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 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 underlying 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, amyloidosis, viral infections, malaria, pre-eclampsia, systemic lupus erythematosus, or other systemic disorders that affect the kidneys. Immune complex injury of the glomerulus by cancer antigens may cause membranous nephropathy. It has also been associated with nonsteroidal anti-inflammatory drugs, gold, lithium, mercury, interferon-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, hypertension, or systemic involvement such as amyloid deposition. Electrolyte disorders and hormonal changes may also ensue due to nephrotic syndrome or the associated treatment, causing neurologic sequelae. The numerous systemic features and neurologic sequelae of nephrotic syndrome are readily apparent or simplified through consideration of the underlying renal pathophysiology.

PATHOPHYSIOLOGY OF NEUROLOGIC SEQUELAE Glomerular disorders in the kidney may result from endothelial damage, disruption of the glomerular basement

membrane, or podocyte injury to cause abnormal glomerular permeability. Increased glomerular permeability allows for albuminuria and subsequent proteinuria, with more severe injury that leads to leakage of all plasma proteins. 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 systemic edema. Intravascular volume depletion then occurs with sodium retention.

Hypercoagulability Hypercoagulability is a seminal feature of nephrotic syndrome, emanating from several alterations in coagulation, fibrinolysis, and platelet function (Table 26.3). In general, the degree of dysfunction in these pathways correlates with the severity of proteinuria. Platelet aggregation abnormalities in nephrotic syndrome have been attributed to thrombocytosis, increased b-thromboglobulin, elevated von Willebrand factor, and increased release of b-thrombomodulin and platelet factor 4 (Richman and Kasnic, 1982). Secondary effects of hypoalbuminemia and hyperlipidemia may also exacerbate 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: [email protected]

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Table 26.1

Table 26.3

Causes of nephrotic syndrome

Causes of hypercoagulability on hematologic assays

Primary

Antiphospholipid antibodies Decreased antithrombin Decreased factor IX Decreased factor XI Decreased factor XII Decreased free protein S Decreased plasminogen Decreased protein C Decreased a1-antitrypsin Diuresis Factor V Leiden mutation Increased D-dimers Increased factor I Increased factor V Increased factor VII Increased factor VIII Increased factor X Increased fibrinogen Increased lipoprotein(a) Increased plasminogen activator inhibitor-1 (PAI-1) Increased release of platelet factor 4 Increased release of b-thrombomodulin Increased tPA Increased von Willebrand factor Increased a2-antiplasmin Increased a2-macroglobulin Increased b-thromboglobulin Infection Steroid use Thrombocytosis

Secondary

Congenital nephrotic syndrome Focal and segmental glomerulosclerosis IgA nephropathy Membranoproliferative glomerulonephropathy Membranous nephropathy Minimal-change nephropathy Alport syndrome Amyloidosis Cancer (adenocarcinoma, multiple myeloma, lymphoma) Diabetes Fabry disease Gold Henoch–Sch€onlein purpura Hepatitis B and C Heroin HIV Interferon-b-1a Lithium Malaria Mercury Mixed cryoglobulinemia Nonsteroidal anti-inflammatory drugs Pamidronate Parvovirus Penicillamine Polyarteritis nodosa Pre-eclampsia Sarcoidosis Sj€ogren disease Syphilis Systemic lupus erythematosus Takayasu arteritis Wegener’s granulomatosis

Table 26.2 Mechanisms of neurologic sequelae Hypercoagulability Hyperlipidemia Hypertension Microalbuminuria Infection Electrolyte disorders Hypovolemia Hormonal abnormalities Systemic involvement (e.g., amyloidosis)

1996). Selective loss of smaller molecular size proteins alters the balance in coagulation factors. Specifically, factors IX, XI, and XII are lost into the urine with relative elevation of factors I, V, VII, VIII and X in 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 simultaneously increase atherogenecity and hypercoagulability (Kronenberg et al., 1996). The vast array of changes in homeostatic pathways makes it difficult to isolate an individual cause of hypercoagulability in nephrotic syndrome. It remains most likely that these concomitant changes all contribute to the increased tendency to clot in such patients. Other relative prothrombotic states such as factor V Leiden mutation and the presence of antiphospholipid antibodies due to related disorders may become more virulent given the multitude of hypercoagulable factors in nephrotic syndrome (Petaja et al., 1995). Venous thrombosis, systemic or cerebral, due to the resultant

NEPHROTIC SYNDROME hypercoagulability may also be compounded by hypovolemia 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 syndrome (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. Lipoprotein(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. Hypertension may be more common in adults with minimalchange 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 nephropathy. In cases of end stage renal disease, due to any underlying 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 microvascular injury in diabetes and hypertension (Turaj et al., 2003; Wada et al., 2007; Rocco et al., 2010). Diabetic or hypertensive 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.

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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 neurologic disorders have been reported that implicate systemic 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 combination of effects in the brain, including edema, hypertension, 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 strategies 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 thrombosis (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–Barre´ syndrome Myasthenia gravis Pituitary and hormonal disorders Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) Myoclonic encephalopathy Stiff person syndrome Multiple sclerosis

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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 syndrome 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. Hemorrhagic 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 administration has been used to treat cerebral venous thrombosis 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 coagulation 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 descriptions 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 occlusion due to arterial thrombosis with concomitant peripheral 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 relatively 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 hypercoagulability 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

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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

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, hypertension, amyloidosis, or vasculitis. Vasculitides potentially culminating in nephrotic syndrome and ischemic stroke include glomerulonephritis, Wegener’s granulomatosis, 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

The pathogenesis of posterior reversible encephalopathy syndrome (PRES) and similar entities such as preeclampsia 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 syndrome. Many of the reports on PRES in nephrotic syndrome 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 syndrome 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). Hypertensive 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 implicated as a cause of PRES (Shimizu et al., 1994; Taque

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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 manifestations when treating nephrotic syndrome.

effective treatment of the proteinuria caused exacerbation of the myasthenia and increased antibody titers (Almsaddi et al., 1997). This example shows the paradoxically beneficial effect of proteinuria in nephrotic syndrome to filter antibodies out of the system.

Guillain–Barre´ syndrome

Pituitary and hormonal disorders

Guillain–Barre´ 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 mechanism 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 immunosuppressive therapy strongly suggests an immune-mediated mechanism. The simultaneous neurologic and renal disorders have also been attributed to exposure to a common organic solvent (Chen et al., 2002).

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 cyclophosphamide treatment have not demonstrated alterations in pituitary or gonadal function, yet the potential exists (Bogdanovic et al., 1990). Animal studies have also suggested a potential direct effect of nephrotic syndrome on pituitary–ovarian function (Menjivar et al., 1995).

Myasthenia gravis Myasthenia gravis has been reported in nephrotic syndrome 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 myasthenia due to loss of acetylcholine receptor antibodies into the urine (Almsaddi et al., 1997). In that case,

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 secondary to MELAS. Only a few other cases have described MELAS with nephrotic syndrome (Yoneda et al., 1989; Ban et al., 1992). Early myoclonic encephalopathy 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 therapy (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 numerous alterations in systemic pathophysiology that accompany nephrotic syndrome may make it difficult to predict neurologic complications, although most pathogenic 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 nephrologist, 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 neurologic sequelae. Various treatment strategies have been employed that encompass steroid or immunosuppressive therapy, and renal transplantation in cases where prognosis 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 manifestations of nephrotic syndrome mainly target the recognized predisposition or alterations in hypercoagulability, hyperlipidemia, hypertension, and infection. Maintenance of normovolemia is essential to offset intravascular hypovolemia, yet fluid management must balance the need for volume expansion without exacerbating edema or progressive renal dysfunction. Diuretics may also be needed to reduce systemic edema. Despite the prominent hypercoagulable or prothrombotic 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

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underlying cause of renal involvement, documented laboratory 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 management of acute ischemic stroke in nephrotic syndrome. Following cerebral venous thrombosis or arterial ischemic stroke in nephrotic syndrome, anticoagulation is reasonable and should be continued until remission, or the patient is no longer nephrotic. Heparin administration followed 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 cerebral venous thrombosis may be complicated due to excessive 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 offset 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 infection 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 encephalopathic 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

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throughout the body. Diverse etiologies of nephrotic syndrome may affect individuals of all ages, from congenital causes during childhood to acquired causes late in adulthood. Abnormalities in hypercoagulability, hyperlipidemia, 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 strategies may be tailored to the complex features of a given case.

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