SRNS Lapkas Sham & Justin

7/29/2019 SRNS Lapkas Sham & Justin

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CHAPTER 1

INTRODUCTION

1.1. BACKGROUND

The first recorded description of nephrotic syndrome dates to the 15th century. Later,

Volhard and Fahr popularised the term nephrosis, using it to describe a major classification of

bilateral renal disease. Today, nephrotic syndrome is recognised as a common chronic illness in

childhood (Eddy AA & Symons JM, 2003)

The estimated annual incidence of nephrotic syndrome in healthy children is 2 to 7 new

cases per 100,000 children younger than 18 years of age, making it a relatively common major

disease in pediatrics. The peak age of onset occurs at 2 to 3 years except for the rare, congenital

type of nephrosis. Approximately 50% of affected children are ages 1 to 4 years; 75% are

younger than age 10 years. In addition, even the most benign form of the nephrotic syndrome is,

by nature, a recurrent disorder, so each new-onset case likely will continue to manifest disease

for some time. Nephrotic syndrome is one of the most frequent reasons for referral to a pediatric

nephrologist for evaluation, although its insidious onset frequently causes delay in diagnosis.

Careful examination of the anatomy of a nephron permits characterization of the glomerular

basement membrane as the barrier between the circulation and the external environment. Thus,the glomerular membrane, which permits passage in an adult of approximately 180 L/d of fluid,

is the final determinant of how much of the solute originally contained in this volume enters the

tubular lumen. The normal glomerular membrane is remarkably selective for protein compared

with other solutes. Once this selectivity is lost, the ensuing proteinuria defines not only the

diagnosis of nephrotic syndrome, but many pathophysiologic consequences as well (Roth KS et

al, 2002)

Childhood nephrotic syndromes are most commonly caused by one of two idiopathic

diseases: minimal-change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis

(FSGS). A third distinct type, membranous nephropathy, is rare in children. Other causes of

isolated nephrotic syndrome can be subdivided into two major categories: rare genetic disorders,

and secondary diseases associated with drugs, infections, or neoplasia. The cause of idiopathic

nephrotic syndrome remains unknown, but evidence suggests it may be a primary T-cell disorder


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that leads to glomerular podocyte dysfunction. Genetic studies in children with familial nephrotic

syndrome have identified mutations in genes that encode important podocyte proteins. Patients

with idiopathic nephrotic syndrome are initially treated with corticosteroids. Steroid-

responsiveness is of greater prognostic use than renal histology. Several second-line drugs,

including alkylating agents, ciclosporin, and levamisole, may be effective for complicated and

steroid-unresponsive MCNS and FSGS patients. Nephrotic syndrome is associated with several

medical complications, the most severe and potentially fatal being bacterial infections and

thromboembolism. Idiopathic nephrotic syndrome is a chronic relapsing disease for most steroid-

responsive patients, whereas most children with refractory FSGS ultimately develop end-stage

renal disease. Research is being done to further elucidate the disorders molecular pathogenesis,

identify new prognostic indicators, and to develop better approaches to treatment (Eddy AA,

Symons JM, 2003)

1.1. Objective

The aim of this study is to explore more about the theoretical aspects on Nephrotic

Syndrome, also to emphasis and to integrate the theory and application of Nephrotic Syndrome

case in daily life.


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CHAPTER 2

NEPHROTIC SYNDROME

2.1. DEFINITION OF NEPHROTIC SYNDROME

Thesine qua non of the diagnosis of nephrotic syndrome is the presence of urinary protein, with

the albumin disproportionately greater than the globulin, deriving from a loss of glomerular

membrane selectivity. In the pediatric age group, urinary protein loss of 50 mg/kg per 24 hours

or greater is a firm diagnostic criterion. It is imperative to recognize the distinctive origin of the

proteinuria in the glomerulus rather than the tubule; nephrotic syndrome may be seen as

exclusively glomerular in origin without any associated tubular dysfunction. Additionally, as a

syndrome, the clinical picture may be either primary or secondary, and underlying causes must

be excluded (Roth KS et al, 2002).

The nephrotic syndrome (NS). consisting of massive proteinuria, hypoalbuminemia, edema, and

hyperlipidemia, is a common complication of glomerular disease in children and adults (Tune

BR & Mendoza SA, 1997).

2.2. EPIDEMIOLOGY OF NEPHROTIC SYNDROME

Idiopathic nephrotic syndrome has a reported incidence of two to seven cases per 100 000

children and a prevalence of nearly 16 cases per 100 000. There are three distinct histological

variants of primary idiopathic nephrotic syndrome: minimal-change nephrotic syndrome

(MCNS), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy. MCNS

and FSGS may represent opposite ends of one pathophysiological process or distinct disease

entities. By contrast, membranous nephropathy is a distinct disease associated with prominent

immune complex deposits located between glomerular podocytes and the glomerular basement

membrane. Membranous nephropathy is rare in children (Eddy AA, Symons JM, 2003).

The annual incidence of nephrotic syndrome in most countries in the Western Hemisphere is

estimated to range from 2 to 7 new cases per 100,000 children, and the prevalence is about 16

cases per 100,000 children. There is a male preponderance among young children, at a ratio of


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2:1 to females, although this gender disparity disappears by adolescence, making the incidence in

adolescents and adults equal among males and females (Gbadegesin R & Smoyer WE, 2008).

The incidence of nephrotic syndrome has been fairly stable over the last 30 years, but there are

suggestions that the histopathologic patterns may be changing. For example, reports from

different parts of the world indicate an increasing occurrence of focal segmental

glomerulosclerosis (FSGS) not only after adjusting for variations in renal biopsy practices but

also based on the generous assumption that all patients who did not have a renal biopsy had

minimal change nephrotic syndrome (MCNS) (Gbadegesin R & Smoyer WE, 2008).

Ethnic origin may affect the histological variant and the response to immunosuppressive

treatment. In particular, Hispanic and black patients are more likely to have steroid-unresponsive

nephrotic syndrome than are white patients. Age at initial presentation has an important impact

on the disease distribution frequency. 70% of MCNS patients are younger than 5 years; 2030%

of adolescent nephrotic patients have MCNS. FSGS develops in children at a median age of 6

years. During the first year of life, congenital (birth to age 3 months) and infantile (312 months)

genetic disorders and congenital infections are much more common than MCNS and FSGS.

Inherited forms of steroid-responsive and steroid-resistant nephrotic syndrome are being

increasingly recognised (Eddy AA, Symons JM, 2003).

Not all cases of MCNS or FSGS are idiopathic. MCNS can occur in association with lymphoid

tumours or immunomodulatory drugs. FSGS is the most common histological variant in patients

with HIV nephropathy. Renal lesions resembling idiopathic FSGS may also be present in

proteinuric patients with other primary renal disorders, such as chronic glomerulonephritis,

reflux nephropathy, and oligomeganephronia (Eddy AA, Symons JM, 2003).

2.3. CLASSIFICATION OF NEPHROTIC SYNDROME

Idiopathic (primary) nephrotic syndrome

- Minimal change (80-90%)

- Focal segmental glomerulosclerosis (FSGS) (10-20%)

Secondary nephrotic syndrome (HSP, SLE, MPGN)

Congenital nephrotic syndrome

(Fahmi N, 2011)


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Children who present with the typical features of nephrotic syndrome (see below) are generally

responsive to steroid treatment and a renal biopsy, were it performed, would be likely to show

minimal change nephrotic syndrome. Those with atypical features are more likely to be

unresponsive to steroid treatment, and a biopsy more likely to show FSGS or one of the other

forms of nephrotic syndrome. Therefore children with typical features are started on steroids

without recourse to renal biopsy. Those with atypical features should therefore undergo renal

biopsy before receiving steroid treatment (Fahmi N, 2011).

TYPICAL FEATURES ATYPICAL FEATURES

Age 1-10 years < 1yr, > 10years

Normotensive Hypertensive

Normal Adrenal Function Elevated Creatinine

+/- Microscopic Haematuria Macroscopic Haematuria

2.4. ETIOLOGY OF NEPHROTIC SYNDROME

NO CAUSES OF CHILDHOOD NEPHROTIC SYNDROME

1 Genetic Disorders

Nephrotic Syndrome Typical

- Finnish-type congenital nephrotic syndrome

- FSGS- Diffuse mesangial sclerosis

- Denys-Drash syndrome

- Schimke immuno-osseous dysplasia

Proteinuria with or without Nephrotic Syndrome

- Nail-patella syndrome

- Alports syndrome

Multi system syndromes with or without Nephrotic Syndrome

- Galloway-Mowat syndrome

- Charcot-Marie-Tooth disease

- Jeunes syndrome


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- Cockaynes syndrome

- Laurence-Moon-Biedl-Bardet syndrome

Metabolic disorders with or without Nephrotic Syndrome

- Alagille syndrome

- -1 antitrypsin deficiency

- Fabry disease

- Glutaric acidaemia

- Glycogen storage disease

- Hurlers syndrome

- Lipoprotein disorders

- Mitochondrial cytopathies

- Sickle-cell disease

Idiopathic Nephrotic Syndrome

- MCNS

- FSGS

- Membranous nephropathy

2 Secondary Causes

Infections

- Hepatitis B, C

- HIV-1

- Malaria

- Syphilis

- Toxoplasmosis

Drugs

- Penicillamine

Gold

Non-steroidal anti-inflammatory drugs


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Pamidronate

Interferon

Mercury

Heroin

Lithium

Immunological or Allergic Disorder

- Castlemans disease

- Kimuras disease

- Bee sting

- Food allergens

Associated with Malignant Disease

- Lymphoma

- Leukaemia

Glomerular hyperfiltration

- Oligomeganephronia

- Morbid obesity- Adaptation to nephron reduction

*May also be consequence of inflammatory glomerular disorders, normally associated

with features of nephritiseg, vasculitis, lupus nephritis, membranoproliferative

glomerulonephritis, IgA nephropathy.

(Allison A Eddy, Jordan M Symons., Nephrotic syndrome in childhood, THE LANCET, Vol

362, August 23, 2003)

2.5. PATHOGENESIS OF NEPHROTIC SYNDROME


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The pathogenesis of MCD is unclear, but there is a strong evidence of immune dysregulation,

chiefly involving cell-mediated immunity (CMI). The tendency of nephrotic syndrome to

manifest and relapse after viral infections or an atopic episode, the association with HLA

antigens and Hodgkins lymphoma, and the therapeutic response to steroids and cyclosporine A

(CsA) support this view. The occurrence of prolonged remissions following measles, which

downregulates CMI further endorses this hypothesis. Abnormalities of T cell subsets and/or

function have been variably reported in a number of patients with MCD9-11. Most of the

functional abnormalities that are described are not specific and might represent an effect (rather

than a cause) of the disease (Bangga A & Mantan M, 2005).

2.5.1 Cytokine bias

Recent knowledge on functional subdivisions of the immune response has been applied to

understand the pathogenesis of nephrotic syndrome. Broadly, antigen presentation to T

lymphocytes results in a polarized immune response, which may be type 1 [dominated by -

interferon, interleukin (IL) 2] or type 2 (IL4, IL10 or IL13). Type 1 cytokines predominate in

cell-mediated immunity and type 2 cytokines in some aspects of humoral immunity. Type 2

cytokines are particularly associated with atopy and class switching of B cells for production of

IgG4 and IgE13. The findings of increased plasma levels of IgE, relatively normal IgG4 (with

decreased IgG1 and IgG2), and association with atopy suggest type 2 cytokine bias in subjects

with MCD. Increased systemic production of representative cytokines, chiefly IL4 is also

reported14. In vitro studies suggest that podocytes express receptors for IL4 and IL1314.

Activation of these receptors, by respective cytokines, might disrupt glomerular permeability

resulting in proteinuria. The clinical benefits on treatment with levamisole, which augments type

1 and downregulates type 2 cytokines also support the above hypothesis (Bangga A & Mantan

M, 2005).

Examination, by immunohistochemistry renal biopsies from 30 consecutive patients with steroid-

resistant nephrotic syndrome (SRNS), secondary to MCD and FSGS, for T cells expressing type

1 or type 2 cytokines.It was found that there was a significantly higher proportion of IL4 and

IL10 bearing T cells compared to those expressing interferon-(IFN-) or IL2. The precise

mechanism/s by which the cytokine bias might affect glomerular permeability is however, not

clear (Bangga A & Mantan M, 2005).


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2.5.2. Nephrotic syndrome a podocytopathy

For many years the attention of researchers was focussed on the glomerular basement membrane

or extraglomerular factors as being responsible for increased glomerular permeability. Recent

evidence suggests that the primary defect in idiopathic nephrotic syndrome might be at the level

of podocyte, the glomerular visceral epithelial cell. Injury to the podocyte can occur in many

immune and non-immune renal diseases. Podocyte injury or structural inherited defects are

increasingly implicated in the occurrence of glomerular proteinuria. Some viruses like HIV,

parvovirus B19 and simian SV40 may directly cause injury to the podocyte (Bangga A &

Mantan M, 2005).

Mutations in genes encoding several podocyte proteins have been identified in children with

familial nephrotic syndrome (Table III). A structurally defective podocyte or deficient basement

membrane protein may result in loss of permselectivity and nephrotic range proteinuria. Such

patients are less likely to respond to immunosuppressive therapy and progress to end stage renal

failure19. The most implicated mutation involves the NPHS1 gene, encoding the protein nephrin.

This transmembrane protein is present in the slit diaphragm between the podocytes (Fig. 1).

Mutations in nephrin are responsible for the congenital Finnish nephrotic syndrome8.

Abnormalities of another gene, the NPHS2 gene encoding podocin, results in recessively

inherited FSGS. This mutation is also found in 10-30 per cent of sporadic onset steroid-resistant

FSGS. The gene for autosomal dominant FSGS has been identified on chromosome 19, encoding

alpha-actinin-4. Some other implicated genes are WT1 (Wilms tumour suppressor gene),

FSGS2 and LMX1B (nail patella syndrome). Mutations in WT1 are associated with Denys-

Drash syndrome (characterized by male pseudohermaphroditism, nephrotic syndrome and

Wilms tumour) and Frasier syndrome (male pseudohermaphroditism, FSGS and

gonadoblastomas). Steroid-sensitive nephrotic syndrome (SSNS) may rarely be familial; a locus

has been mapped to chromosome 1q25, close to but distinct from the podocin gene20. Nephrotic

syndrome with FSGS has also been reported in patients with mitochondrial cytopathies,

presenting with isolated nephrotic syndrome or in association with myopathy, encephalopathy

and lactic acidosis (Bangga A & Mantan M, 2005)

A hypothesis unifying the observed immunological abnormalities, increased glomerular

permeability and evidence of podocyte injury is yet to be proposed. The speculation that critical


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podocyte proteins might be potential targets for T cell cytokines or vascular permeability factors,

though attractive needs confirmation. Availability of tests to detect genetic mutations shall

enable screening of patients with SRNS for such defects in the future. The role of

immunosuppressive medications in subjects with these mutations is limited (Bangga A &

Mantan M, 2005)

2.6. PATHOPHYSIOLOGY OF NEPHROTIC SYNDROME

2.6.1. Proteinuria

Children with MCD, although massively proteinuria, do not have a generalized glomerular leak

to macromolecules. The clearance of neutral macromolecules in MCD is actually less than

normal over a range of molecular radii. In contrast, the clearance of anionic macromolecules is

significantly increased. This and several other lines of evidence suggest that proteinuria results

from a loss of the fixed negative charges of anionic glycosaminoglycans in the glomerular

capillary wall. The mechanism by which these charges are lost has not been defined. A highly

cationic protein in the plasma and urine of children with MCD has been recently described, but

the pathogenic significance of this protein has not been determined (Tune BR & Mendoza SA,

1997).

2.6.2. Oedema

The traditional view has been that massive albuminuria in NS causes a decrease in intravascular

oncotic pressure, which allows extravasation of fluid, resulting in hypovolemia, increased

aldosterone and antidiuretic hormone secretion, and renal salt and water retention. Consistent

with this mechanism are the observations that, in MCD of childhood, edema seldom occurs when

serum albumin levels are above 2.0 g/dL and the elevated hematocrit, prerenal azotemia, and

fluid retention during relapse may be improved by intravenous infusions of salt-poor albumin

(Tune BR & Mendoza SA, 1997).

The principal clinical manifestation of nephrotic syndrome is oedema, the pathogenesis of which

remains controversial. Traditional teaching supports the so-called underfill theory, in which

proteinuria and subsequent hypoalbuminaemia lead to decreased intravascular oncotic pressure.

This pressure results in translocation of plasma water into the interstitial space; secondary


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sodium retention develops to compensate for intravascular volume contraction (Eddy AA,

Symons JM, 2003).

The underfill theory is intuitively attractive and data showing that nephrotic patients have

contracted intravascular volume, reduced glomerular filtration rate, and raised renin and

aldosterone concentrations support the concept. Critics of the underfill theory point to studies in

which some nephrotic patients have normal or even increased intravascular pressure. Plasma

renin activity is not universally increased in nephrotic patients. Volume expansion and head-out

water immersion do not consistently suppress the neurohumoral response and cause natriuresis,

as would be expected if the plasma volume were contracted. The overfill theory, proposed in

response to these criticisms, suggests that the abnormality leading to nephrotic oedema is a

primary defect in sodium excretion. The observation that in rats with unilateral proteinuria,

sodium avidity is increased in only the proteinuric kidney provides experimental support. The

cause of the increased sodium retention remains unknown, but is thought to occur in the distal

tubules, perhaps mediated by resistance to atrial natriuretic peptide (Eddy AA, Symons JM,

2003).

Although the overfill theory is gaining favour, it is not universally accepted and may not be

sufficient to explain oedema formation in childhood nephrotic syndrome. Studies of children

with MCNS in particular report variability in measurements of intravascular volume status. The

underfill and overfill mechanisms are not necessarily mutually exclusive, dependent on the stage

of nephrotic syndrome, the rate of development of hypoproteinaemia, and absolute plasma

oncotic pressure (Eddy AA, Symons JM, 2003).

Children with MCNS frequently present with rapid onset of proteinuria and oedema formation;

intravascular volume contraction (underfill) is common in this acute setting but may be less

operant later in their course. By contrast, patients with chronic forms of persistent nephrotic

syndrome may have continuing sodium retention and thus be more prone to oedema from overfill

mechanisms (Eddy AA, Symons JM, 2003).

Finally. patients with congenital analbuminemia typically have little or no edema. An alternative

explanation for retention of salt and water in NS is a decreased GFR, with a decreased filtration

fraction (Tune BR & Mendoza SA, 1997).

2.6.3. Hyperlipidaemia


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Hyperlipidaemia, with raised serum cholesterol and triglyceride concentrations, is a hallmark of

nephrotic syndrome. This complication results from complex interactions between disordered

lipoprotein metabolism, medications, and dietary factors. Increased hepatic lipoprotein synthesis,

in response to low plasma oncotic pressure, as a consequence of the urinary loss of an as-yet

unidentified regulatory substance, or both, is thought to play a key pathogenetic part. Studies in

experimental nephrotic syndrome models have identified several enzymatic changes that alter

lipid biosynthesis and degradation. These include increased hepatic 3-hydroxy-3-methylglutaryl-

coenzyme A (HMG-CoA) reductase and acyl-coenzyme A-cholesterol acyltransferase activities,

and decreased cholesterol 7 hydroxylase and lipoprotein lipase activities. Variability of

apolipoprotein (a) may also contribute to differences in lipid concentrations during active

nephrotic syndrome and remission (Eddy AA, Symons JM, 2003).

2.7. DIAGNOSTIC OF NEPHROTIC SYNDROME

2.7.1. Clinical Diagnostic Criteria

The diagnostic criteria are:

1) Generalized edema;

2) Hypoproteinemia (< 2 g/dL [20 g/L]), with disproportionately low albumin in relation to

globulin;

3) Urine protein (mg/dL) to urine creatinine (mg/dL) ratio in excess of 2 in a first morning void

or a 24-hour urine protein that exceeds 50 mg/kg body weight; and

4) Hypercholesterolemia (> 200 mg/dL [5.17 mmol/L]).

The reduced serum albumin, which can fall to as low as 0.5 g/dL (5 g/L), causes a marked

reduction in plasma oncotic pressure. Consequently, circulatory volume is lost to the interstitial

spaces, resulting in generalized edema. Often, the initial swelling is observed as facial (especially

periorbital) and pretibial edema, with prominent swelling of the scrotum or labia also seen. An

additional consequence of the lowered oncotic pressure is reduced perfusion of the splanchnic

capillary bed, which can cause abdominal pain. Pleural effusions may form, and frank pulmonary

edema also may occur, with either or both resulting in tachypnea and chest pain. Levels of serum

cholesterol, triglyceride, and lipoprotein cholesterol are consistently elevated. The mechanism(s)

underlying these changes are not understood completely, in part due to the complexity of lipid

transport and the difficulties inherent in human clinical studies. Increases in very-low density and


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low-density lipoprotein (VLDL and LDL, respectively) cholesterol are characteristic findings.

VLDL-cholesterol is increased as a consequence of decreased hepatic catabolism, thus increasing

circulating triglyceride and cholesterol. LDL-cholesterol is increased due to an enhanced

synthetic rate. What remains to be elucidated is the cause for these disturbances in hepatic lipid

metabolism. Primary nephrotic syndrome may occur at any age, from the neonate to the adult.

The neonatal or congenital nephrotic syndrome, also called Finnish congenital nephrosis, is

clearly defined as a genetic mutation in the nephrin gene and has been mapped to chromosome

19q13.1. Nephrin is a glomerular basement membrane protein that participates in formation of

anionic-rich sites, causing electrochemical repulsion of plasma proteins. The mutation also has

been reported in a Mennonite group in Pennsylvania who have no Finnish heritage and is

believed to have arisen independent of the Finnish type. Primary childhood nephrotic syndrome

rarely appears before 18 months to 2 years of age and peaks in incidence at about 3 years of age

(Roth KS et al, 2002).

2.7.2. Laboratory Findings

The primary laboratory feature of the nephrotic syndrome is a marked proteinuria, in excess of

50mg/kg per 24 hours. The excreted protein is predominantly albumin, although

immunoglobulins (Igs) also are lost. In uncomplicated cases of idiopathic nephrotic syndrome, it

is unusual to see gross hematuria in the presence of proteinuria, although microscopic hematuria

occurs in a sizeable proportion of cases. For patients who have gross hematuria and proteinuria,

IgA nephropathy always must be a diagnostic consideration (Roth KS et al, 2002).

In the presence of clinical edema, measurement of serum protein will yield low values; the serum

albumin is likely to be 2.0 g/dL (20 g/L) or lower. Albumin concentrations as low as 0.5 g/100

mL can be seen, and the albumin/globulin ratio is commonly less than 1.0. Concomitantly and

directly related to the reduced serum protein, hypocalcemia is found frequently, as reflected in

reduced total and ionized fractions. However, hypocalcemia rarely is manifested clinically. Of

much greater significance than hypocalcemia to patients who have nephrotic syndrome is the

increased concentrations of coagulation factors, especially those of highmolecular weight.

Thrombin also is increased, while fibrinolytic activity and circulating quantities of platelet

adhesion inhibitors are decreased. As a consequence of these changes, as well as the

intravascular hypovolemia, affected patients are at greatly increased risk of thrombosis. In


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addition, IgG in plasma is reduced, which in combination with large steroid doses, may

predispose to infection. Children who become oliguric fromdiminished intravascular volume

have a tendency to develop hyperkalemia. The use of diuretics may complicate the electrolyte

disturbances further, necessitating close monitoring of serum electrolyte levels during treatment

(Roth KS et al, 2002).

2.7.3. The Need for a Renal Biopsy

In the acute stage of childhood nephrotic syndrome, especially during the initial episode, renal

biopsy usually is unnecessary. The key indications for biopsy in any renal disorder are the need

to make a specific diagnosis for therapeutic reasons or to provide a prognosis. The treatment of

initial-onset nephrotic syndrome is the same, irrespective of cause, and the need for determining

a prognosis never can outweigh the risks of thrombosis, bleeding, and infection due to a biopsy

in the acute stage of the disorder (Roth KS et al, 2002).

The subsequent disease course in a patient can help to determine the timing of a renal biopsy. In

an uncomplicated case in which proteinuria clears within a few weeks in response to orally

administered corticosteroids and normal renal function, the diagnosis is presumed to be minimal-

change nephrotic syndrome. If there is no significant proteinuria between relapses that continue

to respond promptly to corticosteroids, this diagnosis is strengthened. If the child is younger than

10 years of age at the initial presentation, no renal biopsy need be considered. At age 10 years or

older, the increasing risk of underlying primary disease compels the need to obtain a biopsy for

histologic diagnosis. In such cases, renal biopsy can be deferred until the child is stable and the

familys anxieties over the immediate medical problems have dissipated (Roth KS et al, 2002).

In contrast, when there is poor or no response of the initial episode after 4 to 6 weeks of standard

treatment (defined as steroid-resistance disease), biopsy should be considered as soon as the

patient is medically stable. In such cases, the biopsy is essential to distinguish the nature and

severity of the glomerular process, which may be primary or secondary (Table 3). It should be

clear from the plethora of types and causes of glomerular nephropathy that treatments and

prognoses vary considerably, making specific diagnosis imperative. Because proteinuria and

microscopic hematuria are injury responses of the glomerulus, the need for clarification through

renal biopsy is plain. (Roth KS et al, 2002).


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Beyond the issue of renal biopsy for initial diagnosis, there are circumstances in which a

subsequent biopsy may be considered. Glomerular injury may evolve over time such that the

clinical findings (eg, increasing proteinuria, development of chronic renal insufficiency) change

significantly. Such cases may represent progression of a disease that initially was diagnosed as

minimal-change nephrosis by biopsy or progressive injury to the kidney by an underlying disease

such as lupus nephropathy. In these situations, a second renal biopsy should be considered for

evaluation of progressive renal disease. Technological developments in ultrasonography have

reduced significantly the risk associated with percutaneous renal biopsy in children. Moreover,

the improvements in electron microscopy equipment and technique, coupled with decades of

observation, have enhanced the ability of the histopathologist to interpret the specimen

accurately. Nonetheless, a renal biopsy is not always essential to good medical care, and its use

should be viewed judiciously in all patients (Roth KS et al, 2002).

2.8. TREATMENT OF NEPHROTIC SYNDROME

Before steroid treatment started, the following examinations must be conducted:

i. Measurement of weight and height

ii. Measurement of blood pressure

iii. Physical examination to look for signs or symptoms of systemic diseases, such as SLE,

Henoch-Schonlein Purpura

iv. Finding focus of infection in the teeth, ears, or worm infections. Each infection have to be

eradicated before start of steroid therapy

v. Mantoux test. If the result is positive, given INH prophylaxis for 6 months with steroids,

and if found tuberculosis, administered antituberculosis drugs.

2.8.1. Spesific Treatment

A. Treatment for Initial Therapy

1) Prednisone

When the diagnosis of nephrotic syndrome has been made, prednisone treatment can be started

in children with typical features. Children with atypical features should be referred to pediatric

nephrology for consideration of renal biopsy.


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There is increasing evidence that longer initial courses of prednisone are associated with a lower

incidence of relapse, and therefore a 12-week initial course is recommended. The dose of

prednisone is based on surface area.

60 mg/m2/day for 4 weeks (maximim 80 mg)

40 mg/m2/on alternate days for 4 weeks (maximum 60mg)

Reduce dose by 5-10mg/m2 each week for another 4 weeks then stop

Prednisone can be given as a single dose in the morning with food, or as divided doses during the

day. Patients should be issued with a steroid warning card, and they should be aware of the side

effects and risks of steroid treatment. If prednisone causes gastric irritation, start ranitidine 2

mg/kgBW bid for the duration of steroid treatment.

2) Albumin

The clinical indications for albumin are:

Clinical hypovolaemia

Symptomatic oedema

A low serum albumin alone is not an indication for intravenous albumin. If there is evidence of

hypovolaemia, give 1 g/kg 20% albumin (5ml/kg) over 4 - 6 hours. Give 2 mg/kg of iv

furosemide mid-infusion. If clinically shocked give 10ml/kg 4.5% albumin. Children should be

closely monitored during albumin infusions, and where possible they should be administeredduring working hours.

3) Penicillin Prophylaxis

Whilst nephrotic, children are at increased risk of infection, particularly with encapsulated

organisms such as pneumococcus. There is no evidence that antibiotic prophylaxis is of benefit,

and some centres do not use prophylaxis. Penicillin V can be given while there is proteinuria and

discontinued when the child goes into remission. Grossly oedematous children are at risk of

cellulitis and may benefit from antibiotic prophylaxis. Dose for under 5 years old is 125 mg bid

and for 5 years or above is 250 mg bid.

4) Salt/Fluid Restriction


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A low salt diet is used to try to prevent further fluid retention and oedema. Fluid restriction may

also be helpful. These restrictions are lifted once the child goes into remission.

5) Vaccination

Pneumococcal vaccination is recommended for children with NS. Consider giving at the time of

diagnosis. Varicella vaccination is only available on a named patient basis.

2.8.2 Treatment for Relapse Nephrotic syndrome

The patient should be examined for infections, which should be treated before initiating steroid

therapy. Appropriate therapy of an infection might rarely result in spontaneous remission,

thereby avoiding the need for treatment with corticosteroids. Antibiotic for infections should be

given 5-7 days.

Prednisone is administered at a dose of 2 mg/kg/day (single or divided doses) until urine protein

is trace or nil for three consecutive days (maximal for 4 weeks). Subsequently, prednisone is

given in a single morning dose of 1.5 mg/kg on alternate days for 4 weeks, and then

discontinued. The usual duration of treatment for a relapse is thus 5-6 weeks. Prolongation of

therapy is not necessary for patients with infrequent relapses. In case the patient is not in

remission despite two weeks treatment with daily prednisone, the treatment is extended for 2

more weeks. Patients showing no remission despite 4 weeks treatment with daily prednisone

should be referred for evaluation.

2.8.3. Treatment for Frequent Relapse or Steroid Dependence Nephrotic Syndrome

There are 4 options for treatment frequent relapse or steroid dependence nephrotic syndrome

- Long term Steroid

Full dose prednisone is given then continued by alternating dose, 1,5 mg/kgBW. This regiment is

decreased tapperingly 0,2 mg/kgBW each 2 weeks. Dose reduction is performed up to the

smallest dose that does not cause relapse of between 0.1 to 0.5 mg / kg alternating. This dose is

called the thershold dose and can be maintained for 6-12 months, then tried to stop.

When relapse occurred at doses between 0.1-0.5 mg/kgBB alternating, it will be treated with

prednisone 1 mg/kgBB in divided doses, given every day until remission occurs. After remission,

the prednisone was reduced to 0.8 mg/kgBW administered in alternating, then lowered to 0.2


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mg/kgBW every 2 weeks, until one phase (0.2 mg/kgBW) in the dose of prednisone at the time

of relapse previous or the last relapse.

- Levamisole

Levamisole is administered at a dose of 2-2.5 mg/kg on alternate days for 4-12 months. Co-

treatment with prednisone at a dose of 1.5 mg/kg on alternate days is given for 2-4 weeks; its

dose is gradually reduced by 0.15-0.25 mg/kg every 4 weeks to a maintenance dose of 0.25-0.5

mg/kg that is continued for six or more months. Occasionally, it might be possible to discontinue

treatment with corticosteroids. The chief side effect of levamisole is leukopenia; flu-like

symptoms, liver toxicity, convulsions and skin rash are rare. The leukocyte count should be

monitored every 12-16 weeks.

- Cytostatistics Agent

Cytostatics agent that most commonly used in the treatment of nephrotic syndrome are

cyclophosphamide (CPA) or chlorambucil. Cyclophosphamide can be administered orally at a

dose of 2-3 mg/kgBW/day in single dose, or intravenously or puls. Puls CPA administered at a

dose of 500-750 mg/m2 BSA, which was dissolved in 250 ml NaCl 0,9% solution, administered

over 2 hours. Puls CPA administered doses of 7 times, with 1-month intervals (total duration of

CPA puls administration is 6 months). Side effects of CPA are nausea, vomiting, bone marrow

depression, alopecia, hemorrhagic cystitis, azoospermia, and in the long term can lead to

malignancy. Therefore need to monitor the examination of peripheral blood hemoglobin,

leukocytes, platelets, each 1-2 times a week. When the number of leukocytes


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In the steroid-sensitive nephrotic syndrome who do not respond to levamisole or cytostatic can

be given MMF. MMF administered at a dose of 800-1200 mg/m2 BSA or 25-30 mg/kgBW

together with a reduction in steroid dosage for 12-24 months. MMF side effects are abdominal

pain, diarrhea, leucopenia.

Idiopathic nephrotic syndrome that is unresponsive to steroid treatment or cytostatics suggested

to cyclosporine administration at a dose of 4-5 mg/kgBW/day (100-150 mg/m2 BSA). The dose

of cyclosporine to maintain blood levels between 150-250 ng/ml. On frequent relapse nephrotic

syndrome or steroid dependent, CYA can cause and maintain remission, so that the steroid can

be reduced or stopped, but when CYA discontinued, relapse will usually return (dependent

cyclosporine).

2.8.4. Treatmet for Steroid Resistance Nephrotic Syndrome

For steroid resistance nephrotic syndrome, the treatment is

Oral cytostatic: cyclophosphamide 2-3 mg/kgBW/day single dose for 3-6 months.

Predison alternating doses of 40 mg/m2 BSA/day for oral administration of

cyclophosphamide. Later prednisone in tapering-off with a dose of 1 mg/kgBW/day

for 1 month, followed by 0,5 mg/kgBW/day for 1 month (long tapering-off of 2

months).

OR

Puls cyclophosphamide at a dose of 500-750 mg/m2 BSA given by intravenous

infusion or once a month for 6 months which may be continued depending on the

patient.

Prednisone alternating doses of 40 mg/m2 BSA/day for administrating

cyclophosphamide puls (6 months). Later prednisone in tapering-off with a dose of 1

mg/kgBW/day for 1 month, followed by 0,5 mg/kgBW/day for 1 month (long

tepering-off 2 months).

2.8.5. Nonspesific Treatment


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A. Diets

A balanced diet, adequate in protein (1.5-2 g/kgBW) and calories is recommended. Patients with

persistent proteinuria should receive 2-2,5 g/kgBW of protein daily. Not more than 30% calories

should be derived from fat and saturated fats avoided. While salt restriction is not necessary in

most patients with steroid sensitive nephrotic syndrome, reduction of salt intake (1-2 g per day)

is advised for those with persistent edema. Salt should not be added to salads and fruits, and

snacks containing high salt avoided. Since treatment with corticosteroids stimulates appetite,

parents should be advised regarding ensuring physical activity and preventing excessive weight

gain.

B. Diuretics

Fluid restriction is recommended as long as there is severe edema. Usually given loop diuretics

such as furosemide 1-3 mg/kgBW/day, if necessary combined with spironolactone (aldosterone

antagonists, potassium-sparing diuretic) 2-4 mg/kgBW/day. Before administration of diuretics, it

should be excluded the possibility of hypovolemia. On diuretic use more than 1-2 weeks is

necessary to monitor blood electrolytes potassium and sodium. If diuretic administration did not

succeed (refractory edema), it usually occurs because of severe hypovolemia or

hypoalbuminemia ( 1 g/dL), albumin infusion may be given 20-25% at a dose of 1 g / kg for 2-

4 hours to draw fluid from the interstitial tissue and ends with the provision of intravenous

furosemide 1-2 mg / kg. If necessary, the suspension of albumin may be given alternate days to

allow a shift of fluid and prevent fluid overload. When ascites so severe that it interferes with

breathing, repeatedly ascites puncture can be performed.

2.9. COMPLICATION OF NEPHROTIC SYNDROME


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Medical complications of nephrotic syndrome are potentially serious. They can be divided into

two major subgroups: acute complications related to the nephrotic state, especially infections and

thromboembolic disease, and long-term sequelae of nephrotic syndrome and its treatment,

especially effects on bones, growth, and the cardiovascular system. A third important area is the

psychological impact and social demands on children who have nephrotic syndrome, and their

families (Eddy AA, Symons JM, 2003).

2.9.1. Infectious complications

Serious infection, especially cellulitis and spontaneous bacterial peritonitis, can complicate

nephrotic syndrome. The rate of peritonitis is 26%, and overwhelming infection still carries a

mortality rate of 15%. Susceptibility to bacterial infection is related to multiple predisposing

factors (figure 4). Impaired complement-dependent opsonisation delays clearance of

encapsulated micro-organisms, especially Streptococcus pneumoniae (figure 4). Pneumococcal

vaccination is recommended for patients who have nephrotic syndrome. Prophylactic treatment

with penicillin during relapses has been suggested but few data support this practice. Patients are

also predisposed to gram-negative bacterial infections. Since many children with idiopathic

nephrotic syndrome are varicella non-immune, varicella exposure and infection require special

consideration. Prophylactic treatment with varicella zoster immune globulin is recommended for

non-immune patients taking immunosuppressive treatments. Once remission is achieved,

immunisation with varicella vaccine seems safe and effective, although additional doses may be

required to achieve full immunity. Concomitant use of oral aciclovir may also prevent serious

varicella infection in patients receiving corticosteroids (Eddy AA, Symons JM, 2003).

2.9.2. Thromboembolic complications

Nephrotic patients are at significantly increased risk of thrombosis, with complication rates

reported as high as 40% in adults. Although thrombosis risk is apparently lower in nephrotic

children (1850%), these events can be severe. Multiple factors contribute to the dysregulated

coagulation state of nephrotic syndrome (figure 5). No one laboratory test can reliably predict the

real thrombotic risk. Fibrinogen concentration has been proposed as a surrogate marker. Other

factors that increase thrombotic risk in nephrotic patients include diuretic use, corticosteroid

treatment, immobilisation, and the presence of in-dwelling catheters. If a clot is noted in a


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nephrotic child, investigation for an inherited coagulation abnormality is still recommended

(Eddy AA, Symons JM, 2003).

Prophylactic anticoagulation is not recommended because of its own inherent risks. However,

after treatment of a documented clot, use of prophylactic warfarin has been recommended for at

least 6 months, and perhaps during future relapses. In-dwelling venous catheters should be

avoided, but if absolutely necessary, prophylactic anticoagulation should be considered. Low-

molecular-weight heparin is an attractive alternative agent, but it requires sufficient antithrombin

III substrate to be effective. Aspirin may also be considered for anticoagulation, especially if

thrombocytosis is severe (Eddy AA, Symons JM, 2003).

2.9.3. Cardiovascular disease

Multiple factors raise concerns for cardiovascular sequelae in children with long-term nephrotic

syndrome, including exposure to corticosteroids, hyperlipidaemia, oxidant stress, hypertension,

hypercoagulability, and anaemia (erythropoietin-responsive anaemia is a rare complication).

Nephrotic syndrome in adulthood is associated with an increased risk of coronary heart disease.

Myocardial infarction in young children with nephrotic syndrome has been reported, but the

relative risk has not been calculated. In adults with nephrotic syndrome, HMG-CoA reductase

inhibitors can control hyperlipidaemia and limit its complications. Whether or not to treat

hyperlipidaemia in nephrotic children has been a source of controversy, especially since most

children have treatable renal disease. Adequate safety and efficacy data for HMG-CoA-reductase

inhibitors in children are not available, despite small case series in which decreased serum lipids

have been reported. Persistent hyperlipidaemia in unremitting childhood nephrotic syndrome is

concerning, but there is little evidence as yet to guide treatment or predict future outcome (Eddy

AA, Symons JM, 2003).

2.9.4. Other medical complications

Despite theoretical risks of bone-density reduction with corticosteroid use, the prevalence of

bone disease in children with nephrotic syndrome is not yet clear. In addition to steroids, there

are other potential causes of bone disease in nephrotic syndrome. Urinary loss of vitamin-D-

binding protein, a 59 kd carrier protein for 25-hydroxycholecalciferol, may cause vitamin D

deficiency and, less commonly, secondary hyperparathyroidism. Other potential medical


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complications include drug toxic effects, hypothyroidism and acute renal failure. Although

diuretics and albumin infusions can successfully treat symptomatic oedema, injudicious use can

lead to either acute volume overload or intravascular depletion, dependent on the cause of

oedema (Eddy AA, Symons JM, 2003).

2.10. PROGNOSIS OF NEPHROTIC SYNDROME

The most important prognostic indicator in nephrotic syndrome is steroid responsiveness.

Overall, 6080% of steroid-responsive nephrotic children will relapse and about 60% of those

will have five or more relapses. Age older than 4 years at presentation and remission within 79

days of the start of steroid treatment in the absence of micro haematuria are predictive of fewer

relapses. In a natural-history study of 398 children, the proportion that became non-relapsers rose

from 44% at 1 year to 69% at 5 years, and 84% at 10 years. For the steroid-resistant FSGS

patients, the clinical course is typically very challenging. With current treatments, a few children

will ultimately achieve a sustained remission with one of the second-line or third-line drugs. For

patients with refractory nephrotic syndrome, progression to end-stage renal disease is inevitable.

Some of these children have such a difficult clinical course because of refractory oedema, severe

infections, thromboembolic complications, or a combination of these, that bilateral

nephrectomies and dialysis provide welcome relief. For this subgroup, the ultimate treatment

goal is renal transplantation, despite the haunting reality that FSGS will recur in about 25% of

renal allografts. For patients who have familial forms of nephrotic syndrome,

immunosuppressive treatment is ineffective; definitive treatment requires renal transplantation.

Most of these patients do well after transplantation. Although the original genetic renal disease

does not recur in the renal allograft, nephrotic syndrome has been noted in a subset of patients as

a consequence of immunological attack on a new antigen encountered for the first time in the

transplanted kidney (eg, injury mediated by antibody to nephrin in children with congenital

nephrotic syndrome). Although much has been learned about the management of childhood

nephrotic syndrome, this chronic disorder remains challenging. Advances in molecular genetics

offer hope of new pathogenetic insights. Multicentre clinical trials are needed to improve current

treatments and prevent acute and long-term complications (Eddy AA, Symons JM, 2003).

2.11. DEFINITION OF STEROID-RESISTANT NEPHROTIC SYNDROME


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Among pediatric nephrologists there are two definitions of steroid-resistant nephrotic syndrome

(SRNS). The definition introduced by the International Study of Kidney Disease in Children

(ISKDC) and used by the Arbeitsgemeinschaft fr Pdiatrische Nephrologie (APN) is widely

accepted as follows:

No urinary remission within 4 weeks of prednisone therapy 60mg/m2/day.

The other definition, employed by the Society of French Speaking Pediatric Nephrologists,

states:

No urinary remission following 4 weeks of prednisone 60mg/m2/day followed by three

intravenous pulses of methylpredisolone.

The rationale for both definitions is the experience that almost all patients with minimal change

who respond will do so within 4 weeks (Figure 16-1) and only a small percentage will respond

later (often called late responders). It is of great importance for interpretation of clinical data and

studies to know the patients age and the definition used.

2.12. EPIDEMIOLOGY OF STEROID-RESISTANT NEPHROTIC SYNDROME

The incidence of SRNs varies throughout the world. The incidence of minimal change versus

other histologies in patients biopsied because of nephrotic syndrome varies among children and

adults and among children from the Northern Hemisphere and those from Africa. There are also

different patterns in South America and Asia. It should be kept in mind that these comparisons

are relative, because the initial therapy with steroids cannot be compared between children and

adults. Furthermore there are no data about how different pharmacogenetic backgrounds and

therapeutic doses of prednisone with different pharmacokinetic and pharmacodynamic profi les

infl uence response to treatment. In addition, race appears to have an important impact on the

histology associated with nephrotic syndrome. Although the incidence of nephrotic syndrome

has remained stable over the last 30 years, evidence from the literature suggests that the total

number of patients with focal segmental glomerulosclerosis (FSGS) is increasing, especially in

South Africa and India.

A weak predictor for the probability of FSGS as opposed to minimal change nephrotic syndrome

(MCNS) is age. In children with MCNS, about 80% are diagnosed before the age of 6 compared

with 50% of those with FSGS lesions in histology.

PATHOGENESIS OF STEROID-RESISTANT NEPHROTIC SYNDROME


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As described in earlier chapters, the key element in the pathogenesis of proteinuria in nephrotic

syndrome is the podocyte. Since the discovery of a mutation in the nephrin gene in patients with

congenital nephrotic syndrome of the Finnish type, the biology of the podocyte has become a

center of interest. With the description of new gene mutations and altered gene products

responsible for the structure function and signaling of podocytes, understanding of diseases with

proteinuria has increased; however, with more knowledge, the number of questions has also

increased. In general, one can distinguish two mechanisms leading to proteinuria: con-

genital and acquired.

During embryonic development, the outer part of the GBM is made by podocytes. Major

podocytes need a full complement of proteins for building up complex structures as well as for

signaling (Figure 16-5). A major function of podocytes is to perform as a buttress against the

pressure of the glomerular capillaries. Any stress and functional impairment, as well as podocyte

loss, may compromise the filtration barrier and lead to proteinuria.

It is logical that congenital defects may be somewhat resistant to any kind of pharmacologic

treatment. In acquired diseases the major goal should be eliminating the cause of podocyte

injury, as well as allowing the podocytes to recover and restoring their function after injury.

Since podocytes have not been shown to replicate, any loss must be compensated by those

remaining. Continuing podocyte loss may be critical below a certain threshold, which is

estimated as a loss of more than 20% (Figure 16-6). As shown by Kriz and others, a decreasing

podocyte number leads to denuded GBM areas that will come into contact with the parietal

epithelial cells lining Bowmans capsule by force of the intracapillary pressure. Once sclerotic

lesions are established, a point of no return for these lesions is reached. Misdirected filtration

(Figure 16-7) via the glomerular basement areas attached to Bowmans capsule and into the

periglomerular and peritubular interstitium leads to infl ammation and scarring of the renal

cortex. Therefore any treatment should try to regenerate podocyte function before sclerotic

lesions appear. It is amazing that the classical hypothesis of the immortal podocyte has never

been questioned. The fact that a cell with such a highly developed structure should live for

almost 70 years is doubtful. If there is podocyte turnover, it might be so low that it has escaped

the attention of investigators. To what extent stem cells might contribute to podocyte turnover

has to be studied. However, such a possibility may be attractive for future therapeutic

approaches. The inflammatory changes leading to tubulointerstitial scarring should be regarded


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as an important part of this disease leading to end-stage renal failure. The understanding of such

processes, especially the epithelial mesenchymal transition (EMT), is of great interest. A detailed

understanding may provide a rationale for specific interventions in the future. Until then,

nonspecific immunosuppressive effects that dampen this process are used.

GENETICS OF STEROID-RESISTANT NEPHROTIC SYNDROME

An overview of the variety of conditions associated with FSGS is given in Table 16-2, and recent

advances in genetics and mutations associated with SRNS are covered in Chapter 13. Recently

Hinkes 12 described a new mutation leading to SRNS, called NPHS3. The gene product is

phospholipase Cepsilon (PLCE1). This mutation causes early-onset nephrotic syndrome leading

to end-stage kidney disease in young children. Kidney histology of affected individuals show

diffuse mesangiosclerosis (DMS). The gene product is expressed in the developing kidney in

mature glomerular podocytes, which has been shown to lead to an arrest of normal glomerular

development. Interestingly, a few patients with this mutation might respond to

immunosuppressive therapy.

SRNS may be part of syndromatic diseases as listed in Table 16-2 (see examples, Figures 16-8

and 16-9). Careful clinical examination is essential to rule out minor abnormalities suggestive of

syndromatic forms of nephrotic syndrome to avoid unnecessary steroid treatment. In many cases,

however, steroid therapy will start first and genetic investigations will be initiated only if steroid

resistance has been confirmed by the classical definition. In the clinical day-to-day practice there

is sometimes a tremendous delay between the request for genetic testing and when the result will

be available. Because there are no markers predicting a gene defect, many patients may undergo

further immunosuppressive therapy until a clear diagnosis is established.

During this time, any therapy with irreversible or severe side effects should be avoided. Up to

now it has been shown that immunosuppressive therapy is of no value in patients with NPHS1,

NPHS2, WT1, and TRPC6 mutations. Ruf et al have reported that out of 165 families with

SRNS, 43 (26%) showed homozygote or compound heterozygote mutations in the NPHS2 gene

(podocin). In contrast, no mutations were found in 120 families with steroid-sensitive nephrotic

syndrome. None of the patients with homozygous or compound heterozygous mutations in the

NPHS2 gene who were treated with cyclosporine or cyclophosphamide demonstrated complete

remission of the nephrotic syndrome. The geographic variation of NPHS2 mutations is of


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importance. Maruyama et al. reported that mutations in the NPHS2 gene are uncommon in

Japanese pediatric patients with SRNS.

NONGENETIC FSGSOF STEROID-RESISTANT NEPHROTIC SYNDROME

There is evidence from many clinical observations that a circulating factor targets the kidney,

leading to proteinuria and glomerular sclerotic lesions. Most striking are observations about the

recurrence of proteinuria within hours after renal transplantation in some patients who had end-

stage renal failure with FSGS. The nature of the factor has yet to be defined. Some call it the

Savin factor, because major work has been carried out by Virginia Savin and her group to isolate

it. This factor is believed to be removable by plasma separation, and anecdotal data on successful

treatment after recurrence of FSGS post-transplant support this possibility. Some clinical

observations point toward suppressive effects with the use of immunosuppressive drugs,

especially calcineurin inhibitors. Such concepts are attractive treatment strategies; however, no

reliable tests for identifying such a factor have been elaborated.

TREATMENTOF STEROID-RESISTANT NEPHROTIC SYNDROME

A review of the current literature about treatment of children with SRNS reveals that many

children with familial or syndromic FSGS or with the known mutations still receive too much

immunosuppressive therapy either initially or after an escalation with current available

immunosuppressive drugs. A metaanalysis of randomized controlled prospective trials in SRNS

with FSGS without genetic testing demonstrates that cyclosporin may lead to a complete

remission in almost one third of children. In contrast, neither oral nor intravenous

cyclophosphamide demonstrates any effect on remission. A major problem in reviewing the

literature was that most studies were nonrandomized and retrospective, with low numbers of

patients. In approximately two thirds of the studies, the number of patients was less than 10.

Other studies have included both children and adults with MCNS and mesangial proliferation.

The fact that different age groups may have different underlying diseases has been ignored. A

further problem is that the steroid therapy used, as well as the definitions, did not meet the

international accepted standards. Most studies focused on short-term effects, and long-term

studies are lacking. In children, attention should be focused on side effects of therapy and

comorbidity, such as impaired growth and body configuration.


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Specific Agents

Glucocorticosteroids

In the early 1990s, Mendoza et al. treated patients with SRNS due to FSGS with a protocol

involving infusions of high doses of methylprednisolone, often in combination with oral

alkylating agents. Twenty-three children have been treated in this manner, with a follow-up of 46

+/ 5 months. Twelve of them went into complete remission, six had minimal to moderate

proteinuria, and four remained nephrotic. Each had a normal glomerular filtration rate. One child

developed chronic renal failure and subsequently died while on dialysis. These results appear

significantly better than in previous series of children with FSGS. More cases have been added to

this first series, and the so-called Mendoza protocol has been used in many centers. However, a

prospective randomized controlled trial has never been published. Concerns about

methylprednisolone side effects left many clinicians reluctant to employ this protocol but

stimulated a search for new drugs allowing steroid sparing.

The mode of action of corticosteroids was speculative and unclear until recently. Experimental

data from Fujii et al. may offer new insights into possible mechanisms for efficacy. Fujii

demonstrated defective nephrin transport following endoplasmic reticulum-stress; that is,

endoplasmic reticulum stress in podocytes may cause alteration of nephrin N-glycosylation,

which may be an underlying factor in the pathogenesis of the proteinuria in nephrotic syndrome.

Dexa-methasone may restore this imbalance by stimulating expression of mitochondrial genes,

resulting in production of ATP, which is an essential factor for proper folding machinery aided

by the ER chaperones. It is unclear if there will be a place for dexamethasone in future

therapeutic proposals.

Calcineurin Inhibitors

Calcineurin inhibitors have been used more in an empirical manner than on the basis of clear

rationale. Cyclosporin is a calcineurin inhibitor that suppresses immune response by

downregulating the transcription of various cytokine genes. The most significant of these

cytokines is interleukin-2, which serves as the major activation factor for T cells in numerous

immunologic processes. Cyclosporin inhibits cytokine production from T helper cells (Th1 and

Th2) and also has an inhibitory effect on antigen-presenting cells (Langerhans and dendritic


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cells), which are the main agents of T-cell stimulation. A further effect of interleukin-2 inhibition

is a reduction in B-cell activation and subsequent antibody production. Interleukin-2 levels are

known to become elevated during proteinuria and to normalize during remission in adults with

idiopathic nephrotic syndrome and in children with MCNS or FSGS.

However, this pattern of interleukin-2 activity is felt to be part of a more widespread disorder of

cellular immunity that results in nephrotic syndrome rather than being causal of proteinuria. It

has been reported that cyclosporin has some antiproteinuric action on glomerular perm

selectivity to proteins that is unrelated to its immunosuppressive properties. Among these are an

influence on perm-selectivity and charge selectivity, and impairment of glomerular filtration rate.

These data come from various human studies and animal models with no immunologically

mediated disease. Some studies revealed that lesions from the primary glomerular disease had

either not regressed or had continued to progress.

An uncontrolled trial in the early 1990s showed that about half of the patients had a stable course

during cyclosporin treatment, whereas the others were resistant to the treatment (Figure 16-10).

Knowledge of the various genetic and nongenetic causes of SRNS might easily explain this

difference in response.

The first controlled data about efficacy of cyclosporin in SRNS came from Lieberman and

Tejani: they performed a randomized double-blind placebo-controlled trial of cyclosporin in 25

children with steroid-resistant idiopathic FSGS. Cyclosporin significantly reduced proteinuria

and increased serum albumin levels. Interestingly, hypercholesterolemia seemed to antagonize

the effect of cyclosporin, leading to the proposal to increase the dose according to cholesterol

levels.

This has been cited in the literature quite often, but apparently has not been translated into

clinical use as discerned from review of the literature. Major concerns were the nephrotoxic side

effects of cyclosporin, as well as a fear that progression of the disease might be indistinguishable

from toxicity. The French Society of Pediatric Nephrology published its experience with 65

children with steroid-resistant idiopathic nephrosis. Patients were treated with cyclosporin at 150

to 200 mg/m2 in combination with prednisone at 30 mg/m2 daily for 1 month and on alternate

days for 5 months. Renal biopsy showed minimal change disease in 45 children and FSGS in 20.

Twenty-seven patients achieved complete remission.


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A study in adult patients provided Level I evidence for efficacy of cyclosporin. In this study a

26-week regimen of cyclosporin therapy was compared with placebo in 49 patients with steroid-

resistant FSGS; both groups also received low-dose prednisone. Further evidence was provided

by Ponticelli et al.

Cyclosporin was compared to symptomatic treatment in 44 patients (adults and children) with

SRNS. Eight (57%) cyclosporin-treated patients attained remission (complete or partial). Three

(16%) control patients had partial remissions, but details regarding their diagnoses were

incomplete. The majority of remitters had relapsed by the end of month when cyclosporin was

stopped.

The Arbeitsgemeinschaft fr Pdiatrische Nephrologie (APN) conducted a prospective

randomized trial that included children with SRNS at initial manifestation. Six months of

treatment with cyclosporin (trough level 80 to 120 ng/L) versus 6 months of treatment with

cyclophosphamide (6 500 mg/m2) were compared. Although the goal was to involve 60

patients, the study was stopped after the inclusion of 32. A complete remission was achieved in 2

out of 15 receiving cyclosporin and in 2 out of 17 receiving cyclophosphamide; a partial

remission was obtained in 7 out of 15 versus 2 out of 17. It was concluded that initial response

with cyclosporin was better than with cyclophos phamide pulses (60% vs. 17%). Complete

remission after week 24 was similar in both groups. In those who did not respond to

cyclophosphamide, a successful remission was achieved in 45% with cyclosporin. Safety in both

arms was comparable.

Recently Franz and colleagues presented data that cyclosporin protects podocyte stress fi bers

through stabilization of synaptopodin protein expression. If this is supported by future

experimental data, a nonimmunologic approach for the treatment might be envisaged. A pilot

trial of tacrolimus in the management of SRNS was published by McCauley et al. in 1993. All

patients except one experienced at least a 50% reduction in protein excretion at some time during

tacrolimus therapy. No controlled study has been carried out, and only uncontrolled experiences

have been published. Loeffl er reported a series of 16 patients resistant to other

immunosuppressive drugs. In this mixed group he concluded that tacrolimus is an effective,

well-tolerated medication for treatment-resistant forms of nephrotic syndrome in children,

resulting in a complete remission rate of 81% and a partial remission rate of 13%.


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More data and a prospective trial are needed to confirm these promising results and to

demonstrate the safety of this approach. As of now, of the newer immunosuppressive agents only

cyclosporin has been approved for use in nephrotic syndrome by licensing authorities in some

countries. An algorithm for the use of cyclosporin in SRNS (Figure 16-11) has been proposed.

(Result of an expert meeting, London, 2005.)

Antiproliferative Agents

Azathioprine and vincristine have been used by some individuals but have not been widely

recommended because of the lack of positive results. Cyclophosphamide has failed to prove any

benefit, although many investigators have included this drug in their armamentarium. In most of

the reports, drug combinations were employed that did not allow separation of single drug

effects. The prospective trial of the APN mentioned earlier was stopped because of the inferiority

of cyclophosphamide to cyclosporin.

Mycophenolate mofetil (MMF) has attracted investigators interest because of its nonnephrotoxic

profi le. Some uncontrolled trials point toward possible benefi ts, but (a) the lack of control

data, (b) the anecdotal character, (c) the possible selection bias in reporting, and (d) the fact that

this drug has been in routine use for more than 10 years in the transplant setting but no robust

data are available demonstrating any effect for prevention of posttransplant recurrence of


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original disease all argue against premature recommendations. One should await the results of

the trial being undertaken in the United States under the auspices of the National Institutes of

Health, wherein treatment with cyclosporin over 26 weeks will be compared with MMF/pulse

steroids and continued for 52 weeks if response of proteinuria occurs. Both treatment arms

include low-dose prednisone and ACE inhibitor therapy. Patients will be recruited at more than

130 sites in North America.

Antiproteinuric Treatment

There is strong evidence from studies in adult patients that ACE inhibitors effectively lower

proteinuria in various diseases involving proteinuria. These results have been accepted by many

pediatric nephrologists as a robust argument for introducing ACE inhibitors for their patients

with proteinuria. The dilemma is that in pediatric patients this has led to off-label use without

proper phase II and III trials. A large series of pediatric patients have been treated with ramipril

in the Escape Triala prospective assessment of the renoprotective efficacy of ACE inhibition

and intensified blood pressure control. In this assessment, 397 children (ages 3 to 18 years) with

chronic renal failure (GFR 11 to 80 ml/min/1.73m2) and elevated or high-normal BP received

ramipril (6 mg/m2) following a 6-month run-in period, including a 2-month washout of any

previous ACE inhibitors.

Blood pressure was reduced with equal efficacy daytime and nighttime. Urinary protein

excretion was reduced by 50% on average, with similar relative efficacy in patients with

hypo/dysplastic nephropathies and glomerulopathies. The magnitude of proteinuria reduction

depended on baseline proteinuria (r = 0.32, p < 0.0001), and was correlated with the

antihypertensive effi cacy of the drug (r = 0.22, p < 0.001). Small, uncontrolled trials in

pediatric patients with persistant nephritic syndrome also found some reduction of proteinuria.

The positive interpretation of a renoprotective effect of ACE inhibitors with and without AT1

receptor antagonist has made it unlikely that children are left without such treatment.


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(Bagga A, Management of Steroid Resistant Nephrotic Syndrome, Indian Society of Pediatric

Nephrology, Volume 46, January 17, 2009)

PROGNOSIS OFSTEROID-RESISTANT NEPHROTIC SYNDROME

Steroid-resistant nephrotic syndrome is not a single entity. The most dominant lesion is focal

segmental glomerulosclerosis (FSGS). Better understanding of the underlying diseases and

mechanisms will guide future treatment. Early genetic diagnosis might help to avoid ineffective

but harmful immunosuppressive therapy (Hoyer PF et al, 2008)


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REFERENCES

1. Karl S. Roth, Barbara H. Amaker and James C.M. Chan, Nephrotic Syndrome: Pathogenesis

and Management, Pediatr. Rev. 2002;23;237

2. Allison A Eddy, Jordan M Symons., Nephrotic syndrome in childhood, The Lancet, Vol 362,

August 23, 2003


35/35

3. Bruce M. Tune, Stanley A. Mendoza, Treatment of the Idiopathic Nephrotic Syndrome:

Regimens and Outcomes in Children and Adults, Journal of the American Society of

Nephrology, 1997

4. Fahmi, N., Nephrotic Syndrome, Banghdad Medical College, 2011

5. Arvind Bagga & Mukta Mantan, Nephrotic syndrome in children, Review Article Indian J

Med Res 122, July 2005, pp 13-28

6. Miller Christopher A, Patrick T. OGara, Leonard S. Lily. Nephrotic Syndrom in Childhood.

Sudoyo, Aru W, dkk. Buku Ajar Ilmu Penyakit Dalam Jilid III Edisi IV. Jakarta: FK UI 2007;

1566-1571

7. Konsensus Tata Laksana Sindrom Nefrotik Idiopatik pada Anak Edisi 2,Unit Kerja Koordinasi

Nefrologi Ikatan Dokter Anak Indonesia, 2008

8. Peter F. Hoyer, Udo Vester, and Jan Ulrich Becker, Chapter 16 Steroid-Resistant Nephrotic

Syndrome, OMIN PubMed, 2008; 257-266

9.

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