune deficiency, growth hormone deficiency, hypo-thyroidism, Addison’s disease, and external ophthalmoplegiawith a suspected mitochondrial cytopathy. The child withlearning disabilities and no other extrarenal features had a re-currence after transplantation.

There were 25 patients with pathogenic genetic mutations(n=18) and positive family histories (n=7). None of these pa-tients recurred after transplantation (odds ratio [OR], 0.02;95% confidence interval [95% CI], 0.001 to 0.39; P,0.001).Because patients with genetic mutations are known to have alow risk of recurrence, we excluded these 25 patients from thesubsequent analyses. We also excluded the two patients forwhom recurrence could not be determined.

Initial Steroid SensitivityInitial steroid sensitivity was defined as complete remission ofproteinuria (3 days of trace or negative proteinuria on dipstick

testing) on at least one episode after steroid therapy. Of 28patients with initial steroid sensitivity, 26 developed recurrentdisease after transplantation, comprising 45.6% (26 of 57) ofthe patients who recurred. One patient had initial steroidsensitivity but became anuric immediately after transplanta-tion and never recovered function. Although delayed graftfunction is a common presentation of early recurrence, we didnot include this patient as a definite recurrence because thepresence of proteinuria could not be established. In 9 of 123children, steroids were either not used initially (n=3) or thesepatients were in ESRF at presentation (n=6). Our resultsshowed that 26 of 28 patients (92.9%) with initial steroid sen-sitivity recurred after transplantation, whereas only 26 of 86(30.2%) of those resistant from the outset recurred. Initialsteroid sensitivity at presentation was an accurate and highlysignificant risk factor for recurrence (OR, 30; 95% CI, 6.62 to135.86; P,0.001) (Figure 1, Table 2). None of these patientshad extrarenal abnormalities.

We also performed a subgroup analysis of those patientswho had genetic testing and were found to have no geneticvariants. This group comprised 41 patients, 37 of whichreceived steroids initially. Of the 37 patients, 9 were initiallysteroid sensitive and 28 were steroid resistant. Recurrence washigher in the initially steroid-sensitive group (8 of 9; 88.9%)compared with the initially steroid-resistant group (15 of 28;53.6%), but this difference was not significant (OR, 6.93; 95%CI, 0.76–63.05; P=0.06).

Donor TypeA small proportion of patients (11 of 123) had living donortransplants. Living donor transplants confer an increased riskof recurrence (OR, 6; 95% CI, 1.24–29.06; P=0.02).

EthnicityWe compared African-European patients with non-African-European patients and found that there was no significant

Table 1. Patient characteristics

Characteristic Recurrence No Recurrence Unable to Determine Recurrence P Valuea

Patients (n) 57 91 2Ratio of male patients/female patients 1.02:1 1.38:1 0:2 0.40Ethnicity 0.13Caucasian (European/North American) 66.7 82.4 100Caucasian (North African) 17.5 7.7 0Afro-Caribbean 5.3 3.3 0East African 1.8 4.4 0Indian/Pakistani 5.3 1.1 0Other Asian 1.8 0 0Mixed race 1.8 0 0Unknown 0 1.1

Deceased donor 84.2 94.5 50 0.05Age at diagnosis (yr) 4.5 (0.7–12.5) 3.5 (0.3–15.5) 2 0.97Time to ESRF (yr) 4 (0–17) 3 (0–16) 7 0.09Age at first transplant (yr) 12.5 (3–23) 11 (2.5–23.5) 8.5 (7.5–9.5) 0.16

Data are presented as percentages or medians (ranges), unless otherwise indicated.aP value between the recurrence and nonrecurrence groups.

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difference in recurrence rates (OR, 0.92; 95% CI, 0.24 to 3.6;P.0.99). We included Afro-Caribbean and East African pa-tients in our African-European group.

Age at Diagnosis, Time to ESRF, Time on Dialysis, andAge at First TransplantNo significant difference was detected in age at diagnosis (OR,0.88; 95% CI, 0.39 to 1.9; P=0.84), time to ESRF (OR, 0.68;95% CI, 0.31 to 1.47; P=0.44), time on dialysis (P=0.18; OR,0.56; 95%CI, 0.26 to 1.19), or age at first transplant (OR, 0.74;95% CI, 0.36 to 1.53; P=0.47) (Figure 1, Table 2) between therecurrent and nonrecurrent groups.

DISCUSSION

Our study is the first to clearly identify a highly predictiveclinical feature for post-transplant disease recurrence in SRNS,and secondarily shows that the presence of genetic disease isprotective.

The mechanism remains speculative,but our data keep immune-mediated path-ogenicity in the spotlight. Anumber of linesof evidence point to a putative circulatingfactor being central to the pathogenicmechanisms in SSNS as well as recurrencein post-transplant SRNS.14 Although anumber of candidates have been proposed,the factor has not yet been conclusivelyidentified. This concept is supported bydocumented high rates of recurrence inSRNS after transplantation, response toplasma exchange, as well as supportive invitro data showing the deleterious effects ofdiseased plasma on isolated glomeruli,16

the slit diaphragm, the actin cytoskeleton,and podocyte motility.18 Furthermore, theresponse of cultured podocytes exposed toSRNS disease plasma from consecutive pa-tients is consistent, indicating that this islikely to be a discrete cellular response,caused by a specific circulating factor

rather than heterogeneous effects.19,20 Because there is evi-dence to suggest that the putative circulating factor may resultfrom immune activation, we hypothesized that the initial re-sponse to steroids might by definition indicate the presenceof a similar process and thus predict risk of recurrence aftertransplantation. Conversely, we predicted that steroid resis-tance from the outset, especially if combined with a definitivepodocyte gene mutation, might be protective.

We first examined all factors including aggressive coursebefore transplantationwith a time interval betweenonset of thedisease and CKD stage 5 of ,3 years, male sex, mesangialhypercellularity in most glomeruli as well as fewer scleroticlesions, age at diagnosis, donor type, and time to ESRF, whichhave been correlated with increased risk for SRNS recurringafter transplantation.5,7,21–26 We were unable to draw conclu-sions on the relationship between mesangial hypercellularitybecause detailed histology was not available for all patients.None of the above factors were statistically significant in pre-dicting recurrence except for donor type (Figure 1, Table 1).Patients who received a living donor transplant had a signif-icant risk of recurrence in our study; however, there were fewliving donors in our study. Previous studies of living donorsand recurrence risk have had inconsistent results.21 A recentstudy of 2157 children who were transplanted for FSGS dem-onstrated that a living donor transplant significantly increasedrecurrence risk but this risk became insignificant if correctedfor age and race in multivariate analysis. This study, however,did not differentiate between genetic and nongenetic FSGS.27

In addition, collapsing FSGS is also a well described risk fac-tor.28 This was true for the only patient in this series withcollapsing FSGS (HIV-negative), who recurred immediatelyafter transplantation and lost graft function soon afterward(patient 3, Supplemental Material).

Figure 1. Forest plot of ORs for recurrence in nongenetic/nonfamilial cases. Clinicalrisk was calculated for each factor listed in the left column. Calculated significance isgiven in Results.

Table 2. ORs for post-transplant recurrence in children withnongenetic/nonfamilial SRNS

Characteristic OR (95% CI) P Value

Age of diagnosis ,6 yr 0.88 (0.40 to 1.90) 0.84Time to ESRF ,3 yr 0.68 (0.31 to 1.47) 0.44Age of first transplant ,12 yr 0.74 (0.36 to 1.53) 0.47Time on dialysis ,2 yr 0.56 (0.26 to 1.19) 0.18African-European race 0.92 (0.24 to 3.61) .0.99Living donor transplant 6.00 (1.24 to 29.06) 0.02Steroid sensitivity 30.00 (6.62 to 135.86) ,0.001

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Decreased risk of post-transplant recurrence has beenpreviously linked to the presence of a genetic mutation, aswell as to African-American race.21 African-American race hasconsistently been shown to decrease the risk of recurrenceafter transplantation.5 Our study demonstrates differentresults in our African-European population, in which no sig-nificant racial effect on recurrence was seen. There is someevidence that MYH9 risk alleles (for FSGS), which are morecommon in Africans, have differential frequencies across dif-ferent countries, and there is the potential that these risk allelesmight play a part in SRNS recurrence.29,30

A histologic diagnosis of FSGS was traditionally thought tocorrespond to an increased risk of steroid resistance inchildhood nephrotic syndrome. With the advent of genetictesting and the increasing rate of detectionof genemutations inSRNS, it is becoming apparent that children with monogenicinheritance of SRNS are more likely to display permanentsteroid (and secondary immunosuppression) resistance.12 Ge-netic mutation was confirmed as a potential protective bio-marker in our series, because patients with SRNS carrying apathogenic dominant negative, homozygous, or compoundheterozygous podocyte gene mutation and/or familial diseasedid not develop recurrent disease. This finding also supportsthe concept that detection of a biallelic gene mutation mightprovide an appropriate biomarker of reduced risk, althoughmore patients need to be studied. However, our data also sup-port the notion that NPHS2 haploinsufficiency is insufficientto prevent post-transplant disease recurrence.

In this study, none of the patients with isolated renal diseaseand pathogenic podocyte gene mutations recurred after trans-plantation; in addition, three patients had a positive familyhistory of SRNS. Only one of eight patients with extrarenalabnormalities suffered recurrence, and these features were mildin this child (patient 5, Supplemental Material). The knownexception is patients with Fin-major nephrin mutations (andan early truncation) who may develop post-transplant recur-rence secondary to neoantigen exposure.31 We had no knownFin-major patients in our series. Notably, no patients with othernephrin mutations were recorded as developing transplant re-currence in either center during the study time period.

We found that a significant proportion of patients (19.3%)were initially steroid sensitive and only developed steroid re-sistance later on in the course of the disease, at times delayed by5–7 years after onset. This initial sensitivity was strongly corre-lated with a complete risk of recurrence after transplantation.Posttransplant recurrence was also observed in all subsequentgrafts, supportive of disease caused by the presence of a circulat-ing factor. None of these patients had a documented gene mu-tation, family history, or extrarenal abnormalities, although it ispossible that circulating factor nephrotic syndrome is triggeredby genetic variants present within the genome together with arelevant environmental stimulus such as a viral trigger. Predict-able recognition of this group might therefore facilitate accurateprognosis as well as identification of which patients to targetfor more intense therapy pretransplant, with strict emphasis

on better control of nephrotic relapses earlier in their course ofdisease to avoid secondary steroid resistance. Therapy is also cur-rently limited by a lack of consensus for the optimal manage-ment of post-transplant SRNS recurrence, such as ciclosporinversus tacrolimus, peritransplant plasmapheresis, rituximab(anti-CD20),32 or infliximab/eternacept (anti-TNFa),33 all strat-egies that have been used in attempts to control post-transplantdisease with varying success.

In summary, our data highlight two identifiable clinicalgroups before transplant: those who are initially steroid sensitiveand have a predicted high risk of recurrence and those withgenetic mutations or familial disease with a low risk. There is avigorous ongoing debate about whether steroids and calcineurininhibitors play a direct role in stabilizing the podocyte cytoskel-eton and reversing podocyte damage without any effect on theimmune system. Our data suggest that this is not a significantcontributor in the group of patients with steroid sensitivity,becausewecanlinktheresultsof immunosuppressionearly inthedisease process to an immune-mediated recurrence after trans-plantation. If steroids were able to reverse podocyte damagedirectly, then the prediction would be that there are (genetic)patients who are steroid responsive who would then not recurafter transplantation.This is evidently not the case fromourdata.

The presence of genetic/developmental disease was clearlyprotective for recurrence, because none of our patients withdocumented gene mutations or identifiable syndromes relapsedafter transplantation. Individuals that fall intoagrayareabetweenthese two phenotypes are those patients with treatment-resistantSRNSwith no evidence of initial steroid sensitivity who recurredafter transplantation. Notably, 31 of 57 of the patients withrecurrence did not exhibit initial steroid sensitivity. This remainsunexplained, although possibilities include compliance/toxicityissues or aggressive diseasemasking initial steroid sensitivitywithsubsequent resistance to other standard immunosuppressionregimes. We did not analyze whether any of those 31 patientsexhibited a response tomore intensive immunosuppression, andclearly that would be an important parameter to follow up on inthis group. On the basis of our findings, we have suggested aclinical paradigm to assist in assessing pediatric patients withprogressive nephrotic syndrome who are potentially at risk oftransplant recurrence (Figure 2).

In conclusion, we have detected a highly significant correla-tion between initially steroid-sensitive and post-transplant FSGSrecurrence. We propose that this is a clinically identifiable groupthat is at high risk (Figure 3) and could potentially be aggressivelytargeted with detailed preparation and additional immunosup-pression before transplantation. In addition, transplantationmust be planned with extra care to maximize graft survival inthese patients.

CONCISE METHODS

Patient SelectionWe identified pediatric patients at the Bristol Royal Hospital for

Children (Bristol, UK), the Evelina Children’s Hospital (London,

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UK), and the Necker Hospital for Sick Children (Paris, France) who

were diagnosedwith FSGS/SRNS at between 4months and 16 years of

age and who received a renal transplant between January 1, 1981, and

September 1, 2012. We conducted a retrospective data collection of

clinical characteristics including sex, race, age at

diagnosis, time to ESRF, age at transplant, initial

steroid sensitivity at presentation, genetic mu-

tations, family history, extrarenal abnormalities,

recurrence, rejection, and graft loss.

Patients were included in the study if a

positive biopsy result of FSGS was found in

the patient notes (143 of 150) or, at a minimum,

if SRNSwas the stated diagnosis in their medical

records. We excluded patients with congenital

nephrotic syndrome (onset age,3 months) or

diffuse mesangial sclerosis on biopsy. Proteinuria

was defined by having a urine protein/creatinine

ratio of .300 mg/mmol. Steroid resistance was

defined as the persistence of proteinuria (.300

mg/mmol or 300 mg/dl or equivalent on dipstick

testing) after 4 weeks of daily prednisolone at a

dosage of 60 mg/m2 per day 6 3 daily doses of

intravenous methylprednisolone at 600 mg/m2.

Patients were deemed to have recurred if they

had persistent proteinuria of .300 mg/mmol or

.1 g/d after transplantation.

Statistical AnalysesNonparametric data were analyzed using the

Mann–WhitneyU test. Contingency tables were

analyzed with Fisher’s exact test and ORs (with

95% CIs) were used to compare recurrence and

nonrecurrence groups. P,0.05 was considered

significant. Values are reported as mean6SEM

or the median (range).

ACKNOWLEDGMENTS

This study was supported by Kids Kidney Re-

search, the Nephrotic Syndrome Trust, Kidney

ResearchUK, and theUKRegistry forRenalRare

Diseases (renalRaDaR.org).

DISCLOSURESNone.

REFERENCES

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Figure 2. A suggested clinical paradigm for idiopathic nephrotic syndrome. Idiopathicnephrotic syndrome is stratified (where possible) according to clinical parameters into“circulating factor disease” and “genetic disease.” This segregates into high and lowrisk factors for post-transplant disease recurrence.

Figure 3. Stratifying patient risk according to initial steroid resistance/sensitivity.Groups are divided into genetic, steroid-resistant, and steroid-sensitive groups to givethe recurrence risk of each group from this study.

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This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2013080852/-/DCSupplemental.

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