What is the role of genetics in the pathophysiology of pediatric nephrotic syndrome?

Updated: Mar 04, 2020
  • Author: Jerome C Lane, MD; Chief Editor: Craig B Langman, MD  more...
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Answer

Podocyte biology and genetics

Perhaps the most exciting developments in understanding the pathophysiology of nephrotic syndrome have occurred in the area of podocyte biology. 

The glomerular filtration barrier consists of the fenestrated capillary endothelium, the extracellular basement membrane, and the intercalated podocyte foot processes, connected by 35-45 nm slit diaphragms. Nephrotic syndrome is associated with the biopsy finding of fusion (effacement) of podocyte foot processes. This effacement of the podocytes long was thought to be a secondary phenomenon of nephrotic syndrome.

Schematic drawing of the glomerular barrier. Podo Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Courtesy of the American Physiological Society (www.the-aps.org) and reproduced from Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008 Apr;88(2):451-87.

However, theories have shifted toward the podocyte as playing a primary role in the development of proteinuria. Insights into the molecular biology of the podocyte have greatly expanded the understanding of the pathophysiology of proteinuria in renal diseases. Various forms of INS have been described with genetic mutations, such as those associated with the following [21, 22] :

  • Slit-diaphragm and podocyte cytoskeleton: NPHS1, NPHS2, TRCP6, CD2AP, ACTN4, INF2, MYH9,MYO1E

  • Phospholipases and second-messenger systems: PLCE1

  • Glomerular basement membrane: LAMB2

  • Transcription factors: WT1, LMX1B

  • Lysosomal proteins: SCARB2

  • Mitochondrial proteins: COQ2

  • DNA-nucleosome restructuring mediator: SMARCAL1

Nephrin is a transmembrane protein that is a major structural element of the slit diaphragm and is encoded by the NPHS1 gene on chromosome 19. Mutations in the NPHS1 gene are responsible for autosomal recessive, congenital nephrotic syndrome of the Finnish type (FNS).

FNS is characterized by massive proteinuria in the first year of life (usually within the first 3 months) and progression to end-stage kidney disease within the first decade of life, although milder forms of the disease have been described. [21] Mutations in NPHS1 are usually associated with congenital nephrotic syndrome, but Philippe et al have described NPHS1 mutations in children aged 6 months to 8 years with later-onset steroid-resistant nephrotic syndrome (SRNS). [23] Santin et al have described NPHS1 mutations in patients with later childhood-onset as well as adult-onset SRNS. [24]

Podocin is another podocyte protein that interacts with nephrin and CD2AP and is integral to the assembly of the slit diaphragm. Podocin is encoded by the NPHS2 gene on chromosome 1. Mutations in the NPHS2 gene were originally described in patients with autosomal recessive, steroid-resistant INS with FSGS on biopsy. Podocin mutations account for approximately 45-55% of familial and 8-20% of sporadic cases of SRNS. [21]

α-Actinin-4, encoded by the gene ACTN4 on chromosome 19, cross-links actin filaments of the podocyte cytoskeleton and anchors them to the glomerular basement membrane. The TRPC6 gene on chromosome 11 encodes for a calcium channel associated with the slit diaphragm. [21] Disruptions in either ACTN4 or TRPC6 are associated with autosomal dominant forms of FSGS. [20]

CD2AP, which codes for a podocyte protein that associates with podocin and nephrin, has been linked to the development of nephrotic syndrome in animal models. However, the role it plays in human nephrotic syndrome is unclear. Various case reports have demonstrated heterozygous mutations in CD2AP in patients with nephrotic syndrome and FSGS. One report describes a single patient with a homozygous mutation in CD2AP and early onset of nephrotic syndrome with FSGS and diffuse mesangial sclerosis. [21]

Because African Americans have a 3- to 4-fold higher risk of end-stage kidney disease compared with persons of European ancestry, genetic studies have sought to explain this greater propensity to kidney disease. A strong association was found in African Americans between idiopathic and HIV-related FSGS, as well as hypertensive end-stage kidney disease and mutations in the nonmuscle myosin heavy chain 9 (MYH9) gene. Nonmuscle MYH9 is a podocyte protein that binds to the podocyte actin cytoskeleton to perform intracellular motor functions. [25]

More recent studies have demonstrated that the increased risk of kidney disease previously ascribed to MYH9 is, in fact, more strongly associated with variations in the neighboring apolipoprotein L1 (APOL1) gene. Interestingly, these APOL1 variations, which are more common in African Americans but absent in whites, are able to lyse trypanosomes and may confer resistance to African sleeping sickness (Trypanosoma brucei rhodesiense infection). [26]

Another nonmuscle myosin gene, MYO1E, was reported to be associated with FSGS in children. Mutation of the MYO1E gene led to disruption of the podocyte cytoskeleton. [27]

Other genetic forms of nephrotic syndrome continue to shed light on the pathogenesis of INS. Mutations in the developmental regulatory gene WT1 are associated with forms of congenital nephrotic syndrome associated with male pseudohermaphroditism, Wilms tumor (Denys-Drash syndrome), and gonadoblastoma (Frasier syndrome).

Mutations in phospholipase C epsilon 1 (PLCE1), a cytoplasmic enzyme required for podocyte maturation, have been associated with as many as 28% of cases of congenital nephrotic syndrome due to isolated (nonsyndromic) diffuse mesangial sclerosis. Nail-patella syndrome, a disorder characterized by skeletal and nail dysplasia as well as nephrotic syndrome, is caused by mutations in the LMX1B gene, which regulates expression of type IV collagen and the podocyte proteins nephrin, podocin, and CD2AP. [28]

Pierson syndrome, characterized by microcoria, abnormal lens shape, cataracts, blindness, severe neurologic deficits, congenital nephrotic syndrome, and progressive kidney failure, is caused by a mutation in the LAMB2 gene that codes for laminin b2, which is found in glomerular basement membrane, retina, lens, and neuromuscular synapses. [21]

Other rare forms of nephrotic syndrome have been associated with mutations in SCARB2, which codes for a lysosomal protein; disruption of this gene causes a syndrome of myoclonus epilepsy and glomerulosclerosis. Alterations in the mitochondrial protein coded by the gene COQ2 are associated with a syndrome of encephalopathy and nephropathy. Finally, mutations in the DNA-nucleosome restructuring mediator SMARCAL1 cause Schimke immuno-osseous dysplasia, a syndrome characterized by spondyloepiphyseal dysplasia (SED) resulting in disproportionate short stature, nephropathy, and T-cell deficiency. [22]

Monogenic causes of INS primarily result in SRNS. More than 39 genes have been associated with SRNS, and approximately 30% of children with SRNS may be found to have a single-gene cause of their disease. [3]

The role of podocyte gene alterations in minimal change nephrotic syndrome (MCNS) is unclear. Podocin appears to be expressed normally in MCNS but is decreased in FSGS.

Mutations in nephrin and podocin do not appear to play a role in steroid-sensitive nephrotic syndrome. However, acquired alterations in slit diaphragm architecture might play a role in INS apart from actual mutations in the genes encoding podocyte proteins. Various authors have reported changes in expression and distribution of nephrin in MCNS.

Coward et al demonstrated that nephrotic plasma induces translocation of the slit diaphragm proteins nephrin, podocin, and CD2AP away from the plasma membrane into the cytoplasm of the podocyte. [29] These authors also demonstrated that normal plasma might contain factors that maintain the integrity of slit diaphragm architecture and that the lack of certain factors (rather than the presence of an abnormal circulating factor) might be responsible for alterations in the podocyte architecture and the development of INS.

CD80, a T-cell costimulatory transmembrane protein, is expressed in podocytes and has been implicated in the pathogenesis of MCNS. Urinary CD80 levels are higher in patients with MCNS than in controls and patients with other glomerular diseases such as FSGS. Binding of interleukins or microbial products to toll-like receptors on the surface of the podocyte may lead to overexpression of CD80, as well as another protein, C-mip. CD80 and C-mip, in turn, may interfere with the proteins Nck and Fyn, leading to dephosphorylation of nephrin and dysruption of the podocyte actin cytoskeleton, which result in conformational changes in the podocyte and slit diaphragm that cause proteinuria. [30]

Blockade of CD80 by abatacept and belatacept has not been shown to attenuate proteinuria, however. [31] Hemopexin, a glycoprotein synthesized by the liver, may also induce nephrin-dependent changes in the podocyte skeleton that lead to proteinuria. [30]

Apart from the podocyte and slit diaphragm, alterations in the glomerular basement membrane also likely play a role in the proteinuria of nephrotic syndrome. In INS, the glomerular capillary permeability to albumin is selectively increased, and this increase in filtered load overcomes the modest ability of the tubules to reabsorb protein.

In its normal state, the glomerular basement membrane is negatively charged because of the presence of various polyanions along its surface, such as heparan sulfate, chondroitin sulfate, and sialic acid. This negative charge acts as a deterrent to filtration of negatively charged proteins, such as albumin. Experimental models in which the negative charges are removed from the basement membrane show an increase in albuminuria. Children with MCNS have been reported to have decreased anionic charges in the glomerular basement membrane. [28] Angiopoietin-like 4 and IL-8 may play a role in reducing anionic charges in the glomerular basement membrane. [30]


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