Focal segmental glomerulosclerosis

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Focal segmental glomerulosclerosis
Other namesfocal glomerular sclerosis, [1] focal nodular glomerulosclerosis [1]
Focal segmental glomerulosclerosis - high mag.jpg
Light micrograph of focal segmental glomerulosclerosis, hilar variant. Kidney biopsy. PAS stain.
Specialty Nephrology   OOjs UI icon edit-ltr-progressive.svg

Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes. [2] [3] This process damages the filtration function of the kidney, resulting in protein presence in the urine due to protein loss. [3] FSGS is a leading cause of excess protein loss—nephrotic syndrome—in children and adults. [4] Signs and symptoms include proteinuria and edema. [2] [5] Kidney failure is a common long-term complication of the disease. [5] [6] FSGS can be classified as primary, secondary, or genetic, depending on whether a particular toxic or pathologic stressor or genetic predisposition can be identified as the cause. [7] [8] [9] Diagnosis is established by renal biopsy, [2] [10] and treatment consists of glucocorticoids and other immune-modulatory drugs. [11] Response to therapy is variable, with a significant portion of patients progressing to end-stage kidney failure. [5] An American epidemiological study 20 years ago demonstrated that FSGS is estimated to occur in 7 persons per million, with males and African-Americans at higher risk . [12] [13] [7]

Contents

Signs and symptoms

The most common symptoms are a result of abnormal loss of protein from the glomerulus of the kidney, and include: [2] [5]

Common signs are also due to loss of blood proteins by the glomerulus of the kidney, including: [2] [5] [10]

Pathophysiology

The renal glomerulus consists of a set of capillaries from which blood is filtered into Bowman's space. Large molecules, such as proteins, are usually too large to be filtered and instead are retained in the capillaries. Bowman's capsule and glomerulus.svg
The renal glomerulus consists of a set of capillaries from which blood is filtered into Bowman's space. Large molecules, such as proteins, are usually too large to be filtered and instead are retained in the capillaries.

FSGS is primarily a disease of the renal glomerulus, the site of filtration of ions and solutes. [14] [15] Podocytes are specialized cells lining the Bowman's capsule that contribute to the filtration barrier, preventing molecules larger than 5  nm from being filtered. [16] FSGS involves damage to the renal podocytes such that larger molecules, most notably proteins, are filtered and lost through the kidney. [17] [18] Thus, many of the signs and symptoms of FSGS are related to protein loss. [19]

On histology, FSGS manifests as scarring (sclerosis) to segments of glomeruli; moreover, only a portion of glomeruli are affected. [7] [20] [21] The focal and segmental nature of disease seen on histology help to distinguish FSGS from other types of glomerular sclerosis. [21]

FSGS can be classified by the putative cause of damage to podocytes. Primary FSGS involves cases in which no cause is readily identifiable. [22] It is presumed that a set of unidentified circulating factors in the blood contribute to podocyte damage in these cases. [22] [23]

Secondary FSGS is caused by an identifiable stress or toxin that injures podocytes. [22] Many causes of secondary FSGS contribute to podocyte injury through hyperfiltration, which is a scenario of excess filtration by renal glomeruli. [24] Hyperfiltration can be caused by obesity, diabetes or loss of the contralateral kidney, among other causes. [24]

Secondary FSGS can also be caused by toxins, including anabolic steroids and heroin. [25] [26]

A number of genes have been implicated in FSGS. These include: NPHS1, which encodes the protein nephrin that contributes to the filtration barrier; [27] NPHS2, which encodes the protein podocin found in podocytes; [28] and INF2, which encodes the actin-binding protein formin. [29]

The pathogenesis of HIV-associated FSGS is unclear, but may be primarily due to the presence of the G1/G2 risk alleles for APOL1. There is some data to suggest that HIV can infect tubular epithelial cells and podocytes, but much remains to be known. [30]

Diagnosis

Diagnosis of FSGS is made by renal biopsy that includes at least fifteen serial cuts with at least eight glomeruli. [31] [32] Histologic features include sclerosis (scarring) of a portion (average: 15%) of the glomerular space, with only a portion of glomeruli manifesting any sclerosis. [32]

Other tests helpful in the diagnosis include urine protein, urinalysis, serum albumin, and serum lipids. [2] A clinical picture of proteinuria, low blood protein levels (albumin, antibodies), and high blood cholesterol would support a diagnosis of FSGS, although these do not help to distinguish between FSGS and other causes of proteinuria. [5] [10]

Classification

Micrograph of the collapsing variant of FSGS (collapsing glomerulopathy). A collapsed glomerulus is seen at the top, right-of-centre. PAS stain. Kidney biopsy. Collapsing glomerulopathy - very high mag.jpg
Micrograph of the collapsing variant of FSGS (collapsing glomerulopathy). A collapsed glomerulus is seen at the top, right-of-centre. PAS stain. Kidney biopsy.
Histopathology of collapsing glomerulopathy. (A,B) Periodic Acid Schiff (PAS) and Jones Methenamine Silver (JMS) (40x), respectively show intense podocyte hyperplasia and glomerular tuft collapse. (C) JMS (20x) exhibits microcytic transformation of distal convoluted tubules with accumulations of hyaline material inside of those. (D,E) Fluorescence microscopy (40x) shows, respectively, IgM and C3 trapping in areas of collapse/sclerosis. (F) Semi-fine stained in Toluidine Blue (63x) with collapse of the entire glomerular tuft and hyperplasia of podocytes and dilated Bowman's space. (G,H) Transmission electron microscopy contrasted with Osmium Tetroxide, Lead Citrate and Uranyl in block shows capillary loop collapse with hyalinosis in addition to diffuse fusion and flattening of the pedicels associated with microvillous transformation. (I) Electron microscopy tubes contrasted with osmium tetroxide, lead citrate, and uranyl in block with detail of disorganization of the cytoskeleton in the podocyte cytoplasm, with extensive effacement of the pedicels. Histopathology of collapsing glomerulopathy.jpg
Histopathology of collapsing glomerulopathy. (A,B) Periodic Acid Schiff (PAS) and Jones Methenamine Silver (JMS) (40×), respectively show intense podocyte hyperplasia and glomerular tuft collapse. (C) JMS (20×) exhibits microcytic transformation of distal convoluted tubules with accumulations of hyaline material inside of those. (D,E) Fluorescence microscopy (40×) shows, respectively, IgM and C3 trapping in areas of collapse/sclerosis. (F) Semi-fine stained in Toluidine Blue (63×) with collapse of the entire glomerular tuft and hyperplasia of podocytes and dilated Bowman's space. (G,H) Transmission electron microscopy contrasted with Osmium Tetroxide, Lead Citrate and Uranyl in block shows capillary loop collapse with hyalinosis in addition to diffuse fusion and flattening of the pedicels associated with microvillous transformation. (I) Electron microscopy tubes contrasted with osmium tetroxide, lead citrate, and uranyl in block with detail of disorganization of the cytoskeleton in the podocyte cytoplasm, with extensive effacement of the pedicels.

Five mutually exclusive variants of focal segmental glomerulosclerosis may be distinguished by the pathologic findings seen on renal biopsy: [34]

  1. Collapsing variant
  2. Glomerular tip lesion variant
  3. Cellular variant
  4. Perihilar variant
  5. Not otherwise specified (NOS) variant.

Recognition of these variants may have prognostic value in individuals with primary focal segmental glomerulosclerosis. The collapsing variant is associated with higher rate of progression to end-stage renal disease, whereas the glomerular tip lesion variant has a low rate of progression to end-stage renal disease in most patients. [9] The cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between the other two variants. [9]

Treatment

First-line treatment for primary FSGS consists of anti-inflammatory drugs. [11] Specifically, glucocorticoids are begun in patients manifesting with nephrotic-range proteinuria (>3.5 g/day). [35] [36] For patients who maintain nephrotic-range proteinuria despite glucocorticoids, or for patients who demonstrate glucocorticoid intolerance, calcineurin inhibitors (e.g., tacrolimus) are initiated. [36] Successful treatment is defined as a drop in proteinuria to sub-nephrotic ranges. [6]

The treatment of secondary FSGS involves addressing the particular toxic or stress agent. [35]

Prognosis

The majority of untreated cases of FSGS will progress to end-stage kidney disease. [37] Important prognostic factors include the degree of proteinuria and initial response to therapy.

Patients with nephrotic-range (>3.5 g/day) proteinuria have over a 50% rate of progression to end-stage kidney disease at 10 years. [6] Only 15% of patients with sub-nephrotic ranges of proteinuria progress to end-stage renal failure at 10 years. [6]

Initial response to therapy also dictates long-term outcomes. Those defined as having a "complete response" typically manifest a proteinuria of <300 mg/day; those with a "partial response" manifest a sub-nephrotic range of proteinuria, <3.5 g/day. [38] Either complete or partial response is associated with 80% kidney survival at 10 years, compared with about 50% among non-responsive patients. [38]

Epidemiology

FSGS accounts for 35% of all cases of nephrotic syndrome, making it one of the most common causes of nephrotic syndrome in the United States. [8] FSGS accounts for 2% of all cases of kidney failure. [4] African American patients have four times the likelihood of developing FSGS. Men are about two times as likely to develop FSGS compared to women. [12]

Notable cases

See also

Related Research Articles

<span class="mw-page-title-main">Proteinuria</span> Presence of an excess of serum proteins in the urine

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy. Severe proteinuria can cause nephrotic syndrome in which there is worsening swelling of the body.

<span class="mw-page-title-main">Nephrotic syndrome</span> Collection of symptoms due to kidney damage

Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infections, and high blood pressure.

<span class="mw-page-title-main">IgA nephropathy</span> Disease of the kidney

IgA nephropathy (IgAN), also known as Berger's disease, or synpharyngitic glomerulonephritis, is a disease of the kidney and the immune system; specifically it is a form of glomerulonephritis or an inflammation of the glomeruli of the kidney. Aggressive Berger's disease can attack other major organs, such as the liver, skin and heart.

<span class="mw-page-title-main">Podocyte</span> Type of kidney cell

Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule filters the blood, retaining large molecules such as proteins while smaller molecules such as water, salts, and sugars are filtered as the first step in the formation of urine. Although various viscera have epithelial layers, the name visceral epithelial cells usually refers specifically to podocytes, which are specialized epithelial cells that reside in the visceral layer of the capsule. One type of specialized epithelial cell is podocalyxin.

<span class="mw-page-title-main">Glomerulonephritis</span> Term for several kidney diseases

Glomerulonephritis (GN) is a term used to refer to several kidney diseases. Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the name, but not all diseases necessarily have an inflammatory component.

<span class="mw-page-title-main">Diabetic nephropathy</span> Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

<span class="mw-page-title-main">Hypertensive kidney disease</span> Medical condition

Hypertensive kidney disease is a medical condition referring to damage to the kidney due to chronic high blood pressure. It manifests as hypertensive nephrosclerosis. It should be distinguished from renovascular hypertension, which is a form of secondary hypertension, and thus has opposite direction of causation.

<span class="mw-page-title-main">Membranous glomerulonephritis</span> Medical condition

Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually white people.

<span class="mw-page-title-main">Nephritic syndrome</span> Medical condition

Nephritic syndrome is a syndrome comprising signs of nephritis, which is kidney disease involving inflammation. It often occurs in the glomerulus, where it is called glomerulonephritis. Glomerulonephritis is characterized by inflammation and thinning of the glomerular basement membrane and the occurrence of small pores in the podocytes of the glomerulus. These pores become large enough to permit both proteins and red blood cells to pass into the urine. By contrast, nephrotic syndrome is characterized by proteinuria and a constellation of other symptoms that specifically do not include hematuria. Nephritic syndrome, like nephrotic syndrome, may involve low level of albumin in the blood due to the protein albumin moving from the blood to the urine.

HIV-associated nephropathy (HIVAN) refers to kidney disease developing in association with infection by human immunodeficiency virus, the virus that causes AIDS. The most common, or "classical", type of HIV-associated nephropathy is a collapsing focal segmental glomerulosclerosis (FSGS), though other forms of kidney disease may also occur. Regardless of the underlying histology, kidney disease in HIV-positive patients is associated with an increased risk of death.

Congenital nephrotic syndrome is a rare kidney disease which manifests in infants during the first 3 months of life, and is characterized by high levels of protein in the urine (proteinuria), low levels of protein in the blood, and swelling. This disease is primarily caused by genetic mutations which result in damage to components of the glomerular filtration barrier and allow for leakage of plasma proteins into the urinary space.

<span class="mw-page-title-main">Nephrin</span> Mammalian protein found in Homo sapiens

Nephrin is a protein necessary for the proper functioning of the renal filtration barrier. The renal filtration barrier consists of fenestrated endothelial cells, the glomerular basement membrane, and the podocytes of epithelial cells. Nephrin is a transmembrane protein that is a structural component of the slit diaphragm. They are present on the tips of the podocytes as an intricate mesh and convey strong negative charges which repel protein from crossing into the Bowman's space.

<span class="mw-page-title-main">Glomerular basement membrane</span>

The glomerular basement membrane of the kidney is the basal lamina layer of the glomerulus. The glomerular endothelial cells, the glomerular basement membrane, and the filtration slits between the podocytes perform the filtration function of the glomerulus, separating the blood in the capillaries from the filtrate that forms in Bowman's capsule. The glomerular basement membrane is a fusion of the endothelial cell and podocyte basal laminas, and is the main site of restriction of water flow. Glomerular basement membrane is secreted and maintained by podocyte cells.

Podocin is a protein component of the filtration slits of podocytes. Glomerular capillary endothelial cells, the glomerular basement membrane and the filtration slits function as the filtration barrier of the kidney glomerulus. Mutations in the podocin gene NPHS2 can cause nephrotic syndrome, such as focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Symptoms may develop in the first few months of life or later in childhood.

<span class="mw-page-title-main">Glomerulosclerosis</span> Medical condition

Glomerulosclerosis is the hardening of the glomeruli in the kidney. It is a general term to describe scarring of the kidneys' tiny blood vessels, the glomeruli, the functional units in the kidney that filter urea from the blood.

<span class="mw-page-title-main">NPHS2</span> Protein-coding gene in the species Homo sapiens

Podocin is a protein that in humans is encoded by the NPHS2 gene.

Glomerulonephrosis is a non-inflammatory disease of the kidney (nephrosis) presenting primarily in the glomerulus as nephrotic syndrome. The nephron is the functional unit of the kidney and it contains the glomerulus, which acts as a filter for blood to retain proteins and blood lipids. Damage to these filtration units results in important blood contents being released as waste in urine. This disease can be characterized by symptoms such as fatigue, swelling, and foamy urine, and can lead to chronic kidney disease and ultimately end-stage renal disease, as well as cardiovascular diseases. Glomerulonephrosis can present as either primary glomerulonephrosis or secondary glomerulonephrosis.

Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction. Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.

Monoclonal immunoglobulin deposition disease, or MIDD, is a disease characterised by the deposition of monoclonal immunoglobulins on the basement membrane of the kidney. Monoclonal immunoglobulins are produced by monoclonal plasma cells, which are found in a variety of plasma cell dyscrasias. The deposition of monoclonal immunoglobulins on the basement membrane of the kidney causes renal impairment. As well as the kidney, MIDD may also affect the liver, heart, peripheral nerves, lung and skin.

Monoclonal gammopathy of renal significance (MGRS) are a group of kidney disorders that present with kidney damage due to nephrotoxic monoclonal immunoglobulins secreted by clonal plasma cells or B cells. By definition, people with MGRS do not meet criteria for multiple myeloma or other hematologic malignancies. The term MGRS was introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG). MGRS is associated with monoclonal gammopathy of undetermined significance (MGUS). People with MGUS have a monoclonal gammopathy but does not meet the criteria for the clonal burden nor the presence of end organ damage seen in hematologic malignancies. In a population based study based on the NHANES III health survey; 6% of patients with MGUS were subsequently classified as having MGRS. The prevalence and incidence of MGRS in the general population or in specific populations is not known but it is more prevalent in those over the age of 50 as there is a monoclonal protein (M-protein) present in 3% of those 50 and years older and 5% of those 70 years and older, placing those 50 and older at increased risk of MGRS.

References

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