Lupus Nephritis in Childhood

Saudi J Kidney Dis Transplant 2003;14(1):43-56

© 2003 Saudi Center for Organ Transplantation Saudi Journal

of Kidney Diseases

and Transplantation

Review Article

Lupus Nephritis in Childhood

Abdullah A. Al Salloum

Department of Pediatrics, College of Medicine & KKUH,

King Saud University, Riyadh, Saudi Arabia

ABSTRACT. The manifestations of lupus nephritis (LN) range from minor abnormalities

detected on urinalysis to severe renal insufficiency requiring renal replacement therapy. In

children, LN is often more severe than in adults. The female to male predominance is not as

marked as in adults. The risk of progression to end-stage renal disease in children is 18 to 50%.

The majority of children with LN have proteinuria, while the nephrotic syndrome is seen in

approximately 50% of affected patients. Children with LN have higher frequency of hypertension

which is considered as the most important prognostic clinical finding. The current practice of

estimation of complement components, C3 and C4 does not adequately reflect disease activity.

There are racial differences in renal survival and response to treatment. Arab patients with LN do

not exhibit a distinctive serological profile. Lupus nephritis is classified into six groups depending

on the severity of the histological lesion. Transformation between the histological classes occurs

frequently. Histological outcome predictions have been significantly enhanced by the addition of

activity and chronicity indices. Treatment of the LN may be guided by the severity of the renal

biopsy appearances. Controversy persists as to the most effective cytotoxic treatment in LN and

oral or intravenous (i.v.) cyclophosphamide, azathioprine, cyclosporin, i.v. immunoglobulin,

plasma exchange and recently mycophenolate mofetil have been used in different units. Today,

children with LN much less commonly go into renal failure. Outcome after renal transplantation

of children with end-stage renal disease caused by LN is similar to non-lupus patients. Morbidity

of the disease and the treatment remain a major problem.

Key words: Childhood, Lupus nephritis, Methyl prednisolone, Cytotoxic drugs.

Reprint requests and correspondence to: Introduction

Dr. Abdullah Al Salloum Systemic lupus erythematosis (SLE) is a disease Department of Pediatrics (39)

that is infrequent in childhood. Its importance College of Medicine & KKUH,

is derived from the fact that it is a life-threating King Saud University

P.O. Box 2925, Riyadh 11461 illness associated with significant complications.

Kingdom of Saudi Arabia It is a disease of immunological origin with

1

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44 Al Salloum AA

autoantibodies, polyclonal B-cell activation and

T-cell dysfunction. Ensuing immune complexes

are deposited or formed in situ in many

organs, and affect commonly the kidney as 2

lupus nephritis (LN). Although SLE has been

reported in children in the first 1-2 years of

life, it is rare in those under five years of age.

The peak presentation of childhood SLE 3

occurs around puberty. As in adults, a female

to male predominance is seen in pre-pubertal

SLE, although this is not as marked as in

adult-onset disease. The female-male ratio is in

fact about 4.5:1 throughout childhood and

adolescence, lower than 8-13:1 reported in a 4

series of adult-onset patients. Lupus nephritis is

extremely common in the pediatric presen

tation of SLE. It has been reported that 40-75%

of SLE patients develop clinically apparent

nephritis within five years of disease onset,

and almost all patients exhibit some degree of 5

glomerular abnormality. Both nephritis and the

consequences of its treatment cause signifi

cant morbidity. The risk of progression to end-

stage renal disease in children with renal

involvement is 18-50%.4,6

There is no doubt

that the use of high-dose corticosteroids has

improved the prognosis of severe lupus

nephritis. During the past 20 years, new

therapeutic approaches, including the use of

cytotoxic agents, have further improved renal

survival rates, which have reached 80% at 10 7

years. However, there is still some controversy

regarding the best treatment, mainly due to

lack of well-designed prospective therapeutic

studies with adequate numbers of patients.

Most publications report uncontrolled trials

and retrospective analyses, which do not allow

definitive conclusions to be drawn.

Clinical Presentation of Lupus Nephritis

in Childhood

Renal involvement in children with SLE is

extremely variable, with some patients showing

minimal urinary abnormalities while others

have rapidly progressive renal failure with

the nephrotic syndrome. Hematuria and

proteinuria are the most commonly identified 3

abnormalities. The majority of children with

LN have proteinuria, while the nephrotic

syndrome is seen in approximately 50% of

affected children at diagnosis. Hematuria is

nearly universal, being reported in 67-100% of

affected children in different series. Hyper

tension and decreased renal function are

also commonly seen at the time of diagnosis

of LN, occurring in approximately 50% of 4

affected children. The clinical picture is

related to the severity of histological abnorm7

alities on renal biopsy. In one study of age-

related differences in the clinical manife

stations of SLE, children were found to have

higher rates of hypertension (14% vs 3.4%),

proteinuria (71% vs 44%), hematuria (69% vs

25%), cellular casts (39% vs 15%) and elevated 1

serum creatinine concentration (25% vs 7%).

Serology

The laboratory findings in SLE include a

positive anti-nuclear antibodies (ANA) in

high titers with circulating anti-desoxyribose

nuclear acid (DNA) antibodies. The positive

ANA may demonstrate a specked, homo

genous, mixed or other patterns, and they can

be directed against double-stranded native

DNA or other antigens including Ro, La, Sm 8

and RNP. Anti-Sm antibodies are almost

entirely specific for lupus, but are found only

in about 30% of patients and thus, have a very 4

low sensitivity. Antibodies to ribosomal P

protein are more prevalent in childhood SLE

than in adults and the presence of anti-P

antibodies is strongly associated with severe 9

nephritis. Usually, both adult and childhood

“lupus like” patients with negative ANA show 10

little or no renal disease although there are

exceptions.11,12

Immune complexes can be

detected in the serum of the majority of


Lupus Nephritis in Childhood 45

children with LN and the titer in general and includes distal renal tubular acidosis

rises and falls with clinical activity. However, (dRTA), impaired tubular potassium excretion, 13

their utility in diagnosis is minimal. hyporeninemic hypo-aldosteronism, and decresed

Hypocomplementemia is present in more urinary concentrating ability. According to 25

than 75% of untreated children with LN. Kozeny et al, up to 60% of adult patients

Concentrations of C4 and C1q tend to be more with LN have either overt or latent dRTA.

depressed than C3, suggesting complement However, tubular dysfunction in childhood 26

activation via the classical pathway. Also, low and adolescence is rare.

levels of properdin and factor B level are present 4

suggesting alternate pathway activation. Injuries Renal Biopsy

induced by the formation of immune complexes Patients with hematuria, proteinuria with

involving glomerular or non-glomerular antigens or without the nephrotic syndrome, and a

are largely complement-dependent and can be normal or subnormal glomerular filtrations

greatly ameliorated, or prevented entirely, by rate may have any class of glomerular lesions 14

manouvers that inhibit complement activation. (focal or diffuse proliferative glomerulo

The current practice of estimation of nephritis with varying degrees of severity or

complement components C3 and C4 does not membranous glomerulonephritis). The prognosis

adequately reflect disease activity, as their is different and knowledge of the underlying

serum levels merely express the balance histological lesion is most important to 27

between synthesis and catabolism. Urinary decide the best therapy. The clinical picture

complement degradation products C3d and is not related in some cases to the severity 7

C4d reflect complement activation more of histological abnormalities on renal biopsy;

accurately than C3 and C4 levels and have some patients with the so called silent LN 28

been found to correlate better with disease may reveal severe histological lesions.15

activity of LN. Serum levels of IgG anti– Multiple renal biopsies may be needed

C1q were significantly increased in patients during the course of treatment of LN. 16

with active proliferative nephritis. Transformation between LN classes occurs

Although there are differences in renal frequently, more than two-thirds of follow-

survival rate and response to treatment in up biopsies were different than the first 17-20

LN among different races, Arab patients biopsy, and less than half of patients remained

and Africans with LN do not exhibit a in the original LN class on their last biopsy.5,29

distinctive serological profile.21,22

Some of the transformation may have occurred

The reported prevalence of anti-phospholipid in response to immuno-suppressive therapy. 30

antibodies in LN in children vary from 38 to Lehman et al reported seven children whose 23

87%. The presence of anti-phospholipid initial biopsies were class IV, and had class

antibodies is thought to represent a risk factor II on follow-up after three years of therapy. 1

for thrombotic episodes. Nevertheless, in a Sequential renal biopsy is indicated on the

recent study limited to 36 children with LN, an basis of one of these clinical situations: a)

increased risk of thrombotic episodes could improvement of renal disease but persistent 24

not be demonstrated. of non-nephrotic proteinuria to determine

whether to continue therapy, b) persistent or

Tubular Dysfunctions relapsing nephrotic syndrome to determine

Renal tubular dysfunction is a well- whether to increase immunosuppression, and

recognized complication of LN in adults c) worsening of renal functions to determine


46 Al Salloum AA

whether to administer aggressive immuno29

suppression to rescue renal function.

Histopathological classification of lupus

nephritis

The World Health Organization (WHO)

classification for LN was developed in 1973

to help the clinician distinguish the different

histologic presentations and with the hope

that it may help in guiding treatment. This

classification uses light microscopy, immuno

fluorescence, and electron microscopy, and

is now widely accepted.7,31

This classification

has been modified into six histological

groups and constitutes the first step before 7

deciding on any therapy.

32The (WHO) has classified LN as follows

Class I: Normal glomeruli; (a) nil (by all

techniques), (b) normal by light microscopy

but deposits by electron or immunofluorescence

microscopy.

Class II: Pure mesangial alterations

(mesangiopathy); (a) mesangial widening

and / or mild hypercellularity; (b) moderate

hypercellularity.

Class III: Focal segmental glomerulonephritis

(associated) with mild or moderate mesangial

alterations); (a) “active” necrotizing lesions; (b)

“active” and sclerosing lesions; (c) sclerosing

lesions.

Class IV: Diffuse glomerulonephritis (severe

mesangial, endocapillary or mesangio-capillary

proliferation and/or extensive subendothelial

deposits); (a) without segmental lesions; (b) with

“active” necrotizing lesions; (c) with active and

sclerosing lesions; (d) with sclerosing lesions.

Class V: Diffuse membranous glomerulo

nephritis; (a) pure membranous glomerulo

nephritis; (b) associated with lesions of category

IIa or IIb; (c) associated with lesions of category

III(a-c); (d) associated with lesions of category

IV(a-d). Alternatively, cases in these latter two

sub-categories are sometimes classified under

class III or IV.

Class VI: Chronic, sclerosing glomerulopathy.

In an analysis of nine investigations of the

patterns of glomerular damage seen in renal

biopsies in pediatric LN, comprising 365

children and adolescents, 25% had WHO

Class I–II histology while 65% had Class

III or IV, indicating a high frequency of

severe renal involvement, Class V was seen 1

in only 9% of affected pediatric patients.5

However, Sorof et al noticed a recent

increase in the incidence of childhood Class

V LN; 28% (17/60) of their patients had

Class V LN on the first renal biopsy.

Outcome predictions based on the WHO

classification, were significantly enhanced

by the addition of activity and chronicity 33

indices. A close correlation was observed

between a poor renal outcome and the 34

presence of chronic lesions on renal biopsy.

The combination of cellular crescents and 33

interstitial fibrosis was particularly ominous.

Active histological lesions include fibrous

crescents, endocapillary proliferation, fibrinoid

necrosis, karyorrhexis, thrombi, wire loops

with subendothelial immune deposits,

glomerular leukocyte infiltration, and intersti

tial mononuclear cell infiltration. These active

lesions are each graded 0-3 (with both

necrosis and cellular crescents graded 0-6)

to give an activity index graded 0-24. Active

lesions are potentially reversible with

treatment. Chronicity index includes glomerular

sclerosis, fibrous crescents, tubular fibrosis

and interstitial fibrosis. These lesions are

irreversible and do not respond to treat7

ment. The chronicity index score is the 35

most powerful prognostic factor. The

National Institute of Health (NIH) group

found that an activity index > 12/24 or

chronicity index > 4 were indicative of a poor 33

renal prognosis.


47 Lupus Nephritis in Childhood

The Treatment of Lupus Nephritis

Despite more than 30 years of study, the 36

optimal treatment of LN remains unclear.

This is because it is not clear whether we

are dealing with a primary B-cell overactivity,

a defect in T-suppressor cell regulation of B37

cell, or an excess of T help.

However, the outcome for pediatric patients

with SLE has improved dramatically over the

past three decades. Ten year survival rates

of 30% or less were reported in the 1960’s;

this improved to a 75% 10 year survival in

the 1970’s while in the 1980’s and early

1990’s, 10 years survival in excess of 80% 38

has been reported. These figures allow us

to approach the treatment of this chronic

illness much more optimistically. The effect

of extra-renal lupus may have a major role

in the mortality. Thus, infections have now

replaced renal failure as the most common 39

cause of death in childhood SLE.

The treatment of LN in the pediatric age-

group requires a balance between aggressive

early therapy directed toward controlling the

disease and effective long-term maintenance

therapy minimizing the side effects of the

drugs. Long delay between the onset of LN

disease and the start of appropriate therapy 40

correlates with a poor clinical outcome.

Therapy of Class I, II LN (mild renal lesions)

Class I is a rare situation and patients have 7

no renal symptoms.

Class II patients may have mild proteinuria

and microscopic hematuria but the glomerular

filtration rate is usually normal. Renal disease

in these patients does not need specific

therapy. Evidence that corticosteroid therapy

is beneficial from the standpoint of long-

term renal prognosis is lacking and treatment

is determined by the extra-renal manifestations 1

of the disease. Nevertheless, careful follow-up

of the patient is necessary, as progression to 5

a more severe renal disease is possible.

Therapy of Class III LN (moderate renal lesion)

The natural course of the disease depends

upon the extent of renal lesion. When less

than 20% of the glomeruli are affected by

small segmental lesions, the long-term

prognosis is favorable with probably less

than 5% risk of progression to end-stage 41

renal failure after five years. Patients

usually have mild renal symptoms, with low

grade proteinuria without nephrotic syndrome,

and a normal glomerular filtration rate. In this

setting, there is no indication for specific

therapy, which may however be required for 7

extra-renal symptoms. The situation is

different when cellular proliferation, necrosis

and large sub-endothelial deposits involve

more than 40% of the glomeruli present in

the biopsy sample and clinical symptoms

are more severe with an active urine sediment,

the nephrotic syndrome, hypertension and in

some patients, moderate renal insufficiency.

The course of the disease will be similar to that

of diffuse proliferative glomerulonephritis

(Class IV), and the same aggressive therapy 7

is needed.

Therapy of Class IV LN (severe renal lesions)

Class IV corresponds to diffuse proliferative

glomerulonephritis (DPG). It is widely

recognized that patients with DPG are at risk

for hypertension, the nephrotic syndrome, and 17

progressive renal insufficiency. Prompt

and aggressive therapy directed toward

controlling the renal manifestations of the

disease is indicated in these patients.

Corticosteroids

Patient and renal survival rates in SLE

have dramatically improved with the intro

duction of corticosteroid therapy. 42

Four decades ago, Pollak et al showed

that high-dose of oral corticosteroids could

improve the course of DPG whereas low

doses were ineffective. For two decades this

report was incorporated into all textbooks


48 Al Salloum AA

43 on the subject. Subsequent studies suggest

that high doses of oral corticosteroids are

no better than low doses in the treatment of

DPG in children. High doses of oral predni

solone alone not only give poor results in

the long-term but also are often associated 44

with serious side effects. Tejani A et al

showed that 25% of their patients had died

of renal causes and another 25% were

undergoing dialysis, received transplants, or

in chronic renal failure. These patients were

treated with prednisone in a dose of 60 2 45

mg/m /day. Steinberg et al assessed long-

term preservation of renal function in 111

patients in a randomized treatment trial;

four different drug treatment programs were

used. Each allowed the use of low-dose oral

prednisolone in addition to cytotoxic drugs

and were compared with regimen consisting

solely of high-dose oral prednisone. Patients

randomized to receive intravenous cyclophos

phamide or oral cyclophosphamide had

significantly better preservation of renal

functions than did patients who were

randomized to receive prednisone alone. With 46

similar conclusion Austin et al, showed that

addition of the cytotoxic drugs resulted in

better preservation of renal function than

treatment with oral prednisone alone.

Since 1975, many authors have proposed

initiation of therapy with intravenous methyl

prednisolone pulses for the acute phase of the

disease, mimicking the successful use of similar

treatment in transplant rejection. The justifi

cation for this treatment, was the resemblance

between the interstitial infiltrate of lupus

nephritis and of allograft rejection.47,48

Intravenously administered pulse methyl

prednisolone 20-30 mg/kg, up to 1 gm daily,

for three days often leads to striking impro

vement in renal function in LN, especially

in the subset of patients with recent antecedent 49

function deterioration. However, the long-

term effect of methylprednisolone pulses

alone in preserving renal function was similar

to oral prednisone.48,49

Side effects included

cardiac arrhythmias or even cardiac arrest if

given through central venous lines, unpleasant

flushing sensations, acute hypertension, and 4

occasionally acute psychosis.

Cyclophosphamide

Cyclophosphamide is metabolized, primarily

in the liver to active metabolites that alkylate

and phosphorylate macromolecules.43,50

Selective effects of cyclophosphamide on

different components of the lymphoid system 32

have been described. Several studies have

shown that renal survival is significantly

better when cyclophosphamide is added to

corticosteroids.30,36,40,48,51,52

Although initially

used predominantly in oral regimens in a

dose of 1-3 mg/kg/day for 8-12 weeks,

intermittent intravenous cyclophosphamide 2

bolus therapy, 500-1000 mg/m , on monthly

basis and subsequently bi-monthly or every

three months, has now become a frequently

utilized treatment modality for severe

LN.1,30,45,48

Cyclophosphamide given as monthly 2

boluses at a starting dose of 750 mg/m may

be less toxic than given orally everyday at a 53

dose of 2 mg/kg. The dose of cyclophos

phamide given in bolus form is increased to 2

1000 mg/m if the white blood cell count 3 54

remains above 3000/mm . The duration of

therapy following initial control of LN is 54

not well defined. Lehman et al treated 16

children with cyclophosphamide monthly

for six months and then every three months

until three years elapsed. They reported a

significant improvement at one year in

urine protein excretion, hemoglobin levels,

C3, C4, and creatinine clearance despite a

significant reduction in prednisone dosage.

Short courses of pulse cyclophosphamide

may be effective in reducing the risk of

renal progression within the first few years



and may be more tolerable and less toxic

than extended therapy, but may not be

optimal for preventing exacerbation of the

disease or progression to more renal insuffi48 55

ciency. Valeri et al used a treatment

regimen of six-monthly intravenous pulses of 2

cyclophosphamide (0.5 to 1 g/m ) together

with high-dose corticosteroid therapy which

was rapidly tapered. Over the first six months

of treatment, this regimen resulted in

improvement of clinical activity, lupus

serology, stabilization of renal function and

decreased proteinuria in 19/20 patients.

Over five years of follow-up, there were

five patients with doubling of serum

creatinine over baseline and three patients

required renal replacement therapy.

Patients with severe LN and normal serum

creatinine may have an excellent outcome

with short course (six months duration) of

cyclophosphamide pulses. Patients with more

severe clinical presentation may benefit from

more expanded regimen.

Therapy with cyclophosphamide, carries

considerable risk of toxicity, including

alopecia, bone marrow suppression, hemorr

hagic cystitis, gonadal failure and develop36

ment of malignancy. The incidence of

hemorrhagic cystitis is very low provided

adequate intravenous hydration for 24h is

ensured. As mentioned earlier, tubular

dysfunction has been reported in LN and

periodic electrolyte assessment is needed

during hydration to avoid hyponatremia and 54

seizures. In order to minimize the risk of

hemorrhagic cystitis, administration of mesna,

which binds to cyclophosphamide metabolites

in the urine, is recommended. No cases of

hemorrhagic cystitis or bladder cancer have

yet been reported in the various treatment 50

studies. Nausea and vomiting were common

during the first 24 hours after i.v. cyclophos54

phamide administration. This may be in part

prevented by the concomitant use of antiemetic

7agents such as Ondansetron (Zofren). Hair

thinning of variable severity developed in

all children during the first six months of 54

therapy in one study, but most regained a

normal appearance by one year. Cyclophos

phamide pulses often result in neutropenia,

with a serious risk of infection. Herpes

Zoster infections are frequent in these 56

patients. The risk of amenorrhea depend

on the age of the patient at the start of the

treatment and the total number of pulses.

When treatment is given for six months, the

risk of amenorrhea is very low if the patient

is less than 25 years of age. When the total

number of pulses exceeds 15, the likelihood

of developing amenorrhea is 17%. The

gonadal toxicity of pulse cyclophosphamide 7

in males with LN has not been studied.

Azathioprine

Azathioprine has been the anti-metabolic used

most frequently to treat patients with LN. It

interferes with protein synthesis by competing 50

for, and blocking specific receptors. Azathio

prine in doses of 2 to 2.5 mg/kg per 24hrs has

proved remarkably safe in the long-term,

although higher doses will induce leuco37

penia. Azathioprine may be used in combi

nation with prednisone in the early treatment of 57

severe LN, or it may be substituted for

cyclophosphamide following 8-12 weeks of

initial therapy with oral cyclophosphamide 1

and prednisolone, or as a substitute to i.v.

cyclophosphamide after six months, if the 7

disease is under control. Azathioprine has

steroid sparing effect,34,43,50

and as such

withdrawal of the drug without change in 37

steroid dosage may lead to relapse.

Azathioprine can cause bone marrow

suppression after 7 to 14 days of admini

stration, the hematopoietic suppression being

dose dependent and reversible on dis50

continuation of treatment. Rare reports have

mentioned cases of intrahepatic cholestasis,


50 Al Salloum AA

pancreatitis, cancer of the skin and uterine

cervix and central nervous system lymphoma 43

after long period of azathioprine administration.

Cyclosporin A

Cyclosporin A (CsA) was introduced in

recent years for the treatment of LN in

patients with steroid resistance or in those 58

with severe corticosteroid toxicity. The

basis for its use relates to its interference with

the production of lymphokines produced by

activated T-lymphocytes. By inhibiting the

production of interleukin-2, the recruitment

of cytotoxic T cells is arrested, decreasing

the inflammatory response to precipitating

and depositing immune complexes in the 1

kidney. In individuals with severe LN, CsA

use in conjunction with corticosteroids has

been shown to decrease proteinuria and

stabilize renal function. There was a significant

increase in growth rate, compared to the

prednisolone plus cyclophosphamide patients.

However, it seems that CsA alone is not

effective in controlling serological activity.58,59

Toxicity is minimal, with hypertension,

transient elevations of serum creatinine

concentration, hypertrichosis, gingival 1

hyperplasia and paresthesia.

Mycophenolate mofetil

Mycophenolate mofetil (MMF) is a novel

immunosuppressant that now forms part of

routine prophylaxis and treatment of acute

renal allograft rejection. MMF is a morpholino

ethyl ester of mycophenolic acid (MPA),

which inhibits de novo purine synthesis.

Because lymphocytes rely on de novo purine

synthesis, whereas other cells do not, MMF

is more selective for lymphocytes than 60

other cells.

Anecdotal reports of the successful use of

MMF in LN have recently been published.60,61

Of the 20 cases published, the majority

received MMF after failure of frequent cycles

of i.v. cyclophosphamide. MMF was used in a

dose of 20-25 mg/kg/24h for 10-12 months.

There was dramatic response to MMF in this

group of patients, with rapid achievement of

clinical and laboratory remission of nephritis.

Corticosteroid-sparing effects were noted in 61

each case. MMF was well-tolerated, the only

adverse effects noted being mild gastro

intestinal symptoms. Numerous unanswered

questions remain. As yet, no randomized

controlled trials of MMF in LN have been

conducted to define the indications or compare

the efficiency of MMF with standard therapies.

Also, the cost of MMF is considerable in

comparison to traditional immunosuppressive

agents. Over all, MMF might be a promising

drug for cyclophosphamide-resistant LN.

Intravenous Immunoglobulins (i.v. Ig)

Currently i.v. Ig is used for the treatment of

immunodeficiency states, and various auto

immune and inflammatory conditions that

include idiopathic thrombocytopenic purpura,

Guillian-Barre syndrome and Kawasaki

disease. Additionally, i.v. Ig is used empirically

in other autoimmune diseases, in which its role 62

remains controversial.63

In a recent pilot randomized trial, the

safety and efficacy of maintenance therapy

with monthly i.v. Ig in proliferative LN was

compared with cyclophosphamide. The i.v.

Ig was given in a dose of 400 mg/kg for 18

months, while, cyclophosphamide was given 2

i.v. in a dose of 1 g/m once a month for six

months and then every three months for one

year. Both groups received oral prednisolone

in addition. At the end of the follow-up period

(24 months) neither groups showed deterio

ration of renal functions and none of the

patients developed nephrotic range proteinuria.60

Similar observation by Lin et al showed

that high-dose i.v. Ig therapy is effective in about

half of the cases in steroid and immuno

suppressive drug-resistant Class IV lupus nephritis.



The few reports of i.v. Ig use in LN are

case reports in adults.62,63,64

The toxicity of

high-dose i.v. Ig was minimal. It included

chills, fever, hypotension, acute urticuria, 64

twitching and skin rash. The occurance of

transient and reversible renal failure after

i.v. Ig therapy has been reported in one 65

patient with borderline renal function. The

most likely explanation for the renal damage

induced by i.v. Ig is sucrose nephropathy;

sucrose is used as a stabilizer in i.v. Ig

preparations and can cause severe proximal

tubular vacualization with cellular swelling

as evident in humans and animals given 62

intravenous infusion of hypertonic sucrose.

However, acute renal failure also has been

reported after treatment with i.v. Ig

preparations not containing sucrose and may

be related to dehydration or rapid infusion of

the drug.62,65

Plasma exchange

There is an obvious rational for plasma

exchange in lupus, since in the active

disease, the plasma contains antibodies and

immunecomplexes that are believed to play

a role in tissue injury. Most workers have

assumed that concomitant immuno

suppression should be given to avoid

“rebound” antibody synthesis when exchange 37

ceases. However, treatment with plasma

exchange plus standard regimen of

prednisolone and oral cyclophosphamide

therapy does not seem to improve the clinical

outcome in patients with severe LN as 66

compared with the standard regimen alone.

Treatment of patients with Class V LN

A greater frequency of Class V LN has

been recently noted in childhood than has 57

been reported earlier. In some patients, the

membranous lesions are associated with

mesangial proliferation. This category

resembles diffuse proliferative glomerulo

17 nephritis. The nephrotic syndrome often

develops. Moderate renal failure and 7

hypertension are observed in 25% of patients.

Patients with pure membranous nephro

pathy, mild proteinuria, and normal renal

functions have a good prognosis with a 55

year–renal survival close to 85%. The

management of the patient having Class V

with proliferative lesions must be aggressive

treatment with cytotoxic agents including 5

i.v. cyclophosphamide.

Patients with Class V pure membranous

nephropathy should receive oral prednisolone

either alone or in conjunction with i.v. methyl

prednisolone.5,7

Infantile Lupus Nephritis

Infantile LN is extremely rare, and only a

few cases have been reported.67,68

The

presentation of the disease tends to be 67

severe, the pathology mainly shows

proliferative lesions. Intravenous cyclophos

phamide seems to be beneficial in these 67

patients.

Prognosis of LN in Children

Diffuse proliferative glomerulonephritis

(Class IV LN) is associated with a poor

prognosis.69,70

A positive correlation was

observed between the presence of chronic

lesions (high chronicity index) on renal

biopsy and a poor renal outcome.34,35

The

presence of high degree of interstitial fibrosis

in the first renal biopsy is associated with a 36

poorer renal prognosis.

The combination of cellular cresent and 33

interstitial fibrosis is particularly ominous.

Renal survival is significantly worse in some

races like American blacks inspite of more 44

aggressive treatment.

Patients with normal initial serum creatinine

levels have low risk of renal failure.36,71

The

presence of hypertension at the time of

diagnosis and persistent hypertension lasting


75

52 Al Salloum AA

greater than four months is considered the

most important poor prognostic clinical

finding in LN in children.69,70,72

Also, severe

nephrotic syndrome and anemia are considered 32

as predictors of poor renal outcome. Age,

gender, degree of hypo-complementemia and

ANA positivity are not associated with

progression to renal failure.4,69,70

The occurance of renal flares characte

rized by rapid increase in plasma creatinine

after cessation of treatment is a strong predictor

of development of irreversible deterioration

of renal functions. It is recommended that

all patients with LN, particularly hyper

tensive patients, continue to be closely

monitored in order to catch and treat early

and vigorously any possible deterioration of 29

renal function caused by LN flares.

End-stage renal disease (ESRD) in LN children

The risk of progression to ESRD in 6

children with LN is 18 to 50%. This compli

cation developed after a mean period of five 7

years. However, the progression of LN

severe enough to require dialysis does not

necessarily indicate that it is “end-stage”.

Ten to 28% of patients with LN who

develop renal failure requiring dialysis will

recover enough function to come off

dialysis.73,74

Dialysis and Transplantation

Dialysis, either hemo or peritoneal, can be

started, and these patients do as well as non-

lupus patients with end-stage renal disease.

Clinical and biological symptoms of the

disease most often improve in patients on

chronic dialysis, thus allowing discontinuation

of corticosteroids and immuno-suppressive

therapy.7,74

However, clinical manifestations can

persist or even get exaggerated at this stage 7

secondary to stress factors.

Renal transplantation is the treatment of

choice for those who progress to renal failure.

Patients with ESRD secondary to LN are

excellent candidates for renal trans

plantation and recurrence of LN is rare.

Graft and patient survival after the first

cadaveric and first living-related renal

transplantations are similar in patients with

ESRD caused by LN and patients with 76

ESRD from other causes. The results of 100

renal transplantations in children with LN 6

reported recently by Batrosh, were

comparable to those seen in an age, race,

and gender-matched control group. This is

despite the fact that SLE patients have an

underlying disease with multi-organ involve

ment and have received immunosuppression

for prolonged periods before transplantation.

Conclusion

The treatment of LN has been one of the

success stories of nephrology during the

past three decades. However, this condition

continues to cause significant mortality and

morbidity. Improvement in survival has

come at the expense of long-term

complications of therapy, which in the pediatric

age group have profound consequences.

The treatment of diffuse proliferative

glomerulonephritis should be vigorous. There

are still some questions on the duration of

treatment, the physician should bear in

mind that inadequate treatment of severe

nephritis exposes the patient to the risk of

progression to renal failure. Lupus nephritis

requires long-term and careful follow-up of

affected patients and meticulous attention is

required to optimize patient outcome.

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