Nephrotic Syndrome

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Chapter 521 Nephrotic Syndrome

Priya Pais, Ellis D. Avner

Nephrotic syndrome, a manifestation of glomerular disease, is characterized by nephrotic range proteinuria and the triad of clinical findings associated with large urinary losses of protein: hypoalbuminemia, edema, and hyperlipidemia. Nephrotic range proteinuria is defined as protein excretion of > 40 mg/m2/hr or a first morning protein : creatinine ratio of >2-3 : 1. The annual incidence is 2-3 cases per 100,000 children per year in most Western countries and higher in underdeveloped countries resulting predominantly from malaria. Though early referral to a pediatric nephrologist is recommended, once nephrotic syndrome has been diagnosed, management should be a collaborative effort between the nephrologist and primary care physician.

Etiology

Most children with nephrotic syndrome have a form of primary or idiopathic nephrotic syndrome (Table 521-1). Glomerular lesions associated with idiopathic nephrotic syndrome include minimal change disease (the most common), focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, membranous nephropathy and diffuse mesangial proliferation (Table 521-2). These etiologies have different age distributions (Fig. 521-1).

Table 521-1 CAUSES OF CHILDHOOD NEPHROTIC SYNDROME

GENETIC DISORDERS

Nephrotic Syndrome (Typical)

Finnish-type congenital nephrotic syndrome (absence of nephrin)
Focal segmental glomerulosclerosis (mutations in podocin, α-actinin 4, TRPC6)
Diffuse mesangial sclerosis (mutations in laminin β2 chain
Denys-Drash syndrome (mutations in WT1 transcription factor)

Proteinuria with or Without Nephrotic Syndrome

Nail-patella syndrome (mutation in LMX1B transcription factor)
Alport syndrome (mutation in collagen biosynthesis genes)

Multisystem Syndromes with or Without Nephrotic Syndrome

Galloway-Mowat syndrome
Charcot-Marie-Tooth disease
Jeune syndrome
Cockayne syndrome
Laurence-Moon-Biedl-Bardet syndrome

Metabolic Disorders with or Without Nephrotic Syndrome

Alagille syndrome
α1 Antitrypsin deficiency
Fabry disease
Glutaric acidemia
Glycogen storage disease
Hurler syndrome
Lipoprotein disorders
Mitochondrial cytopathies
Sickle cell disease

IDIOPATHIC NEPHROTIC SYNDROME

Minimal change disease
Focal segmental glomerulosclerosis
Membranous nephropathy

SECONDARY CAUSES

Infections

Hepatitis B, C
HIV-1
Malaria
Syphilis
Toxoplasmosis

Drugs

Penicillamine
Gold
Nonsteroidal anti-inflammatory drugs
Pamidronate
Interferon
Mercury
Heroin
Lithium

Immunologic or Allergic Disorders

Castleman disease
Kimura disease
Bee sting
Food allergens

Associated with Malignant Disease

Lymphoma
Leukemia

Glomerular Hyperfiltration

Oligomeganephronia
Morbid obesity
Adaptation to nephron reduction

Note: Childhood nephrotic syndrome can also be consequence of inflammatory glomerular disorders, normally associated with features of nephritis, e.g., vasculitis, lupus nephritis, membranoproliferative glomerulonephritis, IgA nephropathy.

From Eddy AA, Symons JM: Nephrotic syndrome in childhood, Lancet 362:629–638, 2003.

Table 521-2 SUMMARY OF PRIMARY RENAL DISEASES THAT MANIFEST AS IDIOPATHIC NEPHROTIC SYNDROME

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Figure 521-1 Kidney biopsy results from 223 children with proteinuria referred for diagnostic kidney biopsy (Glomerular Disease Collaborative Network, J. Charles Jennette, MD, Hyunsook Chin, MS, and D.S. Gipson, 2007). n, number of patients; C1Q, nephropathy; FSGS, focal segmental glomerulosclerosis; MCNS, minimal change nephrotic syndrome; MPGN, membranoproliferative glomerulonephritis.

(From Gipson DS, Massengill SF, Yao L, et al: Management of childhood onset nephrotic syndrome, Pediatrics 124:747–757, 2009.)

Nephrotic syndrome may also be secondary to systemic diseases such as systemic lupus erythematosus, Henoch-Schönlein purpura, malignancy (lymphoma and leukemia), and infections (hepatitis, HIV, and malaria) (see Table 521-1).

A number of hereditary proteinuria syndromes are caused by mutations in genes that encode critical protein components of the glomerular filtration apparatus (Table 521-3).

Table 521-3 NEPHROTIC SYNDROME IN CHILDREN CAUSED BY GENETIC DISORDERS OF THE PODOCYTE

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Pathophysiology

The underlying abnormality in nephrotic syndrome is an increased permeability of the glomerular capillary wall, which leads to massive proteinuria and hypoalbuminemia. On biopsy, the extensive effacement of podocyte foot processes (the hallmark of idiopathic nephrotic syndrome) suggests a pivotal role for the podocyte. Idiopathic nephrotic syndrome is associated with complex disturbances in the immune system, especially T cell–mediated immunity. In focal segmental glomerulosclerosis, a plasma factor, probably produced by a subset of activated lymphocytes, may be responsible for the increase in capillary wall permeability. Alternatively, mutations in podocyte proteins (podocin, α-actinin 4) and MYH9 (podocyte gene) are associated with focal segmental glomerulosclerosis (see Table 521-3). Steroid-resistant nephrotic syndrome can be associated with mutations in NPHS2 (podocin) and WT1 genes, as well as other components of the glomerular filtration apparatus, such as the slit pore, and include nephrin, NEPH1, and CD-2 associated protein.

Although the mechanism of edema formation in nephrotic syndrome is incompletely understood, it seems likely that in most instances, massive urinary protein loss leads to hypoalbuminemia, which causes a decrease in plasma oncotic pressure and transudation of fluid from the intravascular compartment to the interstitial space. The reduction in intravascular volume decreases renal perfusion pressure, activating the renin-angiotensin-aldosterone system, which stimulates tubular reabsorption of sodium. The reduced intravascular volume also stimulates the release of antidiuretic hormone, which enhances the reabsorption of water in the collecting duct.

This theory does not apply to all patients with nephrotic syndrome because some patients actually have increased intravascular volume with diminished plasma levels of renin and aldosterone. Therefore, other factors, including primary renal avidity for sodium and water, may be involved in the formation of edema in some patients with nephrotic syndrome.

In the nephrotic state, serum lipid levels (cholesterol, triglycerides) are elevated for 2 reasons. Hypoalbuminemia stimulates generalized hepatic protein synthesis, including synthesis of lipoproteins. This is also why a number of coagulation factors are increased, increasing the risk of thrombosis. In addition, lipid catabolism is diminished as a result of reduced plasma levels of lipoprotein lipase related to increased urinary losses of this enzyme.

Patients with nephrotic syndrome are at increased risk of infections (sepsis, peritonitis, pyelonephritis), especially with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenza. Some reasons for this include loss of complement factor C3b, opsonins such as properdin factor B, and immunoglobulins in the urine. An additional risk factor is the use of immunosuppressive medications to treat nephrotic syndrome.

Nephrotic syndrome is a hypercoagulable state resulting from multiple factors: vascular stasis, an increase in hepatic production of fibrinogen and other clotting factors, decreased serum levels of anticoagulation factors, increased plasma platelet production (as an acute phase reactant), and increased platelet aggregation. The coagulopathy manifests with thromboembolic events.

Bibliography

Del Rio M, Kaskel F. Evaluation and management of steroid-unresponsive nephrotic syndrome. Curr Opin Pediatr. 2008;20:163-170.

Hodson EM, Alexander SM. Evaluation and management of steroid-sensitive nephrotic syndrome. Curr Opin Pediatr. 2008;20:145-150.

Liapis H. Molecular pathology of nephrotic syndrome in childhood: a contemporary approach to diagnosis. Pediatr Dev Pathol. 2008;11:154-163.

1978 Nephrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int. 1978;13:159.

Tryggvason K, Patrakka J, Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med. 2006;354:1387-1399.

Van de Walle JGJ, Donckerwolcke RA. Pathogenesis of edema formation in the nephrotic syndrome. Pediatr Nephrol. 2001;16:283.

521.1 Idiopathic Nephrotic Syndrome

Priya Pais, Ellis D. Avner

Approximately 90% of children with nephrotic syndrome have idiopathic nephrotic syndrome. Idiopathic nephrotic syndrome is associated with primary glomerular disease without evidence of a specific systemic cause. Idiopathic nephrotic syndrome includes multiple histologic types: minimal change disease, mesangial proliferation, focal segmental glomerulosclerosis, membranous nephropathy, and membranoproliferative glomerulonephritis.

Pathology

In minimal change nephrotic syndrome (MCNS) (about 85% of total cases of nephrotic syndrome in children), the glomeruli appear normal or show a minimal increase in mesangial cells and matrix. Findings on immunofluorescence microscopy are typically negative, and electron microscopy simply reveals effacement of the epithelial cell foot processes. More than 95% of children with minimal change disease respond to corticosteroid therapy.

Mesangial proliferation is characterized by a diffuse increase in mesangial cells and matrix on light microscopy. Immunofluorescence microscopy might reveal trace to 1+ mesangial IgM and/or IgA staining. Electron microscopy reveals increased numbers of mesangial cells and matrix as well as effacement of the epithelial cell foot processes. Approximately 50% of patients with this histologic lesion respond to corticosteroid therapy.

In focal segmental glomerulosclerosis (FSGS), glomeruli show lesions that are both focal (present only in a proportion of glomeruli) and segmental (localized to ≥1 intraglomerular tufts). The lesions consist of mesangial cell proliferation segmental scarring on light microscopy (Fig. 521-2 and see Table 521-2

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