systemic lupus erythematosus ( sle ) is a chronic systemic autoimmune disease that is caused by the loss of tolerance to one s own antigens and the production of autoantibodies forming immune complexes that are deposited in various organs , which induces an inflammatory response .
sle development is triggered by genetic , environmental , infectious , and hormonal factors [ 1 , 2 ] .
women are more frequently affected than men ( incidence ratio : 8 - 13 : 1 ) [ 14 ] .
sle onset before puberty and in the elderly is uncommon [ 1 , 510 ] .
the incidence in children was estimated at 0.36 - 0.9/100,000 children / year , morbidity : 3.3 - 24/100,000 children / year .
the diagnosis of sle is currently performed with the use of slicc criteria ( systemic lupus international collaborating clinics ) .
sle manifests with a broad spectrum of clinical signs , high variability of severity , and various response to implemented treatment [ 1 , 3 , 5 , 1115 ] .
50 - 70% adults with sle and 37 - 82% of children [ 58 ] .
at the early stages of sle the clinical signs of ln occur only in 25 - 40% of patients [ 13 , 58 ] and may present as minor abnormalities in the urine ( microhaematuria and/or proteinuria and/or leukocyturia ) or as nephrotic syndrome , nephritic syndrome , hypertension , or renal failure [ 13 , 710 ] . prior to the decision of treatment of ln
it is recommended to perform renal biopsy [ 13 , 16 , 17 ] . nowadays ,
renal histological examination is classified with the use of the isn / rps scale ( international society of nephrology / renal pathology society ) .
the treatment of adults and children with active sle may be divided into two stages [ 1719 ] : remission induction , aiming at the fastest possible ( usually 3 - 6 months ) regression of symptoms [ 3 , 1722 ] by the administration of immunosuppressive drugs : cyclophosphamide [ 2328 ] or mycophenolate mofetil [ 2931 ] combined with glucocorticosteroids [ 1719 , 2227 ] , cyclosporin a , rituximab ; new biological therapies ( belimumab , epratuzumab , ocrelizumab ) [ 3437 ] , and in particular clinical situations  plasmapheresis and renal replacement therapy [ 3 , 1720 ] ; supportive treatment with the fewest drugs administered in the lowest effective doses , which maintains the remission .
there are no clear guidelines as regards the duration and ways of termination of supportive treatment [ 3 , 1721 ] .
the minimal period of three years of supportive treatment is recommended in ln patients with a complete or at least partial response to treatment .
drugs which may be used in the supportive treatment are azathioprine ( aza ) [ 17 , 18 , 27 , 28 ] or mycophenolate mofetil ( mmf ) [ 17 , 18 , 2931 ] and then prednisone in monotherapy [ 17 , 18 ] .
moreover , long - term administration of an antimalarial drug ( chloroquine ) is recommended becuase it reduces the risk of renal exacerbations , permanent renal injury , thrombotic episodes , and the number of deaths [ 3 , 17 , 20 , 38 ] .
if ln occurs with proteinuria of over 0.5 g / day or hypertension , it is necessary to introduce the inhibitors of renin - angiotensin - aldosterone system [ 1720 ] .
however , in spite of treatment , 10 - 20% of ln patients develop end - stage renal failure [ 3 , 58 , 17 , 18 ] . the development in sle diagnosis and treatment leads to an improvement in the prognosis [ 13 , 6 , 10 , 1315 ] .
however , the comparison with the general population shows a 2 - 5-fold higher risk of death in sle patients .
the clinical factors of poor prognosis in sle include : young age at onset , initial high activity of the disease , severe nephropathy , and central nervous system involvement [ 13 , 5 , 9 , 10 ] .
data collected worldwide show that the clinical course of sle in children is more severe in comparison with adults [ 1 , 5 , 10 ] .
the aim of the study was to assess the clinical and morphological presentation and treatment outcomes in children with ln in a paediatric nephrology centre during 10 years .
the study included 18 children ( 16 girls and 2 boys ) with sle diagnosed at the average age of 14.4 1.86 years .
the children were hospitalised due to ln in the university hospital in the years 2004 - 2014 .
the following elements were considered in the assessment : the age of sle onset , the type of non - renal manifestations , the age of ln onset , clinical picture of nephropathy ( microhaematuria , leukocyturia , proteinuria , nephrotic syndrome , hypertension , renal failure ) , activity of disease , renal biopsy result , recurrences of the disease , and complications .
the patient may be diagnosed with sle if at least four clinical and immunological criteria are met , including at least one clinical and one immunological criterion , or if biopsy confirms the diagnosis of ln with the presence of ana or anti - dsdna antibodies .
the assessment of the activity of disease was performed with the sledai scale ( sle disease activity index ) .
the activity of disease was classified as high with the score of  25 points , moderate with 16 - 24 points , and low with  15 sledai points .
biopsy was not performed before treatment in a 17.5-year - old girl with severe mental impairment and critical state .
prior to obtaining renal biopsy results all the children with ln were administered prednisone ( encorton ) at 1.5 - 2 mg / kg / day ( max . 60 mg / day ) and/or pulses of intravenous methylprednisolone ( mp ) 10 - 15 mg / kg ( max
. 1000 mg / pulse ) , then prednisone 1 mg / kg / day with the dose reduced individually .
induction therapy included cyclophosphamide ( cyp ) pulses in 16 children and mmf in two children .
fourteen children were administered intravenous cyp according to the national institute of health - nih guidelines   at a dose of 750 mg / m ( max . 1000 mg / infusion ) modified according to leukocytosis and gfr levels .
the regimen was : once a month for six months , then once every three months .
two children were administered cyp according to euro - lupus regimen , i.e. six infusions of 500 mg every two weeks .
two children were administered mmf at a maximum dose of 1200 mg / m with prednisone at 1 mg / kg / day .
apart from immunosuppressive drugs , the induction therapy in five children with renal failure and/or multiorgan failure and/or septicaemia was combined with renal replacement therapy : haemodialysis ( hd ) , continuous veno - venous haemodiafiltration ( cvvhdf ) and plasmapheresis ( pe )  four children .
all the children with proteinuria were administered an angiotensin - converting - enzyme inhibitor ( acei ) : enalapril maleate at 2.5 - 10 mg / day or angiotensin receptor blocker ( arb ) : losartan 25 - 50 mg / day .
hypertension was treated with acei , arb or betablocker : amlodipine at 2.5 - 10 mg / day .
supportive treatment included aza for 2 - 5 years or mmf for 2 years with prednisone at an individually decreased dose , then prednisone as monotherapy . at baseline
all the patients underwent the following tests : complete blood count , glucose , urea levels , c3 and c4 complement component , ana and ds - dna antibody titres , creatinine , and creatinine clearance ( calculated with schwartz equation ) .
prior to the treatment all the patients underwent ophthalmological examination , chest x - ray , ecg , and abdominal ultrasound . throughout ln treatment with immunosuppressive drugs and prednisone ophthalmological examination
ln remission was reported if serum creatinine normalszed appropriately for the child s age and gfr was > 90 ml / min/1.73 m , proteinuria < 0.5 g / day , ana  1 : 80 .
clinical data of 18 ln children , renal biopsy result , and the type of treatment are presented in table 1 .
the average observation period until 18 years of age was 33.4 26.13 months in 15 children and 16.3 16.19 months in the remaining three children .
clinical date , renal biopsy results , and treatment in children with lupus nephritis ln  lupus nephritis , n  number , f  female , m  male , yrs  years , sledai  sle disease activity index , obs .  observation , aki  acute renal injury , ht  hypertension , ns 
nephrotic syndrome , ins / rps  international society of nephrology / renal pathology society classification , g 
chronic , mp iv  intravenous methylprednisolone pulse , cyp  cyclophosphamide pulse , nih  national institute of health - nih guidelines , euro - lupus  euro - lupus regimen , mmf  mycophenolate mofetil , i  induction , s  supportive , aza  azathioprine , p 
chloroquine during the prodromal period of sle the following non - specific clinical manifestations were reported : weakness in 10 children ( 55.6% ) , recurrent fever in 10 children ( 55.6% ) , body weight reduction in seven children ( 38.9% ) , headache in four children ( 22.2% ) , and recurrent diarrhoea in three children ( 16.7% ) .
the most common initial sle clinical manifestations in the study group were : haematologic in 14 children ( 77.8% ) , musculoskeletal in 13 children ( 72.2% ) , and cutaneous in 12 children ( 66.7% ) .
the involvement of vital organs was reported in eight children ( 44.4% ) including : heart in four children ( pericarditis in two children , libman - sacks endocarditis in one child , dilated cardiomyopathy in one child ) , central nervous system in five children ( headache in three children , convulsions in two children , depressive symptoms in one child ) , and respiratory insufficiency in one child .
the results of ana testing showed the titres from 1 : 160 to 1 : 5120 ( table 1 ) .
the presence of ds - dna was reported in 11 children ( 61.2% ) , the reduction of c3 complement in 12 children ( 66.7% ) , and c4 in 14 children ( 77.7% ) .
the average activity of disease at onset according to sledai was 23.2 4.98 points ( fig . 1 ) and was assessed as high in 44.4% of children and moderate in 55.6% children .
the ratio of non - renal to renal symptoms was 57% : 43% ( table 1 ) .
systemic lupus erythematosus disease activity index ( sledai ) , glomerular filtration rate ( gfr ) and mean proteinuria at the onset and at the end of observation of children with lupus nephritis the signs of ln were reported in the first four months ( average : 79 77.6 days ) since sle onset .
all the children had microhaematuria and proteinuria at the average level of 92.5 66.4 mg / kg/24 h. nephrotic syndrome was diagnosed in 15 children ( 83.3% ) , hypertension in 13 children ( 72.2% ) , and acute renal injury in 15 children ( 83.3% ) .
2 ) . clinical presentation lupus nephritis in children renal biopsy was performed in 17 children between days 7 and 64 ( average  38 days ) after the onset of nephropathy .
renal biopsy most commonly revealed ln class iv according to isn / rps ( table 1 ) .
seventeen children were administered 3 - 13 ( average : 6.6 3.55 ) mp pulses , and one child was treated with oral prednisone .
fourteen patients treated with intravenous cyp according to nih regimen were administered the average of 107.2 61.79 mg / kg / treatment ( i.e 5.5 2.71 g / treatment ) .
cyp pulse therapy lasted for the average of 9.6 7.66 months and depended on the clinical status of the patient and the activity of disease .
one girl ( patient 15 , table 1 ) developed pneumonia with underlying aspergillus infection , which excluded her from further cyp treatment . she was continued on oral steroids in combination with aza .
two girls ( patients 8 and 11 ) were administered only four and three cyp pulses , respectively , before they turned 18 and were transferred to nephrological centres for adults .
the highest number of cyp pulses ( 13 ) were administered over 27 months to a boy ( patient 12 ) who , at the critical state at the beginning of the disease ( septicaemia , multiorgan failure , pulmonary oedema , dilated cardiomyopathy , anuria ) , was treated with cvvhdf and plasmapheresis ( nine procedures ) . a similar induction treatment regimen : cyp ( 500 mg / infusion ) , plasmapheresis ( 6 - 9 procedures ) and renal replacement therapy ( hd  two children , cvvhdf  two children )
was implemented in four children ( patient 7 , 8 , 10 , 16 ) . throughout cyp treatment according to nih regimen , the following complications were observed : leukopaenia in 10 children ( 71.4% ) , nausea in 10 children ( 71.1% ) , hair thinning in eight children ( 57.4% ) , menstruation disorders in four girls ( 30.8% ) , shingles in four children ( 28.5% ) , oral fungal infections in three children ( 21.4% ) , recurrent herpes in three children ( 21.4% ) , pneumonia / aspergillosis in one child ( 7.1% ) , and recurrent enterobiasis in one child ( 7.1% ) .
three children ( 21.4% ) treated according to this regimen experienced one recurrence of the disease after six months , three and five years after onset .
two children treated according to euro - lupus regimen ( patients 3 and 7 ) with 3  of intravenous cyp over three months did not develop any complications .
at the end of observation period these children had the nephrotic proteinuria reduced to 0.8 - 1.0 g / day and gfr at 63 - 105 ml / min/1.73 m both patients had hypertension which was well - controlled with antihypertensive drugs .
two children in induction therapy received mmf : a girl ( patient 2 ) with membranous ln ( class v according to ins / rps ) and a girl ( patient 10 ) with neurological symptoms and ln class iv - s(a ) .
proteinuria regressed and diminished to < 0.5 g / day and renal function normalised in these children .
eleven children ( 61.1% ) were administered 250 mg of chloroquine over 1 - 2 years with no adverse effects . during supportive treatment 12 children
aza was effectively substituted with mmf in one girl who had a tendency towards leucopaenia ( patient 6 ) .
supportive treatment included prednisone in doses reduced individually ( table 1 ) . during chronic steroid treatment the following manifestations
were observed : transient glucose intolerance in one child ( 5.6% ) , cataract in two children ( 11.1% ) , osteoporosis in four children ( 22.2% ) , and hypertension in 72.2% of children .
microhaematuria and leukocyturia regression were observed in all the children and a complete ln remission in seven children ( 38.9% ) , during the first year of treatment . the average duration of observation was 32.1 23.36 months ( 7 months  7.3 years ) . during that period renal function
improved in all the children ( final average gfr at 90.87 12.13 ml / min/1.73 m vs. baseline average gfr 54.55 33.09 ml / min/1.73 m ) , including gfr normalisation in 12 children ( 66.7% ) , proteinuria regression in 66.7% of children , and proteinuria reduction in 33.3% of children down to 32.9 11.67 mg / kg / day ( fig .
fifteen children were transferred to nephrological centres for adults when they turned 18 years old .
three girls are still being treated : patient 9 is currently receiving cyp pulses according to nih , and two other girls are undergoing supportive treatment : mmf and prednisone ( patient 6 ) , aza and prednisone ( patient 4 ) .
the onset of sle in children from the study group was at the average age of 14.4 years .
as regards the gender  girls dominated ( 8 : 1 ) , which is consistent with the literature [ 13 , 710 ] .
the initial activity of sle was moderate - high according to sledai , with the predominance of non - renal signs ( 57% ) .
it is stated that in the early period the clinical signs of renal diseases occur only in 25 - 40% of sle patients [ 13 ] , being more common in children than in adults [ 58 ] and their presence translates into poorer prognosis both in adults [ 13 ] and in children [ 510 ] . in the study group ,
nephropathy was present at onset or developed in the first four months since sle onset .
all the patients had microhaematuria , and 89% children presented with a severe ln onset : nephrotic syndrome , renal failure , and hypertension .
therefore , the assessment of active and chronic abnormalities conducted according to isn / rps revealed the predominance of active abnormalities ( mainly class iv ) in histopathological examination , which could influence treatment results . in proliferative ln
it is necessary to combine immunosuppressive drugs with glucocorticoids at high doses [ 1720 ] . according to numerous authors , children
are administered higher doses of steroids in comparison with adults [ 5 , 6 ] .
94.4% of patients in this study group were administered pulses of methylprednisolone at onset . according to eular / era - edta guidelines ,
it is necessary to administer high doses of intravenous cyp in the induction of remission in proliferative ln with poor prognostic factors , i.e. severe deterioration of renal function , the presence of cellular crescents , and/or fibrinoid necrosis in renal biopsy [ 1620 ] .
the induction therapy in 88.9% of children in this study group involved the intravenous administration of cyp and administration of mmf only in 11.1% of children .
mmf is considered the first - line treatment in african americans and hispanic patients due to its more marked effectiveness , and also in young patients due to a lower risk of infertility and in patients with lupus membranous nephropathy [ 58 , 1820 , 30 , 31 ] .
the minimum of 25% of proteinuria reduction and normalisation of c3 and/or c4 complement components after eight weeks and serum creatinine reduction and proteinuria < 1 g / day after six months of induction therapy are considered good prognostic factors of ln .
microhaematuria and leukocyturia regression were observed in all the children in our group and a complete ln remission in seven children ( 38.9% ) during the first year of treatment . according to the literature , even half of ln patients experience the recurrence after obtaining a complete or partial remission [ 1 , 3 , 58 , 18 ] .
each ln exacerbation , particularly a nephritic one , can lead to permanent renal injury .
therefore , it is recommended to treat all ln exacerbations as a new renal involvement .
amaral et al .   conducted an analysis and demonstrated an increased risk of renal involvement in the course of juvenile sle and an increased risk of mortality compared to patients with adult - onset symptoms . in his group ,
the most common class of histopathological lesions in adolescents and adults was class iv , which was consistent with the results of the present study . according to the data of institute of rheumatology in warsaw
the assessment of the course of the disease in those children revealed a decreased initial activity of disease according to sledai scale , renal involvement and epilepsy were less common , while psychosis and the presence of anti - ds - dna antibodies were more common .
mortality was most frequently due to generalised infections ( renal failure was indicated as one in previous years ) .
high initial activity of sle was observed in the present study group of children with ln . at the onset of the disease about one third of children
required renal replacement therapy or plasmapheresis due to renal / multi - organ failure and/or septicaemia .
induction therapy with intravenous cyp in the majority of children resulted in a final average gfr of 90.87 12.13 ml / min/1.73 m and proteinuria regression in 66.7% of children .
microhaematuria , nephrotic syndrome , hypertension , and renal injury are frequent manifestations of lupus nephritis in children .
induction therapy with intravenous cyclophosphamide is an effective treatment in the proliferative forms of lupus nephritis in children .
long - term assessment of the course of lupus nephritis in polish children requires multi - centre cooperation and evaluation of new immunosuppressive agents including mmf and rituximab .
 systemic lupus erythematosus ( sle ) in children is usually more severe than it is in adults and there is a higher incidence of renal involvement . 
 we described 18 children ( 16 girls , 2 boys ) with lupus nephritis ( ln ) , whose average age was 14.4 1.81 years . 
 disease activity was assessed according to sledai ( sle disease activity index ) . 
 renal biopsy was classified according to the ins / rps ( international society of nephrology / renal pathology society ) . 
 the patients were treated with steroids ( 100% ) and pulses of cyclophosphamide ( 88.9% ) or mycophenolate mofetil ( 11.1% ) , next azathioprine or mycophenolate mofetil with prednisone in reduced doses . in children with renal / multi - organ insufficiency and/or septicaemia , renal replacement therapy ( 27.8% ) , and plasmapheresis ( 22.2% ) 
 were used in the initial treatment . 
 the sledai initial activity was high in 44.4% and moderate in 55.6% of children . 
 ln manifested as : nephrotic syndrome ( 83.3% ) , microhaematuria ( 100% ) , leukocyturia ( 60% ) , hypertension ( 72.2% ) , and acute renal injury ( 83.3% ) ; mean gfr was 54.55 33.09 ml / min/1.73 m2 . in the renal biopsy , class iv ln according to ins / rps 
 was mainly diagnosed ( 82% ) . at the end of follow - up , mean observation time 
 32.123.36 months : mean gfr was 90.87 12.13 ml / min/1.73 m2 , proteinuria disappeared in 66.7% and decreased in 33.3% of children to the average of 1.7 g / day ( range : 0.5 - 4.0 g / day ) , hypertension was observed in 83.4% of children . 
 intensive immunosuppressive treatment with pulses of cyclophosphamide in early stage of ln in children is very effective . 
Introduction
Material and methods
Treatment
Results
Induction therapy
Discussion
Conclusions