Source document: https://docs-lawep.s3.us-east-2.amazonaws.com/1694840502477.pdf (Malta)
L-ERBATAX-IL LEĠIŻLATURA P.L.

0379 Dokument imqiegħed fuq il-Mejda tal-Kamra tad-Deputati fis-Seduta Numru 18 tal-15 ta’ Ġunju 2022 mill-Onor.

Malcolm Paul Agius Galea, MP.
___________________________ Raymond Scicluna Skrivan tal-Kamra Nephrol Dial Transplant (20 18) 1-10 doi: 10.1093/ndt/gfy01 5 ndt Nephrology Dialysis Transplantation Treat1nent and outcome of congenital nephrotic syndron1e 5 • Sandra Berodi, Laurence Heidet 1 ' Veronique Baudouin2 Olivier Dunand 10 Marie-Alice Macher5 Caroline Rousset-Rouviere 19 Rachel Vieux23 , Hugues Flodrops 11 , Adrien May15 , Aria ne Zaloszyc2 2 3 2 , Olivier Gribouvae, Jerome Harambat\ Patrick Niaudet 1 • 3 • ' , , Justine Bacchetta6 , Bernard Boudailiez7 , Maud Dehennault 8 , Lo"ic de Parscau9 , , Marc Fila 12 , Elodie Merieau 16 , Arnaud Garnier 13 , Ferielie Louiliet 14 , , Fran~oise Monceaux 1 7 , Gwenaelie Rousse/ 0 , Sophie Taque21 , Julie Tenenbamn 12 .t, Vincent Moriniere3 2 , Remi Salomon 1 ' ' 3 and Olivia Boyeru·3 , Christine Pietrement18 , 22 , T im Ulinski2 • , 1H6f'ital :--:cckcr-Enf,mt< mabdc<, Ncphrologie p.-:di.1triquc, A~~ist.uK.
: Publiquc des H6pitJux de Pari<.

l-niver~itc P.1ris Dcs~.utrs-Sorbonnc P.1ri~-Citc, P.1ris.

f-rance, !Centre de r~fercncc des Mal:ldi,'s Rcnab Hcrcdit.lirc~ de I"EnfJnt rt de !

"Adultc (1\L-\RHEA).

Centre de refcrcn~r du syndrom,~ n~phrotique idiopathiquc de l"ent>mt rt de l'.1dultc, Hopit~l Nc\krr-Enfants 1\·IJl.ltks.

PJris, FrJnn'.

JJnscrm U 1163.lmaginc Institute.

Paris, Franc~.


~Ct>ntre Ht>Spitalier Universitaire de flordcaux.l'ephroh>gic pcdi,ltrique, Bordeaux, Fran(c. 3 H6pit,tl Univer<i tair~ Robert Oebr.!.

1\ephrnlogie pe<.liatriqu~.

Paris, Fmn(e, "H6pital Femme lvlerc Enfants, 1\.

:phmlogic p,.;diatrique.

Bnm, Fran(c. 'Centre Hn,pitalier Uniwr;, it .lir~ tfi\mielh, Pe<.liatrie, i\miem, France, 8CHRLT leanne d~ Flandre.

PcJiatrie, Lillc, Fra n~e.

9CHRll de Brest, PeJiatrk.


B r~;,t. Fr.mce, 1°C HU Fdix Gu)'lHl, Pr:di.ltrie.

Saint- Dc:nis.

La Reuni.

)n, France, 11CH U (; J-ISR S.1inl Pierre.

Pediatrie, La Reunion.

Fr.ut.

:r:, "Cc:ntre Hospitalier Regional Universit•lire de J\·lontpell ier,l\'c:phrologic: pediatrique, Monlpellier, FrMKt:.

1 )Centre 1-lospitalier lfni\'t:rsitaire dr: Toulouse, 1'\~phn>logie peJia triqur:, Toult.>usc.

France, 11Ccn trc: Hnspitalier Universitaire Je RtJuen, Pctli.tlrie, Rouen, France.

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!.

'Centre H,>,pit.dier Sud Fmncilien.

Petliatrie, Corbeil Essonnes, France.

"CHU Cloche\iUe.

J>ediat:rie, Tours.

1-r.mce, ':Centre llospitalier Regional d'Orlean>, Pediatric:.

Orbu1s.

Fra1Kc, '"American Memori,l!

Hospital.

l\'ephrologie pedi.1trique, Reims.

France, 1"1-lopital dt·la Timone, :"-kphrologie f'cxli.ttrique, Mnrseille.

Fr.mce.

2''Ccntre Hospit.11ier Universit,lire de 1\'antes.t"ephrologie pedinu·ique.t".mtes.

France.

21 Ccntre 1-lospitalier Universit,lire de Rcnncs, Ped.i.ltrie.
Rcnncs, france.

:lHopiJal Armand -Trousseau, 1\:ephrologir pcdi.1triquc.

Paris.

Frnn~c.

~'Centre 1-lospit.llier LniYrrsitJircdr :-\.mry, Pcdiatri.:.

1\',tnC}, frnn~e Jnd ~ 1CHU H.mtepierrc, Pediatric:.

Strasbourg.

France Correspondence and offprint requests to: Sandra Berody; E-mail: sandra.berody@gmail.com; Twitter handle: @NeckerNephroPed ABSTRACT Background.
Recommendations for management of Finnish type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrec tomy, dialysis and transplantation.

We aimed to assess the treat ment and outcome of patients with CNS in France.

Methods.

We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated to r non- infectious CNS.

Results.

The estimated cumulative incidence of CNS was 0.5/ 100 000 live births.
The underlying defect was biallelic muta tions in NPHSI (36/55, 65%) , NPHS2 (5/55, 7%), PLCEI (1/ 55, 2%) , heterozygous mutation in WTI (4/ 55, 7%) and not identi fied in nine children (16%) .

Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days) , which were spaced and withdrawn in 10 patients.

Twenty chil dren (35%) were managed as outpatients.

Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months.
The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively.

Thirteen children died during the study period including four at d iagnosis, two of nosocomial catheter- related septic shock.

six on dialysis and one after trans plantation.

The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9- 52) ].

Renal and patient survivals were longer in patients with NPHSJ mutations than in other patients.
The invasive infection rate was 2.4 1/patient/year.

Conclusions- Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a d iscontinuation of albumin infusio ns allowing ambulatory care in a subset of patients.

These results highlight the need for new therapeutic guidelines for CNS patients.
Keywords: albumin, chronic renal fail ure, nephrotic syn drome, quality of life, survival analysis I NTROD UCTIO N Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by m assive proteinuria and Downloaded f~oliJu,rA~tlt C'Vbll olMll.cP.ul>\ishod)l)lio..f<)rdn\:i•1i versi~ I?

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:.arr 2018 marked oedema manifesting in utero or during the first 3 months of life [ 1).
CNS can be caused by congenital infections, allo-immune maternal clisease or a primary glomerular clisor der due to genetic defects [2).

Several genes have been impli cated in the aetiology of isolated CNS {mainly NPHSl encoding nephrin [3, 4], NPHS2, WTl and PLCEJ) or in less common syndromic forms of the disease (mostly WTl) [5, 6].
CNS was initially referred to as the Finnish-type nephrotic syndrome due to its high incidence in Finland (1:8000 live births), with two NPHSJ founder mutations (Fin-major and Fin-minor) underlying most cases (7-10).

This disease was later reported worldwide with >200 rare NPHSl mutations found in the non-Finnish populations [4, 10-16), along with other gene mutations.

NPHS2 mutations are the second genetic cause of CNS, accounting for 15-51% of cases of European decent [4, 12, 15, 17).
Progression to end-stage kidney disease (ESKD) occurs inevitably within a few years in most patients [1 8-20].

In the past, all children died before the age of 3 years [ 8).

The survival of these children was made possible with the advent of kidney transplantation [21].

In 1995, Finnish physicians proposed an 'aggressive' management ofCNS with a continuous hospitaliza tion during the first year of life for intra-venous albumin substitution [ 1].
Moreover, they recommended to perform pre-emptive bilateral nephrectomy and start peritoneal dialysis (PD) followed by kidney transplantation when the infant's weight exceeded 7 and 9 kg, respectively, at about 1 year of age.

This strategy Jed to a tremendous increase in life expectancy of children with CNS.

This management of CNS is still currently used in Finland and in many other countries.

However, other groups have reported different disease courses [1.

19, 22- 26].
19, 22- 26].

For instance, a recent report from the European Society of Pediatric Nephrology (ESPN)/European Renal Association European Dialysis and Transplant Association (ERA_EDTA) registry highlighted an older age at ESKD in the 104 non Finnish patients as compared with the 66 Finnish patients with CNS, which may reflect different management approaches with non-systematic bilateral nephrectomies in some children [22].
This registry report did not provide detailed information on diagnostic features, molecular finclings, pre-ESKD management and complication rates [24].

We sought to assess the therapeu tic management and outcome of CNS patients in France.

MATERIALS AND METHODS We carried out a retrospective epidemiological nationwide study including all CNS patients born between 2000 and 2014 and treated in 18 French paecliatric nephrology centres.
The diagnosis was in accordance with International Study of Kidney Disease in Children (ISKDC) criteria, including generalized oedema, proteinuria exceeding 40 mglm2/h and hypoalbumi naemia ( <25 g/L) starting within the first 3 months of life, whatever the molecular testing results [27].

Charts were abstracted for family history and perinatal events, clinical fea tures, CNS complications, renal function, kidney histology medical and surgical treatments and the hospital course.
Genomic DNA was isolated from peripheral blood after informed consent had been obtained.

Patients were screened for NPHSl mutations, then for NPHS2 mutations if no NPHSl mutation was identified, and then for WTl, LAMB2 and PLCEl mutations as described elsewhere (4, 28] .

We selected previ ously published variants as well as nonsense, frameshift and splice variants.
Alamut Visual (Version 2.7.1; Interactive Biosoftware, http://www.interactive-biosoftware.com/alamut visual/) was used fo r missense variant analyses, providing com (http://sift.jcvi.org/), putational algorithms fo r SIFT PolyPhen-2 [30] (http://genetics.bwh.harvard.edu/pph2/) and MutationTaster [31) (http://www.mutationtaster.orgl).

We excluded mutations \vith poor segregation in pecligrees and/or low precliction scores, and/or with minor allele frequency > 1/ 1000 in Exome Aggregation Consortium [32].
[29] We classified mutations accorcling to published in vitro data [ 13, 33, 34] and in silico predicting algorithms.

NPHSl muta tions were classified as 'severe' when they resulted in the absence of nephrin expression or its mislocalization in podo cytes.

When no functional data were available, we considered nonsense, frameshifting and splice mutations as 'severe muta tions' and missense variants as ' mild mutations'.
Patients were classified in the NPHSl 'mild genotype' group when they bore at least one 'mild' mutation [33).

The statistical analyses were performed using GraphPad Prism software.

Results were expressed as either medians with ranges, means:!

: standard deviation or percentages.

The cumu lative incidence was calculated by the number of new CNS cases divided by the total number of births in France during the entire study period.
Continuous data were tested for normal distribu tion using the Kolmogorov-Smirnov test.

Normally distributed data were analysed with t-test, whereas non parametric data were analysed with Mann-Whitney U-test.

Frequencies and contingency tables were analysed using Fisher's exact test.

Kaplan-Meier method and Jog-rank test were used to compare survival curves.
Statistical tests were two tailed and considered significant when P < 0.05. two-sided The study was approved by the local Institutional Review Board, declared to the Information Technology and Liberty Commission [Commission nationale de l'informatique et des libertes (CNIL) # 1698048v0] and conducted in accordance with the Declaration ofHelsinski.

RESULTS Demographics We identified 55 consecutive CNS children from 51 fami lies born between 2000 and 2014.
This translated into an estimated cumulative incidence of CNS of 0.5 per 100 000 live births.

Demographics and clinical features are reported in Table 1 and Supplementary data, Table Sl.

The median duration offollow-up was 44 months (1-168).

The sex ratio (female/male) was 0.9:1 and consanguinity concerned 46% of families.

Seventeen patients had a relative with congen ital, infantile or steroid-resistant nephrotic syndrome and six patients had a histo ry of intrauterine foeta l death in a sibling.
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~ .... 0 ,, ~ ;,- ~ ~ .., ~ ~ m w w m ~ Table I. Demographic, clinical features and outcome Pt • Gene Status Exon Mutation" Genotype'' St•x Age at first symptoms (days) Ag<' at Dx (days) K llx Albumin withdmwal Agt• at ESKD (months) T ypt' of ESKD Age at death (months) I II I2 13 I4 IS 16 17 18 I9 20 2I 22 23 24 25 26 NPI-IS I NP/-ISI NPIISJ NPIIS J 11om Hom 11om Comp het NPIJSJ Comp het NPTISI Camp het NPTISI Camp het NPIISI Camp het NPIISJ Comp het NPIISJ NPIJS I !I om Comp het NPI/S J Comp het NPIISI Comp het NI'IISI Comphet NPIISI N/'1/S / Hom Hom NPI-ISI NPliSI NPIISI NPHSI NPHSI NP//SI NPHSI NPIISI NPliSI limn Hom !I om Hom Hom Hom Hom Hom Comp het NPIJSI Camp het 2 2 2 2 14 2 22 3 16 4 27 6 I I 6 18 7 7 9 7 9 7 IVS IS 8 27 IVS9 IO II I I II II II 11 II II II 13 12, IVS IS f 27 c.l39 del-p.Aia47Pro fs' 81 c.J39 del-p.Aia47Pro fs'81 c.l39 del-p.Ala47Pro fs' 81 c.J39 del-p.Ala47Pro fs' 81 c.l758-8_1785 del-Splice c.l39 del-p.Aia47Pro fs' 81 c.292R G > T - p.Arg976Ser c.386 T > A-p.Leul29llis c.2149 T > G-p.Tyr717 A'P c.479 G > C- p.Cys 160Ser c.3478 C> T -p.Argl l60• c.712 1'>C-p.Phc238l.eu c. 1423_ 1427 del- p.Ser475Hisfs•71 c.61 9 del-p.Arg207Giy fs•zs c.2500 G > T-p.Vai834Phe c.728 C > T -p.Pro243Leu c.728 C> T - p.Pro243Leu c.I040 G > A-p.Giy347Giu c.728 C> T - p.Pro243Lcu c. I040 G > A-p.Giy347Giu c.802 C>T-p.Arg268' c.2212 + 2_2212 + 3 del-Splice c.995 T > A-p. Ile332Asn c.3478 C>T -p.Argii60' c. I 170 + 2 T>C- Splice (IVS 9) c. I223_ 122S del- p.Arg408_Giu409 delinsGin c. l379 G> A- p.Arg460Gin c.I379 G > A-p.A rg460Gin c.I379 G > A- p.Arg460Gin c. l379 G > A-p.Arg460Gin c.I379 G > A-p.Arg~60Gin c.l379 G> A-p.Arg460Gin c. I379 G> A-p.Arg460Gin c. I379 G> A-p.Arg460Gin c. l394 G> A- p.Cys465Tyr c. I7 15 G> A- p.SerS72Asn [c.ISSS C> T - -p.ProSI9Ser + c.2072- 6 C> Gi i c.347R C> T- p.RII60' Severe Severe Severe Severe Mild Mild Mild Mild Mild Mild Mild Mild Severe Mild Severe Mild Mild Mild Mild Mild Mild Mild Mild Mild Mild Mild M I' F M M M F M M M F F r: M M r: M M M F I' M M M r M
 IS 0 10 26 30 7 12 30 0 30 30 0 0 I6 I4 0 0 0 48 2 0 30 30 I9 41 IS 0 10 26 30 7 14 36 30 4S 30 0 0 I6 24 0 0 0 48 2 0 30 390 19 41 CNF CNF Yes No No No No No Yes No No No Yes No CNF No CNF CNF FSGS CNI' No No No No No No No No No Yes No No Yes 54 27 7 17 12 I~ 12 10 22 6 18 13 6 7 15 13 8 - 26 II s N N N N N N N N N N N s N s N - s N 39 10 16 Continu ed "" ~ g,n> !
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Continued 27 NPHSI Comphet 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 so 5 1 52 53 54 55 NPHS/ NPHSI Hom Comp het NPllSI NPllSI NPllS/ NPHS I NPHSJ NPHSJ NPHSI NPHSJ NPHS2 Hom Hom Hom Hom Hom Hom Hom Hom Comp het NPHS2 Comp het NPHS2 NPHS2 NPHS2 PLCEI WTJ WTl WTI WTI NA No No No No NPllS I Hom Hom Hom Hom Het Het Het 1-let NA NA NA NA NA Het NPHS I NPJJSI 1-let Het 12, IVS IS IVS 14 13 13 24 16 16 18 19 19 21 24 24 IVS I 3 3 5 6 6 6 14 8 8 8 9 NA NA NA NA NA 12, IVS 1 5 2 19 [c.ISSS C>T-p.Pro5 19Ser+ c.2072-6 C>G]+ c.l931- 17 C > A- Splice c.l715 G> A-p.Ser572Asn c. J730 del- p.Asn577Thr fs' 45 c.3250 dup- p.Va11084Gly fs' l 2 c. 213 1 C> A-p.Arg711Ser c.2131 C > A-p.Arg711 Ser c.2417 C>A-p.Ala806Asp c.2587 T>C- p.Cys863Arg c.2587 T>C-p.Cys863Arg c.2881 T >C-p.Trp961Arg c.3250 dup- p.V all084Giy fs' l2 c.3250 dup- p.V ai1084Gly fs"l 2 c.275- 2 A>C c.4 13 G> A- p.Arg138Gln c.413 G> A- p.Arg1 38Gin c.643 C>T- p.Gln21 5' c.779 T > A-p.Vai260Giu c.779 T >A-p.Vai260Giu c.779 T > A-p.Vai260Giu c.3846 del- p.Leu 1283Cys fs'26 c. l 300 C> T -p.Arg434Cys c.1 301 G> A-p.Arg434His c. l 339 + 5 G> A-Splice c. 1385G> A-p.Arg462Gin No available DNA No mutation No mutation No mutation No mutation [c. ISSS C> T -p.Pro5 19Ser + c.2072-6 C> G-Splicel c. l39del-p.Ala47Pro fs"Sl c.2513 C> T -p.Pro838Leu Mild F 0 0 Mild Severe Mild Mild Severe Mild Mild Mild Severe Severe M F M F M F F F M F M M M M F M F F M I' F F F M M F M F 46 5 23 42 0 0 4 61 5 67 90 12 2 0 90 45 0 0 2 14 22 15 36 IS 45 15 1 20 46 5 45 42 21 0 8 6 1 5 67 90 12 2 1 2 10 90 1 7 10 21 39 IS 37 15 45 31 1 20 - - - - - - - - CNF - - CNF - - - MC DMS DMS OMS OMS OMS OMS - OMS - - - CNF Yes No No Yes Yes No No No No No No No Yes No No No No No No No No No No No No No Yes No No II 32 25 10 10 - 28 63 - 0 24 5 0 4 3 1 l I 1 - 45 9 5 64 II 2 6 II 1 14 N s s N N - s T - s T s s s N s s s s - 25 N N CNF, congenital nephrotic syndrome of the Hn nish type: Comp hct, compou nd heterozygous; OMS, diffuse mcsangial sclerosis; Ox, diagnosis; Pt, patien t;
 F, female; FSGS, focal segm ental glomf,.
'rulosdcrosis; Hct, heterozygous; Hom, homozygous; K Bx, kidney biopsy; M, male; MC, m inimal chongcs; N, pre-emptive bilateral nephrectomy; NA, not applicable; 5, spontaneous ESKD.

•NPHSI mutations were classified as 'severe' when they resulted in the absence of ncphrin expression or its mislocalization in podocytes in published in vilro studies.

When no functional dat3 were ;wailable.


we considered nonsense, frameshifting and splice m utations as 'severe mutations' and missense variants as 'mild mutations'.

Severe mutat ions are reported in bold.

bPatients were classified in the NPHSI 'mild genotype' group when lher bore at least one 'mild' mutation 133).

··•·· Me om plasma albumlne (&/II - G- Mf'an dos.age of albumin Infusions !&/kg) ~Mean number of monthly In fils ens in known CNS genes in nine patients including two with no available DNA.
)0 2S 20 IS 10 15} ....................................... ........... ··············,8 7 19.9 10..!

.· ~· 29 2;; - - - - - -~ - - - - - -o- - - - - - -G- - ll lA l l Tlrnf from diaJnosis {monttal 23.9 ····• - - - - 2.9 -CJ 24 FIG UR E I: Mean albuminaemia (giLl.

posology lg/ kgBW) and frequency of albumin infusions at diagnosis (n = 55).

3 months (n = 47).

6 months (11 = 40).

12 months (11 = 2-l) and 14 months (11 = 10).


Clinical features and genotyping data Eleven patients had an early diagnosis at birth because of fa mily history of CNS (n = 8), prenatal signs including hyper echoic kidneys (n = 1) or elevated amniotic fluid alpha fetoprotein level (n = 2).

Twenty-seven children were born pre maturely and median gestational age was 37 weeks (32-41 ), with a median birth weight of2575 g ( 1650-3620).
The median ages at first symptom and at clinical diagnosis were 14 days (0-90) and 16 days (0-390), respectively.

An increased placen tal weight was reported in 12/17 cases.

One patient had a syn dromic form of CNS (Denys-Drash syndrome).

The initial median plasma creatinine, albumin and protein levels, and pro teinuria were 26 ~tmoi/L (3-244), 11 g/L (2.6-19), 30 g/L ( 4- 51 ) and 9 g/L (2.35-87), respectively.
A kidney biopsy was per formed in 18 patients and revealed lesions consistent with CNS tubular d ilations~ microcysts) in of the Finnish-type (i.e.
8 patients with NPHSI mutations and 1 with NPHS2 mutations, minimal changes (MC) in 1 patient with a homozygous NPHS2 mutation; focal segmental glomerulosclerosis (FSGS) in I patient with a NPHSI homozygous mutation; and diffuse mesangial sclerosis (DMS) in 3 children with WTI mutation, 1 with a homozygous PLCE I mutation and 3 with no identified causative mutation.
Causative mutations were identified in 46 patients: 36 NPHSI biallelic mutatio ns, 5 NPHS2 biallelic mutations, 4 WTJ heterozygous mutations and 1 homozygous PLCEJ mutation.

The patients bearing only one heterozygous NPHSI mutation were considered as not mutated, although another variant may have been missed on the other allele in the non-coding regions.

None of the patients bore the Fin-major or Fin-minor muta tions.

Seven of the 31 identified NPHSJ mutations were novel.
All the detected NPHS2, PLCEJ and WTJ mutations were pre viously reported.

No definite causative mutation was identified Medical management Fifty-three patients (96.3%) received albumin infusions at time of diagnosis (Figure 1).

The target albumin trough level commonly adopted by the French paediatric nephrologists was > 20g/L.
Albumin infusions were withdrawn in 10 patients (1 8%) with normal estin1ated glomerular filtration rate at a median age of I I months (5-29) and stable clinico-biological features for a median duration of 26.5 months (5-47).

Seven of these 10 children bore 'mild' NPHSJ mutations, I was homo zygous for a 'severe' NPHSJ mutation, 1 was compound hetero zygous for NPHS2 mutations and 1 was heterozygous for a NPHSJ mutation and, therefore, considered as not mutated (Tab le I).
Two out of 10 eventually progressed to ESKD at 12 and 54 months of age, and 8 remained free from albumin substitution at last follow-up.

One patient with NPHS2 muta tions never received albumin infusion but slowly progressed to ESKD.

The mean d osage of albumin infusions ranged from 2.5 ~ 4.3 to 3.4 ~ 2.4 g/kgBW with a mean frequen cy of to 25.5 ~ 8.7 monthly infusions at diagnosis, decreasing 16.7 ~ 10.1 at 2 years.
Twenty-four children received regular substitution of intra-venous to prevent infectious complications and 22 were prescribed phenoxymeth ylpenicillin.

prophylactic Angiotensin -converting enzyme inhibitor (ACEi), indometha cin and anticoagulation were used in 48, 28 and 5 1 patients, respectively.

immunoglobulins (IVIg) antibiotics with Hospita.lization versus ambulatory management Fifty-four infants (98%) were hospitalized at diagnosis of CNS.
Nineteen of them (35%) could be discharged without ESKD at a median age of 8 months (2- 24), among whom 2 were regularly followed in outpatient clinics and 17 had regular day care hospitalizations for albumin infusions.

Among the lat ter, si.x eventually progressed to ES KD, three were still treated in a d ay care hospital and albumin infusions were discontinued in eight children with normal renal function at last follow-up.

The 35 remaining patients were hospitalized continuously until dialysis or death.
Infectious and thrombotic complications Before reaching ESKD (mean follow-up of 18 m onths), 7 1% (39/55) of patients presented a total of 120 bacterial infections (0- 8/patient), mainly catheter sepsis.
This translated into an infection rate of 2.41 /patient/year that was not statistically dif ferent between patients who were given antibiotic prophylaxis (1.4/patient/year) and those who were not (3 .10/patient/year; P = 0.18), o r between patients who were given regular IVIg sub stitution ( 1.83/patient/year) and those who were not (2.88/ patient/year; P = 0.36).
The catheter sepsis rate of 1.78/patient/ year was not significantly different either in case of antibiotic proph ylaxis (2.32/patient/year; P = 0.09), or in case of regular IVlg substitution ( 1.54/patient/ year) or not (2.02/patient/year; P = 0.22).

The use of these two therapies depended on the practices of each centre.

(0.99/ patient/year) o r not Down:oaded f9ernogrpphia,.,clirtbmlcfe:ttpres>al'l<ii:loll!OOmee-aro lc:e-abs< raco/doi/10 .

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February :018 5 A p < 0.02 100 ~ Patients with NPHS1 ----.., I mutations _._ Patients with no or other _ .. gene mutation Whole cohort - ~ 80 iii ~ 60 z: 40 -a; :I Ill 20 i Q.

0 0 50 100 150 200 Time (months) B p<O.OOS 100 - ~ t.. iii 80 > -~ 60 1/) iii c Ql ... 40 iii 20 a; > 0 0 0 c ~ 100 iii ~ z: 80 40 :I 1/) iii 60 i ... 1/) !
20 .. [ 0 !/) 0 ....._ Patients with NPHS1 mutations _._ Patients with no or other _,__ gene mutation Whole cohort 20 40 Time (months) 60 80 p<0.0001 _._ Patients with NPHS1 mutations ....__ Patients with no or other gene mutation - L .

Whole cohort 20 40 Time (months) 60 FIGURE 2: Patient survival (A), overall renal survival (B) and renal survival taking into account only spontaneous ESKD (C) in 'NPHSJ mutations' group versus 'Other genes or no-mutations' group.
Before ESKD, the total number of thrombotic episodes reported was 22 in 16 patients (29%), mostly catheter thrombo ses (0.25/patient), but also two ischaemic cerebrovascular acci dents that probably occurred before birth.

Patient 55 underwent a brain magnetic resonance imaging (MRI) at birth because of enlarged cranial sutures that revealed a fron tal ischeamic stroke.

Patient 10 was diagnosed with hemiparesia at 6 weeks of age.
Brain MRI images showed a porencephalic cyst suggestive of an antenatal ischeamic accident.

Kidney and patient survival Thirty-nine patients reached ESKD during the study period at a median age of ll months (0- 63); after pre-emptive bilateral nephrectomy for 19 patients at a median age of 10 months (3-27) and in the natural course of their disease in 19 cases at a median age of l3 months (0-63) (P < 0.001).

These data are missing in one patient.


The indications of neph rectomy were the following (sometimes multiple in a single patient): dependence on albumin infusions (n = 9), repeated infections (n = 6), compliance to the Finnish recommendations (n = 5), vascular access difficulties (n = l), uncontrolled hyper tension (n = 1), failure to thrive (n = 1), repeated red blood cell transfusions (n = 1) and Wilms tumour development preven tion (n = 1).
Overall, the renal survival was 64, 45,21 and 5% at 1, 2, 3 and 5 years, respectively (Figure 2).

When considering only patients who were managed conservatively, without pre- Downloaded fror6 https: I / academic .oup .

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Table 2.
Outcome depending on the genetic background "Mrld" NPJISI mutations 'Severe' NPHSI P mutations Other gene mutations mutation ;o.;o identified AU NPHSI mutations ;o.;o or other gene mutation P Number of patients Males/females Median age at Dx in days (range) Number (percentage) of ESKD Median age at ESKD in months (range) Number (percentage) of death Median age at death in months (range) Number (percentage) of albumin withdrawal 7127 (26) 27 16/11 19 (0- 390) 17/27 (63) 12 {6- 26) 4/27 (15) 27.5 (7-64) 10 4/6 12.5 (0- 61) 8/10 (80} 26 (6-54) 2110 (20) 10.5 (10- 11 ) 1/10 (10} Ox.
diagnosis.

Significant values (P < 0.05) are indicated in bold.
11 (1-210} 25.5 (0-45) 10 0.46 6/.J, 0.52 0.45 8/10 (80} 0.20 3.5 (0-63) 0.65 4/10 (40) 0.33 4 (1-1 1) 0.40 1/10 (10} 8 3/5 6/8 (75} 3 (1- 45} 3/8 (38) 1 ( 1-14} 1/8 (13) 37 18 20{17 9/9 16 (0·390) 17.5 (0-2 10) 25/37 (68) 14/18 (78) 13 (6-54} 3.5 (0- 63} 7/18 (39) 6/37 (16) 13.5 (7-64) 4.0 (1-I.J,) 2/18 (11) 8/37 (22) 1.00 0.39 0.53 <0.005 0.09 <0.02 0.47 emptive bilateral nephrectomy the renal survival was 67, 62, 47 and 44% at l, 2, 3 and 5 years, respectively.
The median age at ESKD did not differ between Caucasian and non-Caucasian patients, or in case of initial albuminaemia < 15 or > 15g/L (Supplementary data).

The median age at ESKD was signifi cantly higher in children with initial creatininaemia <50 ~tm ol/ L than in patients with initial creatininaemia >50 ~tmol/L (12.5months versus 2 months; P < 0.005) (Supplementary data).

Thirty-three children were started on dialysis at a median age of llmonths (1-54).
Twenty-four children were trans planted at a median age of29.5months (18-65), including three transplanted pre-emptively.

Notwithstanding, no thrombotic complication was observed in these th ree children.

None of the children presented post-transplant recurrence of nephrotic syn drome.

It was not possible to evaluate the effects of the type of management on patient survival.
Indeed, among the 13 chil dren who died during the study period, 4 died at diagnosis: 2 from ESKD at 1 month of age who were not started on dialysis, 1 died from heart arrhythmia few days after PD and the latter died despite emergency haemodiafrltration.

Two died of noso comial septic shock at 11 and 14 months of age after being man aged conservatively in conventional hospitalization from birth.
Six died on dialysis after bilateral nephrectomy (following Finnish recommendations for two of them) from various causes: enterocolitis, septic shock, intraventricular haemor rhage, heart arrhythmia and acute pulmonary oedema.

Finally, one transplanted patient died suddenly from heart failure when he was 5 years old.

The remaining 13 patients were alive with a normal renal function at last follow-up [median 32 months (9- 52)].
Comparison of patients with NPHSl mutations and other patients The outcome of the 37 patients with biallelic NPHSJ muta tions was better than that of other patients.

Indeed, their renal survival was significantly higher (P < 0.005), as was the patient survival (P < 0.02) (Figure 2A and B and Table 2).

Results were similar when taking into account only natural progression towards ESKD as opposed to pre-emptive bilateral nephrec tomy (P < 0.000 1) (figure 2C).
A total of 68% (25/37) of the patients with NPHSl mutations reached ESKD and 78% (14118) of the patients with no o r other gene mutation.

The median age at ESKD was significantly higher in children with NPHSl mutations than that of the other group [ 13 months (6-54) versus 3.5 months (0-63); P < 0.005].

Moreover, 16% (6/37) of the children with NPHSl mutations died versus 39% (7118) in the other group (P = 0.09).
Last, albumin infusions were transiently interrupted in 26% (8/37) of the children with NPHSJ mutation versus 11% (2/18) of the other children (P = 0.47).

Comparison of patients witl1 severe versus mild NPHSJ mutations We examined the genotype-phenotype correlations between 'severe' and 'mild' NPHSl genotypes (Table 2).
The age at diag nosis, propo rtion of and age at ESKD or death, and proportion of patients who achieved at least transient albumin withdrawal did not significantly differ between the two groups.
DISC USSION In this French national multicentre study, we showed (i) a dis continuation of albumin infusions with normal renal function in 18% of patients, most of whom bore NPHSl mutations and (ii) an ESKD-free survival of 64% at 1 year and 45% at 2 yea rs of age (67 and 61% in the 36 patients who did not undergo pre emptive bilateral nephrectomy).

Consequently, a subset of patients may benefit from ambulatory management even before ESKD.
These observations highlight the need for new therapeu tic recommendations in CNS.

The current therapeutic strategy in CNS proposed by Finnish physicians is schematically as follows: daily alblliTiin infusions in conventional hospitalization, early bilateral neph rectomy, dialysis and early kidney transplantation [I, 9].

It has tremendously increased patient survival from 0% to 90% at 5 years, with similar post-transplant outcome to other nephro pathies [9, 22].
It requires prolonged hospitalization during the first months of life.

In contrast to this, 35% of patients in this study could be managed in ambulatory care starting at a median age of 8 months (2-24).

Similarly, in a Spanish single-centre study, children were only hospitalized for~ 12% oftime before the start of dialysis [25].

Other groups have reported a safe reduction or even discontinuation of albumin infusions in CNS patients [35].
To minimize hospital attendances, British physi cians have recommended a unilateral nephrectomy associated with ACEi and non-steroidal anti-inflammatory drugs to reduce proteinuria and albumin infusion requirements, and delay dialysis until the third year of life and beyond [3 6].

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Literatu re review of infectious and th rombotic complications in CNS series Huttunen [201 Mahan et aL [231 Holmberg et a!.

[I 1 Ljungberg et al.

[371 Finland, 1965-73 USA, 1953-82 Finland, 1985-95 Finland, 1985-88 Canalejo et al.

[25 1 Spain, 1985-2005 Mehrazma et aL [261 Kari et al.
[381 Iran, 1990-2005 Great Britain, 1990-2009 100% death: 1/3 (23 cases) due to infections 35 severe bacterial infections on 41 children lead to death for 19 ( IS before 197 1, 4 after) Mean: 5 sepsis/patient/year 251 infectious episodes on 21 patients, hence 5.2 at 20 infections/patient/year Mean: 2.5 sepsis/patient/year 100% of infectious episodes, 75% of sepsis Mean: 7.5 infections/patient 70% of infectious episodes, 40% of sepsis Death rate = 36% Consequently, the number of days spent in hospital per trimes ter decreased from 55 to 12 days.
Recently, physicians from Newcastle have developed a parental educational programme of home intravenous albumin administration [35].

They reported this safe strategy management in seven children who had a very short length of stay in hospital ranging from 27 to 77 days from the onset.

This seems a very promising strategy in CNS.

The early discharge of patients is an important goal to improve quality of life and psychomotor development and decrease nosocomial infections and hospitalization burden.
Indeed, the three patients who died of septic shock before ESKD in our cohort had been managed in conventional hospi talization since birth and died from nosocomial infections.

They presented a very severe and profound nephrotic syn drome (with anasarca and repeated infections) and were treated with daily albumin infusions.

In contrast, no such severe com plication was observed in patients managed in ambulatory care.
In this cohort, there was a rate of 2.41 bacterial invasive infections/patient/year before ESKD, which is lower than other reported infection rates (Table 3).

This may be explained by the ambulatory management that is expected to decrease the noso comial infectious risk and by the more recent period of inclu sion with advances in medical care.

A trend to reduced infection rates was observed with the use of prophylactic antibi otics and immunoglobulin infusions, although not statistically significant.
Several studies already suggested the effectiveness of these p ractices [I, 25, 37] but only a prospective randomized controlled trial could evaluate the efficiency of these two treat ments in preventing infections in such patients, which is ham pered by the rarity of the disease.

A total of 29% of patients in the present series presented thrombotic complications, which is higher than the rate reported in other studies (Table 3).
Th is may be due to the absence of early systematic bilateral nephrectomy and subse quent prolonged nephrotic stage with hypercoagulability and extended wearing of central venous line.

In this study, 92% of children received systematic anticoagulation.

There is no inter national recommendation about thrombosis prophylaxis in CNS.

Lower serum albumin is a strong independent predictor for venous thrombosis events inNS [39, 40].

In adults, Lionaki et a/.


showed in 898 patients with membranous nephropathy, that the risk of thromboembolism was 9.4% for serum albumin level <28 g/L versus 3.2% in case of concentration >28 g/L [40).

Gyamlani et a/.

demonstrated increases that risk this proportionately with declining albumin levels [39].
However, it is unclear whether hypoalburninaemia promotes hypercoagul ability through hyperfibrinogenaemia and increased arachi donic acid bioavalaibility that favour platelet aggregation, o r whether it is only a surrogate marker of urinary losses of coagu lation regulators [39].

Another alternative is the use of alteplase instillation between catheter uses [ 41].

In this study, 5% of children died before ESKD, which seems lower than in other series.
Dialysis in infants, especially with nephrotic syndrome, is associated with significant morbidity and mortality rates [42- 44).

This is highlighted by the death of seven children on dialysis in the present report (21 %).

Consistently, in the ESPN/ERA-EDT A registry, 16/ 170 children affected with CNS died while on renal replacement therapy at a median age of 1.4 years [22).

According to the above-mentioned data, a subset of children with CNS may be managed safely in ambulatory care.
We hypothesized that the severity of CNS may depend on the genetic background.

We observed significantly better patient and renal survivals in patients with NPHSI mutations com pared with other groups and a similar proportion of patients with a transient interruption of albumin infusions.

We did not highlight differences in outcome between patients with 'mild' and those with at least one 'severe' NPHSJ mutation.
This anal ysis is complicated by the uncertainty of functional effects of mutations that have not been tested by in vitro assays.

Moreover, discrepancies exist between functional data, in silico scores and clinical features.

For instance, truncating mutations such as Fin-major and Fin-minor are expected to be more severe than missense variants.

However, the p.Arg1160* trun cating mutation results in lesser severity in 50% of female patients and preserved podocyte expression of nephrin [ 13].
Other counter examples are the p.Cys465Tyr and p.Ala806Asp missense variants considered as 'severe' since they induce the retention of the mutant nephrin in the endoplasmic reticulum [34].

This has also been demonstrated for >75% of tested mis sense mutants in the same study [34).

Last, the pathogenicity of each individual variant could hypothetically depend on the trans-associated mutation, as previously demonstrated with NPHS2 mutations [45].
This exemplifies the major difficulties to predict consequences of mutations without functional data.

To conclude on this point, NPHSI-mutations consid ered as 'mild' since they have been previously reported to induce late onset steroid-resistant nephrotic syndrome [13, 33, 34] are not associated with less severe nephrotic syndrome in case of Downloaded fror8 https: //academic.

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congenital onset.

Finally, our results showing a safe ambulatory management in some children may not reflect a milder pheno type of non-Finnish patients with CNS but rather different management approaches according to physicians' opinions.

For instance, some clinicians in the present cohort may have toler ated lower albumin trough levels with the aim of spacing infusions.

There were several limitations to this study.

First, its retro spective nature might have led to missing data.
In particular, some complications may have been omitted.

Patients nephrec tomized pre-emptively following recommendations of Finnish colleagues bias the age at ESKD.

The IgG level at the time of infections and IVIg indications were wu<nown, making it impos sible to assess the efficacy of a systematic IVIg supplementation.

The level of semm albumin at the time of thromboembolic com plications was also unknown, precluding the determination of a putative threshold beyond which the risk might be minimized.
Last, there were insufficient follow-up data regarding children receiving ACEi (n = 48) or indomethacin (n = 28) to assess the efficacy of chemical nephrectomy on nephrotic syndrome.
Nevertheless, this multicentre study involving all French Pediatric Nephrology units over a 15-year period and no patient lost to follow-up suggests a safe alternative to the early system atic bilateral nephrectomy, which is minin1izing hospital attendance through ambulatory care without increased risk of infection or mortality.

A subset of the patients of the present series had a favourable evolution since almost half of them were not dialysed at age 2 years.
Consequently, bilateral nephrectomy may not be systematically performed at 7 kg outside Finland but should be discussed on a case by case basis, depending on: (i) the severity of nephrotic syndrome and related complica tions, (ii) the possibility of ambulatory care management, (iii) the response to ACEi and non-steroidal anti-inflammatory drugs and (iv) the potential comorbidities.

Consequently, new recommendations for CNS management are deemed necessary.
SUPP LEMENTARY DATA Supplementary data are available at ndt online.

ACKNOW LEDGEME NTS We thank all the patients and their families for their partici pation in this study.

AUTHORS' CONTRIBUTIONS S.B.

conceptualized and designed the study, coordinated data collection, conducted the initial analyses, interpreted the data and drafted the initial manuscript.

O .B.
O .B.

conceptualized and designed the study, coordinated and supervised data collection, interpreted the data and critically reviewed and revised the manuscript.

V.B., J.B., B.B., M.D., L.d.P, O .D., H .F., M.F., A.G., ).H., L.H., F.L., M. -A.M., E.M., A.M., F.M., P.N., C.P., C.R.-R., G.R., R.S., S.T., J.T., T.U., R.V.

and A.Z.

conceptualized tl1e study, participated in acquisition of data collection and crit ically reviewed and revised the manuscript.

O.G.

and V.M.
O.G.

and V.M.

conceptualized the study, performed the genetic screening, analysed the data and critically revised the manuscript.

All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

CONFLICT OF I NTEREST STATEMENT No author has any relevant conflict of interest to declare.

The results presented in this paper have not been published previ ously in whole or part, except in abstract format.
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