Handbook of Clinical Neurology, Vol.

119 (3rd series)

Neurologic Aspects of Systemic Disease Part I
Jose Biller and Jose M. Ferro, Editors
© 2014 Elsevier B.V. All rights reserved

Chapter 26

Nephrotic syndrome
DAVID S. LIEBESKIND*
UCLA Stroke Center, Los Angeles, CA, USA

BACKGROUND membrane, or podocyte injury to cause abnormal glomer-

Nephrotic syndrome denotes excessive proteinuria, with a
constellation of associated hypoalbuminemia, edema, and
hyperlipidemia (Hull and Goldsmith, 2008; Gipson et al.,
2009; Kodner, 2009). The degree of proteinuria is typically
in excess of 3 grams per day or defined as a single measure
in excess of 2 grams urinary protein per gram of creatinine.
This systemic disorder may result from diverse underly-
ing causes (Table 26.1), including renal diseases such
as minimal-change nephropathy, focal and segmental
glomerulosclerosis, membranous nephropathy, IgA
nephropathy, or a congenital predisposition. Alternatively,
nephrotic syndrome may develop due to diabetes, amy-
loidosis, viral infections, malaria, pre-eclampsia, systemic
lupus erythematosus, or other systemic disorders that
affect the kidneys. Immune complex injury of the glo-
merulus by cancer antigens may cause membranous
nephropathy. It has also been associated with nonsteroidal
anti-inflammatory drugs, gold, lithium, mercury, inter-
feron-b-1a, pamidronate, penicillamine, or heroin use.
Neurologic manifestations of nephrotic syndrome are
linked through several distinct mechanisms (Table 26.2)
that directly implicate the kidneys, such as hypoproteinemia,
resultant hypercoagulability and hyperlipidemia, hyperten-
sion, or systemic involvement such as amyloid deposition.
Electrolyte disorders and hormonal changes may also ensue
due to nephrotic syndrome or the associated treatment, caus-
ing neurologic sequelae. The numerous systemic features
and neurologic sequelae of nephrotic syndrome are readily
apparent or simplified through consideration of the underly-
ing renal pathophysiology.
PATHOPHYSIOLOGY OF NEUROLOGIC
SEQUELAE
Glomerular disorders in the kidney may result from endo-
thelial damage, disruption of the glomerular basement
ular permeability. Increased glomerular permeability
allows for albuminuria and subsequent proteinuria, with
more severe injury that leads to leakage of all plasma pro-
teins. Selective proteinuria, consisting of more than 85%
albumin, may be more common in minimal-change
nephropathy. Excessive glomerular permeability and
albuminuria leads to hypoalbuminemia. The lower plasma
colloid osmotic pressure of hypoalbuminemia causes sys-
temic edema. Intravascular volume depletion then occurs
with sodium retention.
Hypercoagulability
Hypercoagulability is a seminal feature of nephrotic syn-
drome, emanating from several alterations in coagula-
tion, fibrinolysis, and platelet function (Table 26.3). In
general, the degree of dysfunction in these pathways cor-
relates with the severity of proteinuria.
Platelet aggregation abnormalities in nephrotic syn-
drome have been attributed to thrombocytosis, increased
b-thromboglobulin, elevated von Willebrand factor, and
increased release of b-thrombomodulin and platelet fac-
tor 4 (Richman and Kasnic, 1982). Secondary effects of
hypoalbuminemia and hyperlipidemia may also exacer-
bate platelet alterations causing increased thrombotic
events. Finally, platelet aggregation may be enhanced
by changes in the platelet surface membrane.
Fibrinolysis is altered due to changes in numerous
factors associated with leakage of proteins into the
urine. Serum fibrinogen levels are elevated whereas
plasminogen is diminished. Other alterations include
changes in tissue plasminogen activator (tPA) and
a2-antiplasmin levels. Elevated tPA and plasminogen
activator inhibitor-1 (PAI-1) have been noted with
increased D-dimers, suggesting enhanced fibrinolysis
in addition to increased coagulation (Malyszko et al.,

*Correspondence to: David S. Liebeskind, M.D., UCLA Stroke Center, 710 Westwood Plaza, Los Angeles, CA 90095, USA.
Tel: þ1-310-794-6379, Fax: þ1-310-267-2063, E-mail: davidliebeskind@yahoo.com
406 D.S. LIEBESKIND
Table 26.1 Table 26.3
Causes of nephrotic syndrome Causes of hypercoagulability on hematologic assays

Primary Congenital nephrotic Antiphospholipid antibodies

syndrome Decreased antithrombin
Focal and segmental Decreased factor IX
glomerulosclerosis Decreased factor XI
IgA nephropathy Decreased factor XII
Membranoproliferative Decreased free protein S
glomerulonephropathy Decreased plasminogen
Membranous nephropathy Decreased protein C
Minimal-change nephropathy Decreased a1-antitrypsin
Secondary Alport syndrome Diuresis
Amyloidosis Factor V Leiden mutation
Cancer (adenocarcinoma, multiple Increased D-dimers
myeloma, lymphoma) Increased factor I
Diabetes Increased factor V
Fabry disease Increased factor VII
Gold Increased factor VIII
Henoch–Sch€onlein purpura Increased factor X
Hepatitis B and C Increased fibrinogen
Heroin Increased lipoprotein(a)
HIV Increased plasminogen activator inhibitor-1 (PAI-1)
Interferon-b-1a Increased release of platelet factor 4
Lithium Increased release of b-thrombomodulin
Malaria Increased tPA
Mercury Increased von Willebrand factor
Mixed cryoglobulinemia Increased a2-antiplasmin
Nonsteroidal anti-inflammatory Increased a2-macroglobulin
drugs Increased b-thromboglobulin
Pamidronate Infection
Parvovirus Steroid use
Penicillamine Thrombocytosis
Polyarteritis nodosa
Pre-eclampsia
Sarcoidosis
Sj€ogren disease 1996). Selective loss of smaller molecular size proteins
Syphilis alters the balance in coagulation factors. Specifically,
Systemic lupus erythematosus factors IX, XI, and XII are lost into the urine with
Takayasu arteritis relative elevation of factors I, V, VII, VIII and X in
Wegener’s granulomatosis the plasma. Antithrombin-III, protein C and free protein
S are also diminished due to proteinuria (Lau et al.,
1980). Lipoprotein(a) elevation due to reactive hepatic
protein synthesis in nephrotic syndrome may simulta-
neously increase atherogenecity and hypercoagulability
Table 26.2 (Kronenberg et al., 1996).
Mechanisms of neurologic sequelae
The vast array of changes in homeostatic pathways
makes it difficult to isolate an individual cause of hyper-
Hypercoagulability coagulability in nephrotic syndrome. It remains most
Hyperlipidemia likely that these concomitant changes all contribute to
Hypertension the increased tendency to clot in such patients. Other
Microalbuminuria relative prothrombotic states such as factor V Leiden
Infection
mutation and the presence of antiphospholipid anti-
Electrolyte disorders
Hypovolemia
bodies due to related disorders may become more
Hormonal abnormalities virulent given the multitude of hypercoagulable factors
Systemic involvement (e.g., amyloidosis) in nephrotic syndrome (Petaja et al., 1995). Venous
thrombosis, systemic or cerebral, due to the resultant
 NEPHROTIC SYNDROME
hypercoagulability may also be compounded by hypovo-
lemia that develops in more severe cases. Excessive
diuretic use, corticosteroids, and infection may further
promote hypercoagulability.
Hyperlipidemia
Proteinuria also causes hypoproteinemia that stimulates
lipoprotein synthesis by the liver and decreased lipid
catabolism because of reduced lipoprotein lipase. Serum
total cholesterol, very low-density lipoprotein,
intermediate-density lipoprotein, low-density lipoprotein,
and lipoprotein(a) may all be increased in nephrotic syn-
drome (Wheeler and Bernard, 1994). Clearance of these
atherogenic lipoproteins is also impaired by dysfunction
of receptor-mediated mechanisms (Kostner et al., 1998).
As a result, hyperlipidemia develops with potentially
increased atherogenesis and hypercoagulability. Lipopro-
tein(a) may cause accelerated atherosclerotic disease and
may also inhibit fibrinolysis (Edelberg and Pizzo, 1991;
Kronenberg et al., 1996; Peng et al., 1999). Accelerated
atherosclerosis in nephrotic syndrome may cause either
myocardial infarction or ischemic stroke.
Hypertension
The role of hypertension varies with the underlying cause
of nephrotic syndrome and nature of renal disease. Hyper-
tension may be more common in adults with minimal-
change nephropathy, focal and segmental
glomerulosclerosis, or membranous nephropathy. Cardiac
failure and hypertension may also ensue from chronic
edema or result from some underlying causes of nephrop-
athy. In cases of end stage renal disease, due to any under-
lying cause, hypertension may become ubiquitous.
Microalbuminuria
Glomerular permeability may lead to albuminuria before
frank proteinuria of nephrotic syndrome is evident.
Microalbuminuria has been identified as a risk factor
for stroke, serving as a potential marker of microvascu-
lar injury in diabetes and hypertension (Turaj et al., 2003;
Wada et al., 2007; Rocco et al., 2010). Diabetic or hyper-
tensive nephropathy may be recognized at an early stage
by the presence of microalbuminuria, providing critical
opportunities for cardiovascular preventive strategies.
Infection and systemic disorders
Loss of immunoglobulins into the urine may increase the
risk of infection, with susceptibility to bacteria or viral
infections such as varicella. Finally, systemic disorders
such as diabetes or amyloidosis may simultaneously
injure the kidneys and nervous system, from brain to
peripheral nerves.
407
NEUROLOGIC MANIFESTATIONS
A broad range of neurologic disorders has been reported
in association with nephrotic syndrome (Table 26.4).
The vast majority of reports revolve around vascular
manifestations such as cerebral venous thrombosis and
arterial ischemic stroke, although several other neuro-
logic disorders have been reported that implicate sys-
temic pathophysiology described above. Most recently,
several reports have utilized advanced imaging such as
magnetic resonance imaging (MRI) to chronicle serial
changes of leukoencephalopathy that suggest a combi-
nation of effects in the brain, including edema, hyperten-
sion, and hypercoagulability. The following discussion
on neurologic sequelae of nephrotic syndrome describes
clinical manifestations from the most common to
the more unusual, focused on the most influential
mechanisms that may lead to rational therapeutic strat-
egies in the future.
Cerebral venous thrombosis
Cerebral venous thrombosis is a commonly recognized
neurologic complication of nephrotic syndrome
(Fig. 26.1), described in some of the earliest reports
(Barthelemy et al., 1980; Levine et al., 1987). In recent
years, the number of publications on cerebral venous
thrombosis in nephrotic syndrome in both children and
adults continues to grow (Burns et al., 1995; Laversuch
et al., 1995; Meena et al., 2000; Lin et al., 2002; Afsari
et al., 2003; Palcoux et al., 2003; Rodrigues et al.,
2003; Chan et al., 2004; Appenzeller et al., 2005;
Papachristou et al., 2005; Fluss et al., 2006; Balci
et al., 2007; Komaba et al., 2007; Zaragoza-Casares
et al., 2007; Xu et al., 2010). Venous thrombosis, cerebral
or systemic, is a frequent manifestation of nephrotic
syndrome affecting between 10% and 40% of patients
with the disorder. Many different causes of nephrotic
syndrome have culminated in cerebral venous thrombo-
sis (Burns et al., 1995; Fofah and Roth, 1997; Koch et al.,
Table 26.4
Neurologic disorders associated with nephrotic syndrome
Cerebral venous thrombosis
Arterial ischemic stroke
Posterior reversible encephalopathy syndrome (PRES)
Guillain–Barré syndrome
Myasthenia gravis
Pituitary and hormonal disorders
Mitochondrial encephalopathy, lactic acidosis and stroke-like
episodes (MELAS)
Myoclonic encephalopathy
Stiff person syndrome
Multiple sclerosis
408 D.S. LIEBESKIND
Fig. 26.1. Cerebral venous thrombosis associated with nephrotic syndrome. Thrombosis of the right transverse sinus and superior
sagittal sinus (A) are associated with left hemispheric venous infarction (B) on magnetic resonance imaging in a 48-year-old man.
1997; Afsari et al., 2003; Fluss et al., 2006; Nishi et al.,
2006). Renal vein thrombosis or deep venous thrombosis
is particularly common in membranous nephropathy.
Venous thromboses in any location may be clinically
silent and therefore underestimated in prevalence
(Cameron, 1984; Tovi et al., 1988; Nishi et al., 2006).
Particular attention should be paid to headache as a
potential clue to cerebral venous thrombosis in patients
with nephrotic syndrome (Laversuch et al., 1995). Case
reports on cerebral venous thromboses in nephrotic syn-
drome have most commonly described involvement of
the larger venous structures such as the superior sagittal
and transverse sinuses (Tullu et al., 1999; Fluss et al.,
2006), but it remains likely that many other cases
remained occult due to involvement of smaller venous
structures or other locations difficult to diagnose by
even the most advanced imaging approaches. Hemor-
rhagic conversion of venous lesions in the brain has also
been described in the setting of nephrotic syndrome
although this remains a relatively nonspecific and direct
manifestation of venous hypertension due to thrombotic
occlusion (Afsari et al., 2003). Antithrombin III admin-
istration has been used to treat cerebral venous thrombo-
sis in nephrotic syndrome, replacing this critical factor
that is depleted as a result of proteinuria (Akatsu
et al., 1997). Other strategies have included delivering
fresh frozen plasma with heparin (Divekar et al., 1996;
Sung et al., 1999; Al Fakeeh and Al Rasheed, 2000).
Endovascular thrombectomy has also been performed
for cerebral venous thrombosis in nephrotic syndrome,
yet medical management is likely critical to avoid
rethrombosis in such patients with numerous coagula-
tion abnormalities (Philips et al., 1999).
Arterial ischemic stroke
Arterial events are less common than venous thromboses
in nephrotic syndrome. Ischemic stroke due to arterial
causes in nephrotic syndrome (Fig. 26.2), however, has
been reported on numerous occasions. These descrip-
tions have accentuated the specific features of nephrotic
syndrome, such as hypercoagulability, because many
common risk factors for stroke typically accompany
the disorder. Prior reports on ischemic stroke in
nephrotic syndrome have focused on large vessel occlu-
sion due to arterial thrombosis with concomitant periph-
eral clots (Parag et al., 1990; Marsh et al., 1991;
Chaturvedi, 1993; Ahmed and Saeed, 1995; Lee et al.,
2000; Laksomya et al., 2009). Such case reports of rela-
tively young adults with stroke have often lacked typical
vascular risk factors for cerebral ischemia yet harbored
the typical constellation of nephrotic syndrome and the
associated serum and urine abnormalities of hypercoa-
gulability and hyperlipidemia (Raghu et al., 1981;
Takegoshi et al., 1990; Marsh et al., 1991; Fritz and
Braune, 1992; Fuh et al., 1992; Chaturvedi, 1993; Song
et al., 1994; Ahmed and Saeed, 1995; de Gauna et al.,
1996; Pandian et al., 2000; Yun et al., 2004; Kotani
 NEPHROTIC SYNDROME
Fig. 26.2. Arterial ischemic stroke in nephrotic syndrome.
Acute ischemia in the subcortical territory of the right middle
cerebral artery on diffusion-weighted magnetic resonance
imaging of a nephrotic 46-year-old man.
and Kawano, 2005). Extensive thrombosis of the carotid
artery has also been described (Wiroteurairueng and
Poungvarin, 2007), culminating in orbital infarction.
Aside from in situ arterial thromboses of the cerebral
circulation, ischemic stroke in nephrotic syndrome has
also been associated with cardioembolism (Huang and
Chau, 1995). Even when overt thromboemboli due to
confirmed hypercoagulability has not been implicated,
accelerated atherosclerosis has been identified as a
precipitant of ischemic stroke in nephrotic syndrome
(Kallen et al., 1977; Leno et al., 1992). In some cases,
hypoperfusion has been implicated, although the precise
mechanism remains unclear (Ehrich et al., 1995). Diffuse
vascular involvement of the kidneys and brain may lead
to stroke in nephrotic syndrome due to diabetes, hyper-
tension, amyloidosis, or vasculitis. Vasculitides poten-
tially culminating in nephrotic syndrome and ischemic
stroke include glomerulonephritis, Wegener’s granulo-
matosis, polyarteritis nodosa, Goodpasture syndrome,
Churg–Strauss syndrome and Takayasu disease
(Sugino et al., 2009; Park et al., 2010). It should be noted,
however, that the diagnostic evaluation for potential
vasculitis may be complicated in patients with nephrotic
syndrome as the erythrocyte sedimentation rate may be
markedly elevated due to renal causes (Gruener and
Merchut, 1992). On rare occasions, transient ischemic
attacks or ischemic stroke may be the initial presentation
409
of nephrotic syndrome (Marsh et al., 1991; Nandish et al.,
2006; Baris et al., 2010). Many cases of pediatric stroke
in nephrotic syndrome have also been reported (Raghu
et al., 1981; Igarashi et al., 1988; Ehrich et al., 1995;
Baris et al., 2010).
Posterior reversible encephalopathy
syndrome
The pathogenesis of posterior reversible encephalopathy
syndrome (PRES) and similar entities such as pre-
eclampsia and hypertensive encephalopathy has not been
fully elucidated, yet there are many aspects that share
similarity with the pathophysiology of nephrotic
syndrome. In particular, diffuse vascular changes,
edema, and hypertension are common to nephrotic
syndrome and PRES. Interestingly, there have been
many reports of PRES and related diagnoses with
nephrotic syndrome (Yu et al., 1987; Assadi et al.,
1990; Collins et al., 1990; Bettinelli et al., 1991;
Weintraub et al., 1992; Shimizu et al., 1994; Pearson
et al., 1999; Ikeda et al., 2001; Kim et al., 2001; Utsumi
et al., 2003; Aksoy et al., 2004; Taque et al., 2004; Li
Looi and Christiansen, 2006; Onder et al., 2007;
Sharma and Grimmer, 2007; de Oliveira et al., 2008;
Saeed et al., 2008; Nishida et al., 2009; Kabicek et al.,
2010; Sakai et al., 2010). These cases have demonstrated
typical neurologic symptoms of transient blindness or
visual defects, headaches, seizures, and confusion.
Although the clinical features of PRES are well known
by neurologists, most recent reports have been published
in the nephrology literature to increase awareness
amongst those treating patients with nephrotic syn-
drome. Many of the reports on PRES in nephrotic syn-
drome have described pediatric cases. Some have
suggested that this may reflect immaturity of the
blood–brain barrier (Weintraub et al., 1992). In the past,
encephalopathy has been described with nephrotic syn-
drome but the specific nature has been markedly
advanced with the use of MRI (Fig. 26.3) in recent years
(Utsumi et al., 2003; Taque et al., 2004; Onder et al.,
2007; Nishida et al., 2009; Sakai et al., 2010). Hyperten-
sive encephalopathy has been implicated because of an
obvious link (Assadi et al., 1990; Bettinelli et al., 1991;
Pearson et al., 1999; Ikeda et al., 2001; Kabicek et al.,
2010). Variable degrees of hypertension, however, have
been reported in nephrotic syndrome and PRES and a
lack of hypertension has been noted in several cases
where the two conditions coexist (Bettinelli et al., 1991;
Aksoy et al., 2004). A broad range of underlying renal
diagnoses or types of nephropathy have been manifest
with PRES. Immunosuppression with ciclosporin for
the treatment of nephrotic syndrome has also been impli-
cated as a cause of PRES (Shimizu et al., 1994; Taque
410 D.S. LIEBESKIND
Fig. 26.3. Magnetic resonance image of posterior reversible encephalopathy syndrome (PRES) in nephrotic syndrome. Bilateral
fluid-attenuated inversion recovery sequence hyperintensities on MRI of an 18-year-old man with acute confusion and visual field
defects in nephrotic syndrome.
et al., 2004; de Oliveira et al., 2008; Saeed et al., 2008;
Sakai et al., 2010). PRES has also been described with
furosemide use (Sharma and Grimmer, 2007), urging
additional caution about potential neurologic manifesta-
tions when treating nephrotic syndrome.
Guillain–Barré syndrome
Guillain–Barré syndrome (GBS) has been described in
association with nephrotic syndrome in only a few cases,
yet the occurrence in individuals without other medical
history suggests a common link. A presumed viral mech-
anism has been suggested by the development of GBS
and nephrotic syndrome after influenza vaccination
(Kao et al., 2004). In a pediatric case involving a
3-year-old with GBS, nephrotic syndrome developed
3 weeks after the acute neurologic illness (Bouyahia
et al., 2010). In other cases, the onset of GBS occurred
in concert with nephrotic syndrome due to either focal
glomerulosclerosis, membranous or minimal-change
nephropathy (Nicholson et al., 1989; Kitamura et al.,
1998; Chen et al., 2002; Souayah et al., 2008). Although
relapses of these simultaneous disorders have been
reported (Souayah et al., 2008), response to immunosup-
pressive therapy strongly suggests an immune-mediated
mechanism. The simultaneous neurologic and renal dis-
orders have also been attributed to exposure to a com-
mon organic solvent (Chen et al., 2002).
Myasthenia gravis
Myasthenia gravis has been reported in nephrotic syn-
drome in a few cases (Almsaddi et al., 1997; Ogawa
et al., 1999). Glomerulonephritis may be associated with
the autoantibodies of myasthenia gravis and thymoma
(Valli et al., 1998). Interestingly, the proteinuria of
nephrotic syndrome may diminish symptoms of myas-
thenia due to loss of acetylcholine receptor antibodies
into the urine (Almsaddi et al., 1997). In that case,
effective treatment of the proteinuria caused exacerba-
tion of the myasthenia and increased antibody titers
(Almsaddi et al., 1997). This example shows the paradox-
ically beneficial effect of proteinuria in nephrotic
syndrome to filter antibodies out of the system.
Pituitary and hormonal disorders
Nephrotic syndrome during childhood due to congenital
or other causes may require exposure to medications
such as corticosteroids or cyclophosphamide that harbor
potential adverse effects on hormonal status (Friedman
and Strang, 1969). Low baseline plasma cortisol levels
have been demonstrated in children frequently treated
with prednisone for relapsing nephrotic syndrome
(Moel et al., 1980). Long-term effects of such cyclophos-
phamide treatment have not demonstrated alterations in
pituitary or gonadal function, yet the potential exists
(Bogdanovic et al., 1990). Animal studies have also sug-
gested a potential direct effect of nephrotic syndrome on
pituitary–ovarian function (Menjivar et al., 1995).
Other disorders
Mitochondrial encephalopathy, lactic acidosis and
stroke-like episodes (MELAS) has recently been
described in association with nephrotic syndrome,
although the specific association remains somewhat
obscure (Lau et al., 2007). Glomerulosclerosis and the
resultant nephrotic syndrome were considered to be sec-
ondary to MELAS. Only a few other cases have
described MELAS with nephrotic syndrome (Yoneda
et al., 1989; Ban et al., 1992). Early myoclonic encepha-
lopathy has also been associated with the congenital
nephrotic syndrome, microcephaly, multiple minor
anomalies, and cerebellar hypoplasia (Nishikawa et al.,
1997). Stiff person syndrome with nephrotic syndrome
due to minimal-change nephropathy has been attributed
to T cell-mediated immune mechanisms and complete
 NEPHROTIC SYNDROME
resolution was achieved with immunosuppressive ther-
apy (Ergun et al., 2005). Nephrotic syndrome has rarely
been described with multiple sclerosis. Treatment with
interferon-b-1a caused membranous glomerulonephritis
and nephrotic syndrome followed by resolution after
cessation of the drug and immunosuppression (Auty
and Saleh, 2005). In another case, secondary amyloidosis
developed in a multiple sclerosis patient leading to
nephrotic syndrome (Kang et al., 2009).
DIAGNOSIS, THERAPY, AND PROGNOSIS
OF NEUROLOGIC ASPECTS
Diagnosis of neurologic sequelae in nephrotic syndrome
depends on prompt recognition of known complications
and consideration of the key pathophysiology that may
contribute to injury of the nervous system. The numer-
ous alterations in systemic pathophysiology that accom-
pany nephrotic syndrome may make it difficult to
predict neurologic complications, although most patho-
genic mechanisms worsen in parallel with increasing
severity of proteinuria. Recognition of the cardinal
features of nephrotic syndrome and pursuit of the
underlying cause of kidney disease is paramount. This
process typically involves consultation with a nephrolo-
gist, serologic assays, and kidney biopsy in selected
cases. Diabetic nephropathy may not warrant a biopsy
if other diabetic manifestations are apparent.
Treatment of nephrotic syndrome and the underlying
cause are similarly critical in limiting the extent of neu-
rologic sequelae. Various treatment strategies have been
employed that encompass steroid or immunosuppressive
therapy, and renal transplantation in cases where prog-
nosis is otherwise quite poor, as in amyloidosis. The
broad range of underlying disorders leading to nephrotic
syndrome and the diverse neurologic manifestations
make it difficult to ascertain prognosis with unwavering
estimates. Therapeutic strategies for secondary manifes-
tations of nephrotic syndrome mainly target the
recognized predisposition or alterations in hypercoagul-
ability, hyperlipidemia, hypertension, and infection.
Maintenance of normovolemia is essential to offset
intravascular hypovolemia, yet fluid management must
balance the need for volume expansion without exacer-
bating edema or progressive renal dysfunction. Diuretics
may also be needed to reduce systemic edema.
Despite the prominent hypercoagulable or proth-
rombotic features of nephrotic syndrome, a paucity
of data exists to support preventive strategies with
anticoagulation. Various antithrombotic strategies for
complications of nephrotic syndrome have been reported,
although it remains most rational to tailor antithrombotic
regimens to the specific features of an individual case. For
instance, antithrombotic strategies may vary with the
411
underlying cause of renal involvement, documented lab-
oratory abnormalities, and neurologic manifestations.
Limited studies have supported the use of anticoagulation
in selected populations (Sarasin and Schifferli, 1994;
Rostoker et al., 1995). Routine antithrombotic strategies
for cerebral venous thrombosis or ischemic stroke should
likely be employed. There are no data on the specific man-
agement of acute ischemic stroke in nephrotic syndrome.
Following cerebral venous thrombosis or arterial ischemic
stroke in nephrotic syndrome, anticoagulation is reason-
able and should be continued until remission, or the
patient is no longer nephrotic. Heparin administration fol-
lowed by oral anticoagulation with warfarin should be
employed, although careful titration may be necessary
to achieve optimal laboratory parameters due to various
underlying factors. Anticoagulation with heparin for cere-
bral venous thrombosis may be complicated due to exces-
sive renal clearance of heparin (Lau et al., 1980; Divekar
et al., 1996). Titration of heparin dosing may therefore be
difficult in the setting of the advanced renal dysfunction
of nephrotic syndrome. Both heparin and warfarin may be
affected by renal abnormalities, hypoalbuminemia,
hemostatic derangements and concomitant medications.
Empiric treatment of hyperlipidemia in nephrotic
syndrome seems reasonable, although sparse evidence
exists to support this approach. Statins may effectively
reduce low-density lipoprotein and lipoprotein(a) levels
in nephrotic syndrome. Statin therapy may therefore off-
set relative hypercoagulability aside from targeting
accelerated atherosclerotic disease. It should also be
noted that hyperlipidemia may improve spontaneously
during remission of nephrotic syndrome.
Antihypertensive strategies may also be warranted to
limit systemic injury associated with hypertension. Such
approaches may utilize angiotensin-converting enzyme
inhibitors or angiotensin receptor blockers to diminish
proteinuria and even hyperlipidemia (Keilani et al., 1993).
Prophylactic antibiotics may be used to prevent infec-
tion in cases with profound proteinuria and edema.
Neurologic sequelae should be promptly treated as in
routine clinical practice, while simultaneously addressing
the underlying abnormalities of nephrotic syndrome.
Increasing recognition of neurologic complications or
manifestations in nephrotic syndrome and improved
diagnosis with neuroimaging of cerebrovascular and en-
cephalopathic disorders will undoubtedly continue to
expand rational treatment of this unusual diagnosis that
links the kidneys with the brain.
CONCLUSION
Nephrotic syndrome comprises excessive loss of protein
into the urine or proteinuria with numerous secondary
changes in coagulation, lipid, and fluid homeostasis
412 D.S. LIEBESKIND
throughout the body. Diverse etiologies of nephrotic syn-
drome may affect individuals of all ages, from congenital
causes during childhood to acquired causes late in adult-
hood. Abnormalities in hypercoagulability, hyperlipid-
emia, hypertension, and infection may spur cerebral
venous thrombosis, ischemic stroke, posterior reversible
encephalopathy syndrome, and many other neurologic
manifestations. Diagnosis hinges on prompt recognition
of these clinical scenarios and rational therapeutic strate-
gies may be tailored to the complex features of a given case.
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