Focal Segmental Glomerulosclerosis

Definition/Description[edit | edit source]

Kidney anatomy.jpg

Focal Segmental Glomerulosclerosis (FSGS) is a kidney disease that involves the formation of scar tissue in the glomeruli.

  • Frequently encountered cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children.
  • Histologically, it is characterized by segmental scarring, involving a part of the glomerulus, and affects some but not all glomeruli sampled.
  • Recent research has shed light on the pathogenesis of FSGS which is podocyte injury and damage, leading to protein loss and subsequent development of focal sclerosing lesions.
  • FSGS is broadly categorized into primary (idiopathic) and secondary forms, and such distinction carries both prognostic and therapeutic implications[1]

NB: Podocytes are cells in the Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocyte cells make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place[2]

Epidemiology[edit | edit source]

  • The exact incidence and prevalence data of FSGS is difficult to ascertain due to significant racial and geographical differences in incidence. The estimated incidence of FSGS is about 7 per 1 million with a prevalence of 4%.
  • In the United States, approximately 50% of nephrotic syndrome is attributed to FSGS.
  • The prevalence of FSGS has gradually increased over the years, and it is the most common primary glomerular process contributing to end-stage renal disease in the United States.
  • The increasing incidence is likely due to improved recognition and detection of the entity, with a better understanding of the pathophysiology of podocyte injury and development of therapy targeting mediators of such injury[1].

Characteristics/Clinical Presentation[edit | edit source]

  • Children with focal segmental glomerular sclerosis (FSGS) typically present with the full-blown nephrotic syndrome (edema, massive proteinuria, hypoalbuminemia, hypercholesterolemia).
  • Adults can have nephrotic or sub-nephrotic proteinuria, hypertension, microscopic hematuria, or present with renal insufficiency.
  • Patients with primary FSGS often have profound hypoalbuminemia and edema, but these are rare in secondary forms[1].

Diagnostic Tests/Lab Tests/Lab Values[edit | edit source]

A Urinalysis is commonly used to evaluate Blood Urea Nitrogen (BUN), serum creatinine, and 24-hour urinary protein excretion.[3] A Urinalysis usually reveals large amounts of protein, along with hyaline and broad waxy casts, whereas RBC casts are generally absent.[4] A Kidney biopsy however, is the most definitive way to establish the diagnosis of FSGS. The biopsy typically shows focal and segmental hyalinization of the glomeruli, often with immunostaining showing IgM and complement (C3) deposits in a nodular and coarse granular pattern.[3] In HIV-associated FSGS, an ultrasound generally reveals large echogenic kidneys.[4]

Etiology/Causes[edit | edit source]

Recent research has shed light on the pathogenesis and etiology of focal segmental glomerular sclerosis (FSGS), which is podocyte injury. Several genetic and acquired causes of podocyte injury have been identified.

Genetic

  • Several genes encoding slit diaphragm proteins, cell membrane proteins, cytoskeleton proteins, nuclear proteins, mitochondrial proteins, and lysosomal proteins have been identified to be abnormal/mutated leading to loss of integrity of glomerular filtration barrier resulting in FSGS.

Circulating Permeability Factor

  • Primary FSGS has long been thought to be due to the presence of circulating permeability factors/cytokines which causes foot process effacement and proteinuria. These include cardiotrophin-like cytokine factor 1, apoA1b, anti-CD40 Ab and suPAR.[5][6][7]

Viruses

  • Viral causes include HIV, parvo B19, CMV, EBV, hepatitis C, and Simian virus.

Drugs

  • Drugs associated with FSGS include heroin, interferon, lithium, pamidronate, mTOR inhibitors, anabolic steroid[1]

Systemic Involvement[edit | edit source]

“The natural history of FSGS varies a great deal. A typical course runs from edema that is difficult to manage to proteinuria refractory to corticosteroids and other immunosuppressive agents to worsening hypertension and progressive loss of renal function. In patients who do not respond to therapy, the average time from the onset of gross proteinuria to End Stage Renal Disease (ESRD) is 6-8 years, although wide variations in the time course occur. One of the key factors that determine renal survival is the persistence and degree of proteinuria. In patients with unresponsive massive proteinuria of greater than 10 g/d, most will develop ESRD within 5 years.” [4]

“Pleural effusion and ascites may be present; pericardial effusions are rare. Gross edema may predispose patients to ulcerations and infections in dependent areas, such as the lower extremity. Abdominal pain, a common finding in children, may be a sign of peritonitis. Rarely, xanthomas may be evident in association with severe hyperlipidemia. In many patients, physical examination findings are normal except for generalized or dependent edema.”

“Severe hypertension with a diastolic blood pressure of 120 mmHg or more is not uncommon, especially in African American patients with renal insufficiency. Rarely, patients experience severe renal failure with signs and symptoms of advanced uremia (nausea, vomiting, bleeding, seizures) or altered mental status.”

Medical Management[edit | edit source]

  • Glucocorticoids (daily or every other day) are the first line of treatment in children and adults with focal segmental glomerular sclerosis (FSGS). Patients who are resistant or intolerant to steroids are treated with immunosuppressive therapy with calcineurin inhibitors (CNI), mycophenolate mofetil, or rituximab.
  • In patients with subnephrotic proteinuria, adaptive FSGS, a trial of RAS inhibition, and sodium restriction can be tried.
  • In other secondary forms of FSGS, removing the offending agent or treating the underlying disorder is recommended.
  • Optimization of blood pressure, treatment of edema with diuretics, statin therapy for hypercholesterolemia and anticoagulation in select patients at risk for thrombosis/embolization are indicated.
  • Children respond within a few weeks, but adults may take months to respond. [1]

Physical Therapy Management[edit | edit source]

  • Regular exercise or sports and an appropriate diet should be encouraged in order to help decrease or maintain blood pressure and cholesterol levels.
  • Renal Rehabilitation if available is recommended
  • Appropriately informing our patients could also help them in choosing among maintenance hemodialysis, continuous ambulatory peritoneal dialysis, or cadaver or living donor transplantation, when appropriate.[4]

[5]

Dietary Management[edit | edit source]

Low sodium or sodium free diets, as well as Vitamin D supplementation are usually recommended to patients with FSGS.[6] This is important to help lower high lipid values that can place a patient at risk for cardiovascular complications and could help delay the progression toward End Stage Renal Disease. 

Differential Diagnosis[edit | edit source]

Potential differential diagnoses:[4]
     • minimal-change disease
     • mesangial proliferative glomerulonephritis
     • membranoproliferative glomerulonephritis
     • membranous glomerulonephritis

Case Reports/ Case Studies[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 1.2 1.3 1.4 Sangameswaran KD, Baradhi KM. Focal Segmental Glomerulosclerosis.2019 Available from:https://www.ncbi.nlm.nih.gov/books/NBK532272/ (last accessed 21.10.2020)
  2. Dorlands Dictionary Available from:https://www.dorlandsonline.com/dorland/home
  3. 3.0 3.1 McMillan JI. The Merck Manuals Online Medical Library. Nephrotic Syndrome (Focal Segmental Glomerulosclerosis). January 2010. Available at: http://www.merckmanuals.com/professional/sec17/ch235/ch235c.html#sec17-ch235-ch235c-879. Accessed March 16, 2011.
  4. 4.0 4.1 4.2 4.3 4.4 Rao TS, Soman AS. eMedicine from WebMD. Focal Segmental Glomerulosclerosis. February 17, 2009. Available at: http://emedicine.medscape.com/article/245915-overview. Accessed March 16, 2011.
  5. Alonzo Mourning. Overcomes Disease and Inspires Others. Available from: http://www.youtube.com/watch?v=mvvsSDQS4G4 [Last Accessed 04/05/11]
  6. Patel P. Medline Plus. Focal Segmental Glomerulosclerosis. May 20, 2009. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000478.htm. Accessed March 16, 2011.
  7. Glick A. Focal segmental glomerulosclerosis: a case study with review of pathophysiology. Nephrology Nursing Journal. 2007 March; 34(2):176-183.
  8. Lim A, Lydia A, Rim H, Dowling J, Kerr P. Focal segmental glomerulosclerosis and Guillain-Barre syndrome associated with Campylobacter enteritis. Internal Medicine Journal. 2007 October; 37(10):724-728.
  9. Lowik M, Groenen P, LP, et al. Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation. Kidney International. 2007 November; 72(10):1198-1203.
  10. Osunkoya A, Agte S, Laszik Z. A 67-year-old woman with chronic proteinuria. Focal segmental and global glomerulosclerosis with light microscopic and ultrastructural features consistent with Fabry disease. Archives of Pathology & Laboratory Medicine. 2006 June; 130(6):e93-e95.
  11. Hristea D, et al. Successful treatment of recurrent focal segmental glomerulosclerosis after kidney transplantation by plasmapheresis and rituximab. Transplant International. 2007 January; 20(1):102-105.