++
Nephrotic syndrome (NS) is not a disease but a constellation
of clinical findings common to several renal disorders.46 By
definition, it comprises proteinuria greater than 50 mg/kg
per 24 hr (> 40 mg/m2 per hour or
a urinary protein-to-creatinine ratio greater than 2.0 mg/mg)
and hypoalbuminemia (serum albumin less than 3.0 g/dl), edema,
and hypercholesterolemia. The reason for the increased hepatic production
of lipoproteins during the nephrotic state is not entirely understood,
as it appears to be associated with low plasma oncotic pressure
or defects in lipoprotein catabolism. NS may be a manifestation
of any of the proliferative glomerular diseases, but in children
it more commonly occurs as an isolated entity without clinical evidence
of nephritic features or evidence of significant glomerular hypercellularity
on renal biopsy. The pathophysiological sequence of events that
lead to the classical clinical features in nephrotic syndrome, proteinuria,
and hypoalbuminemia are depicted in Figure 472-7.
++
The NS of childhood has been divided into three broad groups:
congenital/infantile, primary or idiopathic, and secondary.
Only 10% to 15% of children have an identifiable
secondary cause for their NS. The histological lesions that are
associated with secondary causes of NS are frequently indistinguishable
from the idiopathic lesions, but the treatment is targeted to the
specific underlying cause. Over the past decade, several genetic
mutations have been identified that define a fourth nephrotic syndrome
category: inherited nephrotic syndrome, which is
associated with clinical symptoms that begin after infancy.
++
Primary (idiopathic) NS is the occurrence of the constellation
of clinical findings that define NS in the absence of an identifiable
causative agent or disease. Primary NS is classified into four categories
based on biopsy findings: minimal change nephrotic syndrome (MCNS), MCNS
with proliferative changes, focal segmental glomerulosclerosis (FSGS),
and membranous nephropathy (MN). From a prognostic perspective,
the histological pattern is less important than the responsiveness
to corticosteroids. Most children with steroid-responsive disease
no longer undergo renal biopsy. For these reasons, the terms corticosteroid-sensitive (SSNS)
and steroid-resistant (SRNS) are generally preferred
in clinical practice. Complications of nephrotic syndrome are discussed
at the end of this section.
+++
Steroid-Responsive Nephrotic
Syndrome (Srns)
++
Minimal-change nephrotic syndrome (MCNS), also known historically
as nil disease or lipoid nephrosis, is the most common cause of
NS in childhood, accounting for 90% of patients presenting
under 10 years of age and 70% to 80% of all pediatric
patients with NS. MCNS is characterized by response to corticosteroids
(> 90%), a chronic relapsing course (60% to 80%),
and an excellent long-term prognosis. Idiopathic FSGS is a more
serious form of idiopathic NS, because only 20% to 25% of
patients respond to steroids. As long as future relapses remain
steroid-responsive, the long-term prognosis is good in this subset
of FSGS patients. Although this is still debated, many believe that
MCNS and FSGS represent different ends in the spectrum of the same
disease rather than distinct disorders.
++
The incidence of MCNS is 2 to 7 per 100,000 children under the
age of 16 per year. The peak incidence is in preschool children,
with a median age of 2.5 years; 80% of patients present
before their sixth birthday. Boys are more commonly affected. Familial
cases have been reported (3% in some series), but the responsible
genes have not yet been identified. There appears to be a higher
incidence in the Asian population. A history of atopy is reported
in 30% to 60% of these children, and occasional
associations with food allergies have been made.
++
In children, MCNS is usually idiopathic, although several secondary causes
are known (Table 472-4). Steroid-sensitive
nephritic syndrome (SSNS) is considered to be a primary disease
of the glomerular epithelial cell (podocyte) that is injured by
an unknown systemic factor. T-cell-derived cytokines such as interleukin-13 have
been suggested as candidates, but thus far, the nature of the “nephrotic
factor” remains elusive. Several subtle differences in
the phenotype and in vitro function of lymphocytes (comparing cells
harvested from nephrotic and non-nephrotic patients) have been ascribed
to the nephrotic plasma milieu rather than to some intrinsic T-cell
alteration. Evidence of a circulating “nephrotic factor” is
supported by the observation that when a renal transplant patient
received a kidney from a deceased donor who had active MCNS, proteinuria
decreased rapidly in the transplant recipient and remained persistently negative
after 6 weeks. Conversely, MCNS was reported to recur in a renal
allograft transplanted into a patient with a history of MCNS.
++
++
Another potentially pathogenic mechanism in MCNS is the loss
of charge-selective barrier function of the glomerular capillary
wall, caused by a decrease in the heparan sulfate proteoglycan content. However,
the mechanisms responsible for this change remain unknown, and loss
of charge selectivity is a feature in many other diseases associated
with the nephrotic syndrome; this suggests that this is a non-specific
change. Recent observations in genetically engineered mice challenge
the charge-selectivity hypothesis.
+++
Clinical Features
and Differential Diagnosis
++
Most patients (95%) initially present with dependent
edema that is most obvious in the eyelids, scrotum, and labia. Early
morning swelling of the eyelids (periorbital edema) is common, and
frequently new patients are misdiagnosed as having allergic conjunctivitis.
Increasing abdominal girth from ascites is also common. Most episodes
of NS are triggered by an antecedent upper respiratory tract infection,
as are most relapses. Less commonly, patients with MCNS present
with symptoms secondary to complications of the nephrotic syndrome,
such as infections (peritonitis, cellulitis) or thromboembolic events. Hypertension
is not typical, but a mild elevation in blood pressure occurs in
10% of patients. Microscopic hematuria is seen in approximately
20% of patients. Macroscopic hematuria is distinctly uncommon
and suggests another diagnosis.
++
In addition to proteinuria, the urinalysis may show oval fat
bodies (lipid-containing tubular cells) and waxy or hyaline casts. Granular
casts are common when the patients are volume-contracted. Cellular
casts are absent in idiopathic NS. When patients first present,
the serum creatinine level is sometimes elevated, especially in the
presence of intravascular volume contraction (frequently associated
with an elevated hematocrit). Hyponatremia suggests dehydration
with an appropriate increase in antidiuretic hormone level. The
serum C3 level is typically normal or elevated. Urinary protein
losses may result in low serum levels of IgG, thyroxine-binding globulin
(nephrotic infants in particular are at risk of clinical hypothyroidism),
vitamin D–binding globulin, alternative complement pathway
factor B, and antithrombin III. Serum fibrinogen levels are often
elevated and can be used as a surrogate marker for a risk of thrombosis.
++
Edema is mild in most patients and can be managed with dietary
salt restriction. Fluid intake is not usually restricted except
in the face of severe hyponatremia. Diuretics are effective but
are rarely needed and must be used cautiously to avoid intravascular
volume contraction. Intravenous albumin infusions may be hazardous
but can be lifesaving in patients with clinical signs and symptoms
caused by severe hypovolemia or generalized anasarca. A low serum
albumin level alone is never sufficient reason to administer intravenous
albumin. Hypertension is relatively uncommon, even during corticosteroid
therapy, but when present, it requires treatment with antihypertensive
medications. In these situations, hypertension is usually transient
and medications can often be discontinued once the disease is in
remission.
++
A major aspect of the initial management is parent education.
The majority of patients will follow a chronic relapsing course,
and the families need to be prepared in advance. All families should
be taught to check the urine for protein using a dipstick. The family should
keep a diary of the urinary dipstick results, along with drug doses
and significant clinical events. The importance of testing the urine during intercurrent
illness must be emphasized. Whereas relapses are frequently triggered
by an upper respiratory tract infection, transient low-grade proteinuria
may also occur and resolve spontaneously. Using nonsteroidal anti-inflammation
drugs as antipyretics is best avoided in these patients due to these
drugs’ potential nephrotoxicity.
+++
Pharmacological
Therapy
++
Although spontaneous remissions may occur, the current standard
of care is to treat these children with corticosteroids. Screening
for tuberculosis and ascertainment of varicella immune status is recommended
before high-dose corticosteroids are given. Corticosteroids will
induce a remission in approximately 90% of children with
MCNS. Therefore, for those with a clinical presentation typical of
steroid-sensitive nephrotic syndrome (SSNS), a renal biopsy is not
indicated prior to initiating steroid therapy. Atypical features
that may require a renal biopsy prior to treatment include age less
than 1 year, macrohematuria, hypertension, hypocomplementemia, extrarenal
symptoms such as a rash of arthritis, or renal failure not caused
by volume concentration.
++
The optimal dose, schedule of administration, and total duration
of steroid therapy is unknown. Most children receive initial treatment with
prednisone (60 mg/m2 per day or 2 mg/kg
per day, maximal dose 80 mg/d). Prednisone can be given
in a single daily dose or can be divided into daily doses. Ninety
percent of children who will respond do so within 4 weeks and 98% by
8 weeks (eFig. 472.3).
The current definition of steroid-responsiveness is response within
8 weeks. Once the urine become negative for protein, the subsequent
duration of daily prednisone is debated. Many centers use 6 weeks
total daily therapy; one group has suggested an additional 30 days.
Thereafter, prednisone is switched to alternate days and tapered
over 6 weeks or longer. The total duration of steroid therapy used
to treat the initial episode influences the subsequent relapse rate.
A meta-analysis47 found that for every additional month
of therapy beyond 2 months and up to 7 months, the relative relapse
risk was reduced by 11%. Due to concerns of steroid toxicity,
additional clinical trials are needed before therapy longer than
3 months (6 weeks daily; 6 weeks alternate day) becomes a new practice
standard. Failure to achieve remission after 6 to 8 weeks of full-dose
daily prednisone is an indication for renal biopsy. Niaudet and
colleagues suggest a modified approach. Patients without a steroid
response after 4 weeks are given three intravenous doses of methylprednisone
(1000 mg/m2) every other day. Lack of response
within 7 days is used as the indication for biopsy.48 Some
of these unresponsive children will prove to have MCNS, which will
ultimately respond to a more prolonged course of steroids or to
an alkylating agent or cyclosporin.
++
++
Almost 50% of children with SSNS experience multiple
relapses. There is no agreement on a standard protocol for treating
relapses. A commonly used protocol is prednisone 60 mg/m2 per
day until the urine is free of protein for 5 to 7 days; this is
followed by alternate-day therapy that is tapered over several weeks. If
the child is experiencing frequent relapses (two or more relapses
within 6 months of initial response or 4 or more relapses within
any 12-month period) or has become steroid-dependent (two consecutive
relapses occurring during steroid therapy or within 14 days of its
cessation), the alternate-days dose is typically tapered to a “threshold
dose” (the dose below which relapses occur) to reduce the
number of relapses and the total cumulative dose of steroid therapy.
This dose is often in the range of 15 to 20 mg/m2 and
is continued for 12 to 18 months. A recent study suggests that taking
this dose every day during upper respiratory tract infections may
reduce relapse rates.49 The possibility of medication noncompliance,
including use of lower than recommended prednisone doses, and the
presence of occult infections (dental infections or sinusitis) should
always be considered in patients with frequent relapses. Regular
assessment of growth (both height and weight) and monitoring for
cataracts are imperative in children receiving chronic or recurrent
corticosteroid therapy.
++
Risks of steroid toxicity (especially reduced height velocity
and overweight) with frequent relapses have led to the use of other
immunosuppressive agents. Before initiating cytotoxic therapy, a
biopsy is recommended for steroid-resistant patients, but most nephrologists
agree that a biopsy is unnecessary in those with steroid-dependent
or frequently relapsing disease.50 Although there
is not a complete consensus on this topic, alkylating agents are
often the next drug used. Cyclophosphamide for 8 to 12 weeks is
generally well tolerated, with minimal risk of gonadal toxicity
(total cumulative dose < 200 mg/kg). Monthly intravenous doses
may also be effective. Chlorambucil is also effective but is less
widely used due to the risk of seizures. The alkylating agent is ideally
started after induction of remission (to minimize the risks of infections
and hemorrhagic cystitis) and is used in combination with low-dose
prednisone. Following treatment, the majority of the patients experience
a prolonged remission (35% to 65% still in remission
at 5 years), but relapses do recur in a sizeable subset. Children
with frequent relapses have a better response to alkylating agents
than does the steroid-dependent subgroup.
++
Cyclosporine (CSA) is effective in inducing and sustaining remission
in 85% to 90% of steroid-responsive nephrotics
and has had a major impact in a small group of patients debilitated
by the disease, by steroid toxicity, and some who have had a poor
response to cyclophosphamide.51 Unfortunately,
relapses commonly occur once CSA is discontinued. Due to nephrotoxic
side effects, CSA levels must be carefully monitored, and renal
biopsies are recommended to evaluate the degree of interstitial
fibrosis if therapy is continued for longer than 18 months. A common
starting dosage is 5 to 6 mg/kg divided into two doses,
with target predose blood levels of 50 to 100 ng/ml. Higher
blood levels (100 to 200 ng/ml) are sometimes necessary
in the more challenging patients, but the potential benefit of higher
levels needs to be weighed against the risk of nephrotoxicity, which
increases with the dose and duration of use. Mild side effects are
common and include hypertension, gingival hypertrophy, and hirsutism. To
avoid the hirsutism and gingival hypertrophy associated with CSA
treatment, tacrolimus is gaining popularity but clinical trials are
lacking.
++
Other medications used for treatment include levamisole, which has
been shown to reduce the number of relapses; however, this drug is
no longer available. MMF (900 to 1200 mg/m2 per
day divided into two doses) appears promising as a steroid-sparing
agent, although efficacy data from randomized clinical trials are
not yet available.52 Mizoribine has been used in
Japan and vincristine in Australia with some success reported in
small case series.
++
Before the introduction of antibiotics and corticosteroids, 40% of
nephrotic children died within 5 years of diagnosis. Deaths were
most commonly due to infectious complications. Although today more
than 95% of these children are alive at 25 years, deaths
secondary to infections or thrombotic complications still occur. Late-onset
renal failure is very unusual, but a small number of patients develop
acute tubular necrosis if a relapse is accompanied by sepsis or
hypovolemia. Nonsteroidal anti-inflammatory drugs increase the risk
of acute renal failure during a relapse.
++
Eight to 10 years after diagnosis, 80% of patients achieve
a long-lasting remission (eFig. 472.4). Younger
age at diagnosis and frequent relapses within the first 6 months
predict longer disease duration. A small number (14% to 42%)
continue to experience relapses into adulthood; the frequency may
be more common than previously known.53 Reported
rates vary widely, from 14% to 42%, and may even
occur after a 20- to 25-year remission. Some patients who are initially steroid-responsive
later become steroid-resistant. Many of these patients have FSGS,
which may have been missed on an early biopsy or may have evolved
from MCNS.
++
+++
Steroid-Resistant
Nephrotic Syndrome (Srns)
++
Approximately 15% to 20% of children with idiopathic
NS have SRNS; the majority (~75%) have focal segmental
glomerulosclerosis (FSGS). It is the most frequent glomerular disease
to cause ESRD in childhood and is second only to congenital anomalies
as a cause of pediatric ESRD. FSGS is diagnosed histologically by
the complete collapse of a segment of the glomerulus associated
with mesangial sclerosis (Table 472-3). Only
some of the glomeruli are affected initially (ie, a focal rather than
diffuse lesion), and the deep juxtamedullary glomeruli are involved
first. FSGS may be idiopathic, or it may develop as a secondary
consequence of prior glomerular injury or hypertension (Table 472-5). The majority of children with
idiopathic FSGS present with SRNS (75% to 80%).
The secondary forms of FSGS more typically present as asymptomatic
non-nephrotic proteinuria.
++
++
In children, idiopathic FSGS typically begins between 2 and 7
years of age and occurs with an incidence of 0.3 cases per 100,000
patient years. There is a slight predominance in boys, especially
when it develops at a young age. There is also a higher incidence
among African Americans, Hispanics, and South Asians. The incidence
of FSGS has been increasing in many pediatric and adult populations,
an observation that is not simply explained by disease resulting from
HIV nephropathy.54
++
FSGS recurs in renal allografts, often within hours of the surgery,
suggesting that a systemic factor(s) leads to the disorder. The
nature and source of this factor and the reason for its production
remain elusive. Pregnant women with FSGS gave birth to infants with
nephrotic syndrome that disappeared spontaneously a few weeks after birth. A
bioassay based on the ability of plasma from FSGS patients to increase
albumin permeability in isolated rat glomeruli has been developed,
but this factor has also been detected in genetic forms of FSGS,
suggesting that it may not be a primary etiological agent.
++
FSGS occasionally is an inherited disease that typically presents
before 6 years of age. Mutations in the slit diaphragm protein podocin (NPHS2)
are most common. Inheritance is autosomal recessive (AR); both
homozygous mutations and compound heterozygous mutations have been
reported. In Israeli-Arab children, the podocin mutation is also
associated with cardiac anomalies. Importantly, 10% to
30% of children with apparent idiopathic SRNS harbor podocin
mutations; no podocin mutations have been reported in individuals
with SSNS. No patients with podocin mutations have achieved remission
with immunosuppressive therapy, so progression to end-stage kidney
disease is predicted.55 Other genes have been linked
to inherited forms of SRNS, and additional genes remain to be identified
(Table 472-1).
+++
Clinical Features
and Differential Diagnosis
++
Most children (90%) with idiopathic focal segmental
glomerulosclerosis (FSGS) present with nephrotic syndrome that initially
may be indistinguishable from SSNS. Less commonly, patients may
present with asymptomatic proteinuria with or without microhematuria.
At the time of disease presentation, approximately 30% of
children have mild hypertension, 55% have microscopic hematuria,
and 20% have an elevated serum creatinine level. Macroscopic
hematuria is rare.
++
Definitive diagnosis requires a renal biopsy, as is recommended
for all patients with SRNS. Patients with FSGS also have tubulointerstitial damage
that may impair proximal tubular function, causing features of Fanconi
syndrome such as glycosuria, phosphaturia, renal tubular acidosis,
and low-molecular-weight proteinuria. Genetic testing for podocin
mutations is recommended for AR familial FSGS and for patients who
fail to respond to calcineurin therapy.
++
Patients with genetic SRNS or secondary forms of FSGS are not treated
with immunosuppressive drugs.55 Idiopathic SRNS
is a challenging disease to treat; optimal therapy is still unclear.47 With
a poor overall response rate to immunosuppressive
therapy and a high rate of recurrence in renal allografts, this disease
can be devastating. At best, 20% to 25% of patients
achieve a remission after treatment with a prolonged course of corticosteroids alone. Often
the steroid therapy must be continued for several months. The role
of alkylating agents in treating SRNS is unclear, but a subset of
patients will respond, especially those who had at least a partial
response to prednisone therapy or who have minimal change disease
on renal biopsy. Combined treatment with high-dose corticosteroids
(oral prednisone with or without pulse doses of methylprednisone)
and alkylating agents has reportedly induced a partial or complete
remission in 30% to 60% in some case series, but
these protocols are associated with significant morbidity and should
be limited to patients with well-preserved renal function. Even
a partial response is associated with a better outcome.
++
There is considerable evidence-based literature to support the
use of CSA as the second-line agent for idiopathic SRNS, together
with low-dose prednisone. Initial plasma trough levels may need
to be higher than those for SSNS, often in the range of 125 to 225
ng/ml. Efficacy of tacrolimus (trough levels in the 4-to-7
ng/ml range) is based only on case series. An unresolved
question is how long a calcineurin drug should be continued before
a patient is declared unresponsive; 3 to 6 months is often suggested.
CSA needs to be continued for long periods of time, because the
NS frequently relapses once CSA is discontinued. Drug levels, blood
pressure, and renal function must be closely monitored.
++
MMF may have a role in the treatment of steroid and calcineurin-resistant
SRNS, although data in children are limited. Triple therapy (steroids,
CSA, and MMF), rituximab (anti-CD20), plasmapheresis, protein adsorption
columns, low-density lipoprotein apheresis, and even bone marrow
transplantation are all reportedly effective in selected individuals,
but there are insufficient data to recommend their use at this time.
++
All hypertensive patients should be treated with ACEi and or
angiotensin receptor blockers (ARB) drugs; these agents may also
be recommended in normotensive patients for their antiproteinuric
effects as long as serum potassium levels remain normal and the
patient is not pregnant or at risk of becoming pregnant. Hydroxymethylglutaryl
CoA reductase inhibitors (statin) therapy is recommended in older
children and adolescents with hypercholesterolemia to reduce cardiovascular
risks and to possibly slow the progression of renal disease.
++
The single best prognostic indicator in patients with idiopathic
NS is responsiveness to steroid therapy. Approximately 50% of
the patients who do not achieve an NS remission develop ESRD within
10 years. The risks of progressive renal failure are higher among
patients of Hispanic and African descent, children with disease
onset under 1 year of age, and patients with the collapsing variant
of FSGS. The severity of the proteinuria and the degree of interstitial
fibrosis on renal biopsy also correlate with the rate of progression
to ESRD. Recurrence of proteinuria and NS after transplantation
occurs in 20% to 30% of patients.
+++
Membranous Nephropathy
++
Membranous nephropathy is a noninflammatory proteinuric glomerular
disease characterized by the presence of hallmark subepithelial
immune deposits (usually containing IgG and C3). Membranous nephropathy
is a rare cause of nephrotic syndrome in childhood, accounting for
approximately 1% of cases in North America. Nephrotic syndrome
secondary to membranous nephropathy does not usually respond to
an 8-week course of prednisone; it is therefore necessary to do
a biopsy for diagnosis.
++
Although this disease is rare in childhood, it can present at
any age, including in infants. Cases affecting identical twins and
siblings have been reported, suggesting a genetic factor. Detailed
epidemiological studies in childhood have not been conducted.
++
Unlike the disease in adults, the majority of childhood cases
are secondary to an underlying disorder (Table
472-6). Idiopathic membranous nephropathy appears to be an
antibody-mediated disease even though the target antigen remains
unknown. Immune complexes are thought to form locally within the
subepithelial space, where the target antigen is located. In a rat
model of membranous nephropathy (Heymann nephritis), the target
antigen is megalin, a normal constituent of rat but not human podocytes. An unusual
antenatal form of membranous nephropathy has been reported and is
associated with transplacental passage of antibodies to the podocyte
antigen neutral endopeptidase (NEP).56 However,
the target antigen in most forms of idiopathic human membranous
nephropathy remains unknown. In addition to the more common associations
with autoimmune diseases listed in Table 472-6,
membranous nephropathy has also been reported rarely in patients
with insulin-dependent diabetes mellitus, Crohn disease, and primary
biliary cirrhosis, suggesting that other candidate autoantigens
will eventually be unveiled. Glomerular inflammation does not explain
the proteinuria; rather, the terminal membrane attack complex of
the complement cascade C5b-9 appears to be the critical mediator.
++
+++
Clinical Features
and Differential Diagnosis
++
Proteinuria is the hallmark of membranous nephropathy. At presentation,
70% have nephrotic syndrome, 70% have microhematuria,
and 20% are hypertensive. The disease is typically insidious in
its onset and progression. When a renal biopsy establishes a diagnosis
of membranous nephropathy (usually after failure to respond to corticosteroid
therapy for nephritic syndrome), an exhaustive investigation is
warranted to look for an underlying cause. Only 3% of children
have renal failure at presentation. A rapid deterioration in renal
function mandates a search for an additional cause. For example,
a small subset of these patients develops a superimposed crescentic
glomerulonephritis, sometimes due to the formation of anti-GBM antibodies. Although
renal vein thrombosis is a common complication among adult patients
with membranous nephropathy, this complication is rare in children.
++
A renal biopsy is required to establish a definitive diagnosis.
Serological tests, including serum complement levels, are typically
normal. Laboratory investigations are particularly helpful during
the search for a secondary cause (Table 472-6).
Hepatitis serology, serum complement levels, and an ANA test should
be obtained in all patients. The renal biopsy suggests a secondary
cause if immune deposits are also found in the mesangium (SLE),
if significant deposits of IgA are present (IgA nephropathy), or
if inflammatory cells are present (postinfectious GM); all these
features are atypical of the idiopathic disease.
++
Established treatment guidelines for children with idiopathic
membranous nephropathy do not currently exist. Children who present
with non-nephrotic proteinuria, normal blood pressure, and normal
renal function appear to have a good prognosis without specific
therapy, but close follow-up is warranted. Spontaneous remissions have
been reported in 3% to 30% of adult patients.
Use of ACEi or angiotensin receptor blocker therapy and a low-sodium
diet are recommended for hypertension and as antiproteinuric therapy;
older children with hypercholesterolemia should be treated with
a statin drug.
++
Treatment guidelines for patients at risk of chronic kidney disease
(> 4 g proteinuria/1.73m2/day, nephrotic
syndrome, renal scarring on biopsy, rising serum creatinine level
during follow-up) have been developed for adults and are often applied
to children for whom there are no evidence-based data, although
the long-term prognosis appears to be better in children.57,58 In
general, corticosteroids alone decrease proteinuria, but effects on
long-term renal function are less clear. For this reason, they are usually
combined with an alkylating agent or a calcineurin inhibitor, either
at the beginning of therapy or within 6 months, depending on the
initial response. Therapy is required for several months. Patients
on tacrolimus are more likely to develop glucose intolerance, but
troublesome side effects such as hirsutism and gingival hypertrophy
with CSA are avoided. The risk of statin-induced rhabdomyolysis
appears to be higher with concurrent use of a calcineurin inhibitor.
Data are emerging to suggest that MMF and rituximab may be useful
in membranous nephropathy.
++
Membranous nephropathy is typically an indolent, slowly progressive
disease with fewer than 5% of children developing ESRD
5 years after diagnosis. Good, long-term follow-up studies are not
yet available for patients who develop membranous nephropathy in
childhood.
+++
Medical Complications
of Nephrotic Syndrome
++
Persistence of nephrotic syndrome is associated with significant
morbidity and even mortality. Short-term mortality rates of 3% are most
frequently due to infectious complications and less commonly to
thromboembolic events. Because nephrotic syndrome frequently follows
a chronic relapsing course, children are at risk for several recognized
long-term complications (eTable 472.3). Not
to be overlooked is the tremendous psychological stress that the
patients and their families endure. The side effects of corticosteroids
and cytotoxic drugs are also significant for many children.
++
++
Even in the current medical era, acute bacterial infections are
relatively common and potentially fatal complications of nephritic
syndrome. The acute onset of fever in a child during relapse of
NS needs urgent evaluation. Primary peritonitis still occurs in
2% to 6% of these children. Patients with serum albumin
levels less than 1.5 g/dl have a greater risk of peritonitis. Fever
associated with abdominal pain must be considered peritonitis until
proven otherwise. Approximately 50% of cases are caused
by Streptococcus pneumoniae while other encapsulated
or gram-negative organisms are occasionally isolated (especially Escherichia
coli). Patients with presumed peritonitis should be treated
with antibiotics to cover both gram-positive and gram-negative
organisms while culture results are pending. Unfortunately, the
peritoneal culture is negative in 15% to 50% of
patients with a presumptive diagnosis of peritonitis. Prophylactic
penicillin has not proven to be effective for preventing pneumococcal
peritonitis.59 Once a nephrotic patient is in remission
and off steroids for a few months, inoculation with the 23-valent
pneumococcal vaccine (Pneumovax) and the heptavalent vaccine (Prevnar)
is recommended.
++
Several abnormalities associated with the nephrotic state predispose
patients to bacterial infections: abnormalities of cellular immunity; low
total serum IgG and specific antibody levels (only partly explained
by urinary losses); and decreased serum levels of complement proteins
B and D, which impair plasma bacterial opsonic activity and may
explain the predisposition to infections caused by encapsulated
bacteria. Local factors related to tissue edema, breakdown of the skin
barrier, and the presence of peritoneal fluid, which is a rich culture
medium, might also facilitate infections. The use of immunosuppressive drugs
is another contributing factor.
++
Varicella zoster infections occurring during a relapse may be
severe. The live attenuated vaccine should be given only after immunosuppressive
drugs have been discontinued for a few months. In the interim, significant
exposures should be treated with zoster immune globulin if available
or antiviral drugs such as valacyclovir. Varicella antibody levels
may decline in patients with multiple relapses or with NS that is
refractory to treatment. Annual immunization with killed influenza
vaccine is recommended.
++
Thromboembolism is one of the most serious complications of nephrotic
syndrome. Virtually all nephrotic patients are in a hypercoagulable state,
and as many as 20% experience thrombotic events that are
often clinically silent (2% to 4% have symptoms).
However, it is still recommended that children with documented thrombotic
complications undergo an evaluation for known genetic causes of
thromboembolic disorders. The cause of the nephrotic syndrome may
affect the absolute risk; thrombosis is relatively common in adults
with membranous nephropathy and is infrequent in children with MCNS.
Which abnormalities of the clotting process best correlate with
the risk of thrombosis is still unclear. Fibrinogen levels appear
to be the best surrogate measure of hypercoagulability. Virtually
every component of the hemostatic pathway is perturbed in some way, including
increased serum levels of clotting factors (especially VIII, V,
and fibrinogen), urinary loss of anticoagulants (antithrombin III,
protein S), and increased platelet number and adhesiveness. Other
contributing factors include hyperlipidemia and hyperviscosity.
The risk of thrombotic disease is significantly enhanced in the
presence of hypovolemia and during prolonged periods of immobilization. Hospitalized young
adult nephrotic patients have a sevenfold increased chance of experiencing
thromboemboli. Indwelling venous catheters impose a major risk and
should be avoided if at all possible.
++
The clinical presentation is highly variable and dependent on
the site of the clot. In children, both arterial and venous clots
occur. The renal vein and sagittal sinus may be targets, as are
the pulmonary and femoral arteries. Aspirin therapy may be recommended
for patients with significant thrombocytosis. Prophylactic anticoagulation
is not recommended in the pediatric age group due to bleeding risks.
In those with a documented clot or very high risk factors (such
as an indwelling catheter), warfarin or low-molecular-weight heparin
is used; the latter requires adequate factor VIII activity levels.60 Guidelines
for the duration of therapy once remission of the nephrotic syndrome
has been achieved are not established.
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Cardiovascular Disease
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An unresolved issue of significant concern is whether children
with chronic relapsing nephrotic syndrome are at risk of premature
atherosclerotic disease. Studies using sensitive imaging techniques
such as electron beam CT or B-mode ultrasonographic imaging of carotid
intima-media thickness have not yet been reported. Autopsies done
on children as young as 5 years who died from nephrotic syndrome
have found atheromatous lesions. In adults with nephrotic syndrome,
the relative risk of myocardial infarction is 5.5 compared with
a control population after adjustment for other known risk factors.
Several factors may contribute to the increased risk of cardiovascular
disease and stroke, including hypertension, the use of steroids
and systemic inflammation, and the atherogenic plasma lipid profile. In
particular, plasma cholesterol and lipoprotein levels are high. Whether
hypercholesterolemia should be treated with statin drugs remains
unclear.
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Although reduced bone formation rates, osteoporosis, and avascular
necrosis are known complications of long-term corticosteroid use
in several patient populations, these complications appear to be
rare in patients with SSNS based on an evaluation of bone density
by dual energy x-ray absorptiometry.61 One proposed
explanation is that the steroid-associated increase in the body
mass index is protective as a consequence of increased biomechanical
loading. Children with multiple steroid-treated relapses may not
reach their final adult height potential.