Focal and Segmental Glomerular Sclerosis
I. What every physician needs to know.
Focal and segmental glomerular sclerosis (FSGS) or focal glomerulosclerosis (FGS) is the leading cause of idiopathic nephrotic syndrome in African Americans and the most common glomerular disease causing end stage renal disease (ESRD). Patients commonly present with features of the nephrotic syndrome which is often accompanied by hypertension and elevated serum creatinine. The diagnosis is made by renal biopsy and defined by the presence of sclerosis in parts (segmental) of some (focal) glomeruli by light microscopy and diffuse (greater than 80% in primary FSGS) effacement of the foot processes on electron microscopy.
II. Diagnostic Confirmation: Are you sure your patient has Focal and Segmental Glomerular Sclerosis?
Features of the nephrotic syndrome:
Proteinuria (>3 grams [g] in 24 hours or spot urine protein/creatinine ratio > 3.5 milligrams [mg] protein/g creatinine)
Hypoalbuminemia (serum albumin < 3 grams/deciliter [g/dL])
Edema (peripheral and/or peri-orbital)
Hyperlipidemia (total cholesterol level usually greater than 300 mg/dL). Definite diagnosis of FSGS is made by kidney biopsy showing loss of foot process’, sclerosis in parts (segmental) of some (focal) glomeruli.
A. History Part I: Pattern Recognition:
Patients initially presenting with nephrotic syndrome often complain of foamy urine, weight gain, swelling of the ankles and/or face and poor appetite. FSGS frequently presents as nephrotic syndrome, a decreased glomerular filtration rate (GFR), microscopic hematuria, and hypertension. FSGS may also present as asymptomatic subnephrotic proteinuria.
FSGS may be primary, familial, or secondary. Primary FSGS is mediated by lymphocytes that release cytokines, causing increased permeability and injury to the glomerular capillary bundle and podocytes. There are numerous secondary causes for FSGS and the injury is attributed to previous glomerular injury, glomerular hypertension, or hypertrophy.
Risk factors associated with progression of FSGS to ESRD include black race, proteinuria greater than 2 g/24 hour, elevated serum creatinine levels, low GFR, body mass index greater than 27 kilograms/meter2, hypertension at onset, lack of remission, and relapse during follow-up.
B. History Part 2: Prevalence:
In children under 18 years of age, FSGS is found in 7-10% of kidney biopsies performed for evaluation of nephrotic syndrome. In adults, FSGS is seen in 20-30% of such biopsies. FSGS is more common in men and is 3-7 times more common in African American and Hispanic Americans compared to Caucasians. Risk factors for secondary FSGS include human immunodeficiency virus (HIV) infection especially in African Americans and obesity. FSGS is the most common cause of ESRD among primary glomerular diseases with an annual incidence of about 2%.
C. History Part 3: Competing diagnoses that can mimic Focal and Segmental Glomerular Sclerosis.
There are numerous causes of nephrotic syndrome. Primary glomerular diseases including minimal change disease (MCD), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN) and FSGS all present with the same cardinal features. Generally, MCD is more common in children and affected patients rarely have hypertension or abnormal glomerular filtration rates; MN is associated with very heavy proteinuria. MPGN most closely resembles FSGS clinically thus differentiating among these requires kidney biopsy.
There are also numerous secondary causes of FSGS and it is important to differentiate from primary FSGS as the treatment is very different. Drugs associated with FSGS include intravenous heroin and long-term use of large doses of analgesics. The most common infectious cause of FSGS is HIV; HIV-associated nephropathy (HIVAN) is associated with the collapsing variant of FSGS. Other viral causes of FSGS include hepatitis B and parvovirus. Hemodynamic causes of FSGS include massive obesity, sickle cell nephropathy and congenital cyanotic heart diseases. Malignancies especially lymphomas can be associated with FSGS. Hypertensive nephropathy eventually leads to FSGS and can be seen as a final stage of Alport’s syndrome, sarcoidosis and radiation nephritis.
FSGS is seen as a result of hemodynamic factors in patients with reduced renal mass. Patients born with a single kidney, with oligomeganephronia or vesico-ureteral reflux are at increased risk of FSGS as are patients receiving a renal allograft (especially those who had FSGS as the primary cause of chronic kidney disease).
D. Physical Examination Findings.
The most common physical examination findings are those typical of nephrotic syndrome (i.e. edema and weight gain). Patients with FSGS commonly have hypertension.
E. What diagnostic tests should be performed?
Diagnosis rests on documenting the presence of nephrotic-range proteinuria (best done with a 24 hour urine collection), hypoalbuminemia and hyperlipidemia. Although not diagnostic, patients often present with microscopic hematuria. Workup for FSGS should include an HIV, hepatitis B and C and a urine toxicology. Evidence for lymphoma (i.e., lymphadenopathy) should also be sought. Other diagnostic tests are not required for the diagnosis of FSGS; however, since kidney biopsy is generally required, measurement of platelet count and coagulation times is helpful.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
The cardinal features of the nephrotic syndrome are:
Proteinuria > 3 g in 24 hours; > 3.5 mg of protein/gram of creatinine in spot urine
Hyperlipidemia: total cholesterol > 300 mg/dL
Hypoalbuminemia: serum albumin < 3 g/dL
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Renal ultrasound is useful to establish suitability for kidney biopsy, the presence of two kidneys, appearance of the kidneys, and ruling out obstructive nephropathy.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
Many physicians order a battery of serologic studies for all patients with nephrotic syndrome. In the absence of clinical features, it is not necessary to send anti-double stranded DNA antibodies, anti-nuclear antibodies, complement levels, anti-neutrophil cytoplasmic antibodies, or tests for syphilis.
III. Default Management.
Edema should be treated with sodium restriction and loop diuretics. Although controversial, it may be necessary to co-administer salt-poor (25%) albumin with the loop diuretics to prevent filtration of the diuretic agent at the glomerulus which would place the drug on the luminal side of the membrane in the ascending limb of the loop of Henle. Lowering intraglomerular pressures and reducing protein excretion may slow the rate of disease progression through the use of angiontensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists. Monitoring for hyperkalemia and a decline in GFR are needed during the initiation and titration of these medications.
Dietary modifications and lipid therapy may also be needed for treatment of hyperlipidemia.
A. Immediate management.
Distinguishing between primary and secondary FSGS is important as the approach to treatment is different. In primary FSGS, immunosuppressive therapy is indicated while renin-angiotensin-aldosterone system blockade is the mainstay of therapy in secondary causes.
Empiric management of a patient with nephrotic syndrome should consist of corticosteroids: prednisone 1 mg/kilogram(kg)/day is the typical starting dose. A patient diagnosed with FSGS should also be treated with cyclosporine 3-4 mg/kg daily divided in two doses. The goal is to maintain a trough cyclosporine level 100-175 nanogram/mL.
B. Physical Examination Tips to Guide Management.
The presence of edema may indicate fluid overload and may require diuretic therapy to control blood pressure in hypertensive patients. Unequal lower extremity edema should prompt consideration of deep vein thrombosis.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
The most common test for monitoring response to therapy in patients with FSGS is spot urine protein/creatinine ratio. Proteinuria should begin to decrease after 1-2 months of cyclosporine therapy and should resolve in 4-6 months. Cyclosporine is typically continued for 6 months after remission is achieved and then tapered over 6 months. Cyclosporine levels should be measured at each follow up visit to ensure that the level is maintained in an appropriate range; dose adjustments are frequently necessary.
D. Long-term management.
A patient who responds to cyclosporine therapy needs to be monitored for recurrence of FSGS once immunosuppressive therapy has been withdrawn. The best test for monitoring is spot urine protein/creatinine ratio.
E. Common Pitfalls and Side-Effects of Management.
Failure to achieve an immediate or complete remission does not mean therapeutic failure. Most patients require a combination of cyclosporine and prednisone and some require a longer course of therapy. Side effects of cyclosporine include hypertension and acute kidney injury so renal function and blood pressure need to be closely monitored while on therapy. Prednisone is associated with a variety of side effects including weight gain, edema, mental status changes, moon facies, osteoporosis, abnormal glucose tolerance and frank diabetes mellitus.
IV. Management with Co-Morbidities.
If FSGS is associated with HIV infection, immunosuppression is contraindicated; most patients respond to anti-retroviral therapy. If FSGS is associated with obesity, weight loss is the most appropriate therapy and immunosuppression is unlikely to add further benefit. If FSGS is associated with hepatitis or lymphoma, it usually resolves when the underlying disease is treated. Recurrent or de novo FSGS following kidney transplantation has been associated with circulating glomerular permeability factors and may respond to plasmapharesis.
A. Renal Insufficiency.
In the setting of renal insufficiency, ACE inhibitors and angiotensin II receptor antagonists are relatively contraindicated. The renal prognosis of a patient with renal insufficiency diagnosed with FSGS is significantly worse requiring a thorough analysis of the risk-benefit ratio of immunosuppressive therapy.
B. Liver Insufficiency.
Depending on the severity of liver disease, dosage of angiotensin converting enzyme inhibitors may need to be reduced. ACE inhibitors should not be used in the setting of liver disease since there are rare reports of liver failure in patients treated with these agents.
C. Systolic and Diastolic Heart Failure.
Corticosteroids may induce fluid retention and worsen heart failure.
D. Coronary Artery Disease or Peripheral Vascular Disease.
Corticosteroids increase the risk of coronary artery disease by worsening glucose tolerance.
E. Diabetes or other Endocrine issues.
Corticosteroids may worsen glucose tolerance so there may be a need for adjustment in diabetes therapy.
Immunosuppressive therapy is contraindicated in the presence of malignancy.
G. Immunosuppression (HIV, chronic steroids, etc).
A patient with HIV-associated FSGS should be treated with antiretroviral therapy rather than immunosuppressive therapy. A patient who develops FSGS while on immunosuppressive therapy is likely to be refractory to therapy.
J. Hematologic or Coagulation Issues.
Proteinuria is associated with an increased risk for deep vein thrombosis so patients with hypercoagulable states need to be monitored closely for this complication. FSGS diagnosed in the setting of malignancy usually resolves with treatment of the malignant disease.
K. Dementia or Psychiatric Illness/Treatment.
Corticosteroids can worsen psychiatric illness so patients need to be monitored closely and antipsychotic therapy may need to be adjusted.
V. Transitions of Care.
A. Sign-out considerations While Hospitalized.
Electrolyte monitoring is needed while on diuretics.
A patient taking corticosteroids is at risk for gastrointestinal bleeding in addition to the risks of the underlying disease (e.g., deep vein thrombosis and pulmonary embolus).
B. Anticipated Length of Stay.
Patients with FSGS often do not require hospitalization.
C. When is the Patient Ready for Discharge.
Outpatient monitoring should be provided by a Nephrologist within a week after discharge. Prior to the visit, the patient should have laboratory studies including cyclosporine level, chemistries, blood count, urinalysis and spot urine protein/creatinine ratio.
F. Prognosis and Patient Counseling.
About 50% of patients with FSGS respond to cyclosporine therapy with at least partial remission, defined as 50% reduction in proteinuria. Most patients develop progressive chronic kidney disease and will ultimately require renal replacement therapy (i.e. dialysis or transplantation). Immunosuppressive therapy can delay the need for such therapy by many years.
VI. What's the evidence?
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Deegens,, JK,, Wetzwls,, JF.. “Immunosuppressive treatment of focal glomerulosclerosis: Lessons from a randomized controlled trial.”. .. vol. 80. 2011. pp. 798-801.
Davin,, JC,, Rutjes,, NW.. “Nephrotic syndrome in children: From bench to treatment.”. . 2011.
Duffy, M,, Jain, S,, Harrell, N,, Kothari, N,, Reddi, AS.. “Albumin and Furosemide Combination for Management of Edema in Nephrotic Syndrome: A Review of Clinical Studies.”. Englert C, ed. . vol. 4. 2015. pp. 622-630.
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Schonenberger,, E,, Ehrich,, JH,, Haller,, H,, Schiffer,, M.. “The podocyte as a direct target of immunosuppressive agents.”. . vol. 26. 2011. pp. 18-24.
McCarthy,, ET,, Sharma,, M,, Savin,, VJ.. “Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis.”. . 2010. pp. 2115-21.
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Troyanov, S,, Wall, CA,, Miller, JA,, Scholey, JW,, Cattran, DC,. “Toronto Glomerulonephritis Registry Group. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission.”. . vol. 16. 2005. pp. 1061
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- Focal and Segmental Glomerular Sclerosis
- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Focal and Segmental Glomerular Sclerosis?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic Focal and Segmental Glomerular Sclerosis.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management.
- IV. Management with Co-Morbidities.
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure.
- D. Coronary Artery Disease or Peripheral Vascular Disease.
- E. Diabetes or other Endocrine issues.
- F. Malignancy.
- G. Immunosuppression (HIV, chronic steroids, etc).
- J. Hematologic or Coagulation Issues.
- K. Dementia or Psychiatric Illness/Treatment.
- V. Transitions of Care.
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge.
- F. Prognosis and Patient Counseling.