Focal segmental glomerulosclerosis N05.1

The term "focal segmental glomerulosclerosis" (FSGS) covers a group of serious, chronic kidney diseases that can occur in adolescence and also in adulthood. The diagnosis "FSGS" is a histological diagnosis. The FSGS is characterized by a loss of the podocyte processes of the renal glomeruli to varying degrees, by sclerosis of the capillary loops in the glomeruli (glomerulosclerosis) and clinically by a nephrotic syndrome of varying severity, possibly with acute consequences. If left untreated, the disease quickly leads to a loss of kidney function and to the need for dialysis.

Primary (idiopathic) focal segmental glomerulosclerosis also known as collapsing focal segmental glomerulosclerosis (FSGS).

Familial or genetic forms of focal segmental glomerulosclerosis (FSGS), often steroid-resistant FSGS, especially when it occurs in children. Autosomal dominant inheritances with varying penetrance have been described, but autosomal recessive inheritances have also been described. Suspect gene loci have been identified on the following chromosomes:

• Chromosome 1 (gene for podocin)
• chromosome 11 (gene for the TRPC6 calcium channel)
• chromosome 14 (INF2 gene: encodes a protein that polymerizes and depolymerizes actin in the podocyte)
• Chromosome 15 (MYO1E gene, encodes for myosin1E). Chromosome 19 (nephrin gene NPHS1; ACTN4 gene encoding protein actinin 4).
• The genes identified to date encode proteins involved in glomerular basement membrane formation and/or podocyte differentiation and function: podocin, nephrin, alpha-actinin-4, TRPC6, CD2AP, inverted formin.

The following clinical syndromes have been identified to date and assigned to the Familial form of FSGS:

• Familial autosomal dominant FSGS: present is a mutation of the ACTN4 gene (19q13), which encodes the actin-binding protein-actinin 4 expressed in the podocyte.
• Familial autosomal dominant FSGS: a mutation of the TRPC6 gene, which encodes a calcium channel, is present. The gene mutation (so-called gain-of-function mutation) leads to calcium channel activation. As a result, both increased and decreased calcium influx via the TRPC6 protein into podocytes, can lead to FSGS.
• Familial FSGS with present mutation in COL4A3-5 gene. Collagen IV mutations were detected in 38% of families in a larger study of familial FSGS (Gast C et al 2015).
• Congenital nephrotic syndrome that is inherited recessively. Present is a mutation of the NPHS2 gene (1q25-31), which encodes podocin. Podocin is expressed exclusively in podocytes and functions as a transmembrane connecting protein between the plasma membrane and cytoskeleton.
• Congenital nephrotic syndrome characterized by mutations of the CD2AP gene, which encodes the CD2 associated protein, a so-called slit membrane protein.
• Steroid-resistant autosomal recessive nephrotic syndrome characterized by a mutation in the NPHS2 gene (1q25-31), which encodes podocin, also a slit membrane protein. Mutations of NPHS2 are a common cause of steroid-resistant nephrotic syndrome (SRN) in childhood. Mutations in the NPHS2 gene can also be identified as a cause of nephrotic syndrome in adults.
• Steroid-resistant autosomal recessive nephrotic syndrome characterized by a mutation in the NEIL gene, which encodes a DNA repair enzyme.
• Steroid-resistant autosomal recessive nephrotic syndrome characterized by a mutation in the MYO1E gene (15q21), which encodes myosin1E, a so-called unconventional myosin (in contrast to the myosins found in muscle fibers, which are called class II or conventional myosins).
• FSGS in African Africans that is characterized by a mutation in the APOL1 gene, which encodes apolipoproteinL1. The seminal discovery that genetic variations in the APOL1 gene are associated with nondiabetic kidney disease in people of African descent has led to investigation of the biological mechanisms underlying this association (O'Toole JF et al 2017). The high allele frequency of these variants is thought to be due to the resistance they confer to the disease-causing trypanosome species involved in human African sleeping sickness. People of African descent have an increased risk of developing kidney disease, largely due to two variants in the apolipoprotein L1 (APOL1) gene that are unique to people of West African descent. These variants are thought to be genetically dominant because they provide protection against African sleeping sickness, which is caused by the parasite Trypanosoma brucei (Tzur S et al. 2010).
• Charcot-Marie-Tooth disease an autosomal dominantly inherited glomerulosclerosis characterized by a mutation in the INF2 gene, which encodes formin2. Formin2 plays a role in the organization of the actin filaments of the cytoskeleton and further in the response to DNA damage, and cellular stress.

Secondary (adaptive) FSGS: This term includes those forms of focal segmental glomerulosclerosis that are due to hypertrophy or hyperfiltration of the glomeruli as a result of previous renal damage that has either led to a relevant decrease in the total number of glomeruli, or has led to dilatation of the renal vessels with a constant number of glomeruli. The initial change is found to be damage to the podocytes. Circulating cytokines (e.g. TGF-beta), inflammatory mediators or increased intravascular pressure within the glomerulus are discussed as causative factors. Progressive destruction of the podocyte feet exposes the basement membrane. The filtration barrier formed by the so-called slit membrane of the podocytes becomes more permeable. Larger amounts of fluid and albumin are filtered. Macromolecules, such as IgM, fibrinogen or complement components, cannot pass the basement membrane. However, they deposit as hyaline depots between the endothelium and basement membrane. Causative diseases:

• Dilatation of renal vessels (renal vasodilation) in: diabetic nephropathy, after renal transplantation (high recurrence rate - Gheith O et al 2013), in sickle cell disease and severe obesity. Glycogen storage diseases and preeclampsia can also lead to dilatation of renal vessels, increase in pressure in the glomerulus and thus secondary FSGS.
• Healing phase after glomerulonephritis: FSGS may also occur in the healing phase of inflammatory renal diseases such as lupus nephritis, IgA nephritis and rapid progressive glomerulonephritis. The cause may be the increased release of TGF-beta.
• Heroin nephropathy: FSGS may occur in heroin abusers, especially those of black African descent. Heroin nephropathy can progress to chronic renal failure over a period of years, and thus progresses more slowly than HIV-associated FSGS (which can lead to renal failure within months).
• Other secondary forms of FSGS: FSGS has been described in abusive use of anabolic steroids, after treatments with lithium, and in lymphoma disease.
• Other causative drugs include: pamidronate, NSAIDs; anabolic steroids.
• Virus-induced secondary FSGS (rare in children): HIV, parvovirus B19, CMV, EBV, HCV (Dettmar AK et al. 2016).

In Europe, FSGS is the cause of a nephrotic syndrome with 12% of the cases. In the U.S., FSGS is the most common primary glomerular disease leading to dialysis-related kidney failure.

The causes of focal segmental glomerulosclerosis are manifold and ultimately unknown (Canaud G et al. 2016). It is possible that a previously unknown systemic permeability factor is the triggering factor. Congenital forms can be traced back to individual mutated podocyte proteins of the glomeruli (Rosenberg AZ et al. 2017).

In the clinical picture the focal sclerosing glomerulonephritis is conspicuous by symptoms of the nephrotic syndrome:

• nephrotic proteinuria: 60-75%
• Micro-haematuria: 30-50
• Renal hypertension: 45-65
• Reduction of renal function: 25-50 %.
• Also: hypalbuminaemia, hyperlipidaemia, edema, tendency to infections
• In primary FSGS the soluble urokinase-plasminogen activator receptor (suPAR) is elevated in 65% of cases (see below plasminogen activator inhibitors). A lowering of the soluble receptor by plasmapheresis leads to remission of the disease.

FSGS is characterized by segmental sclerosis of capillary loops in glomeruli (Nagata M et al. 2017). Based on histological considerations, several types with different courses and prognoses can be distinguished (Han MH et al. 2016):

• Classical FSGS (FSGS, NOS=not otherwise specified); most common form.
• Perihilar variant (perihilar variant)
• Tip lesion (tip variant)
• Collapsing glomerulopathy (collapsing variant)
• Cellular variant: lesions (at the tubular pole)
• C1q nephropathy (controversial variant)

Diagnosis is made by kidney puncture. Based on fine tissue characteristics, several variants have been distinguished since 2004 (Columbia classification - see Han MH et al. 2016), which differ in their course and prognosis:

• Classical FSGS: Light microscopic changes are detectable in some, not all glomeruli (focal). In the altered glomeruli, typically only some segments of the vascular tangle (segmental) are affected. In the affected segments, there is collapse of the capillary loop, sclerosis, and cell proliferation in the mesangium of the glomerulus. Due to increased permeability of the capillary walls, plasma proteins are deposited in the capillary walls in the form of hyaline precipitates. Direct immunofluorescence (DIF) does not show specific deposition.
• Collapsing glomerulopathy (Collapsing glomerulosclerosis): Common in people of black African descent. The entire capillary tangle of the glomerulus, rather than individual segments (segmental), is collapsed and sclerosed. The cause is either idiopathic or triggered by HIV infection. A severe, nephrotic syndrome is usually clinically apparent. Renal function usually deteriorates rapidly (Fogo AB 2015; Raja R et al. 2016).
• Tip lesion (tip variant): onset at the urinary pole (tip) of the glomerulus. Damage to epithelial cells and accumulation of fatty foam cells. Immunohistologically, IgM and complement component C3 can be detected. Clinically characteristic is an abrupt onset of a nephrotic syndrome. Therapeutically remarkable is the good response to therapy with corticosteroids. Occasionally, spontaneous remissions are observed even without immunosuppressive therapy. Overall prognosis is good.
• Perihilar variant: Changes at the hilus of the glomerulus with sclerosis and deposition of transparent hyaline material in > 50% of segmentally sclerosed glomeruli. Immunohistologic and electron microscopic findings are detectable as in classic FSGS. Perihilar variant is frequently seen in diseases associated with glomerulus overload (hyperfiltration).
• Cellular variant: Evidence of at least one glomerulus with a segment in which the glomerular capillaries are occluded by cell proliferation. In the remaining glomeruli, changes are found as in classical FSGS. Electron microscopy shows diffuse fusion of the foot processes of the podocytes.
• C1q nephropathy: Controversial diagnostic entity. Immunohistological evidence of deposition of complement component C1q in the capillaries of the glomerulus. Predominant in children and young adults. Poor response to immunosuppressive therapy. Spontaneous remissions with disappearance of C1q deposits are known.

General therapy of nephrotic syndrome (see there)

Untreated, patients with primary FSGS with nephrotic syndrome have a poor renal prognosis. Important prognostic factors are the extent of proteinuria, impaired renal function, histological characteristics and response to medium-dose steroid therapy (prednisolone 1mg/kgkgKG/day). Steroid resistance occurs if proteinuria persists after > 4 months of treatment with high-dose steroids. As alternatives to the therapy of primary FSGS calcineurin inhibitors, tacrolimus (Raja R et al. 2016), mycophenolate-mofetil (MMF), cyclophosphamide and rituximab (Kronbichler A et al. 2014) are available. Therapy of a relapse: renewed steroid cycle if necessary supplemented with an immunosuppressive agent(Ciclosporin A, mycophenolate-mofetil). Placebo-controlled studies on initial therapy of primary FSGS are currently lacking (Trachtman H 2017).

Without remission, 50% of patients are terminally kidney insufficient after 10 years. With full remission the figure is only 10% (Cohen CD et al. 2017).

The histological picture of FSGS is also perceived as "scarring" in the advanced stages of many glomerulopathies. It must then be separated clinically and histologically from the actual disease FSGS.

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