AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Focal segmental glomerulosclerosis (FSGS) was first described in 1957. The condition causes asymptomatic proteinuria or nephrotic syndrome (NS) with or without renal insufficiency. A diagnosis of FSGS is confirmed only by histopathology findings, but it can be suggested clinically. FSGS arises through idiopathic or secondary causes.

Pathophysiology

Etiologic agents or mechanisms that initiate glomerular injury and lead to glomerulosclerosis are largely unknown, except in certain animal models of viral-induced renal disease. The primary pathophysiologic process in FSGS is an injury to podocytes, with proliferation of mesangial, endothelial, and epithelial cells in the early stages followed by shrinkage and/or collapse of glomerular capillaries and, ultimately, sclerosis.

Proposed mechanisms include viral- or toxin-mediated damage or intrarenal hemodynamic changes such as hyperperfusion and high intraglomerular capillary pressure. FSGS initially begins in the deeper juxtamedullary glomeruli and subsequently extends to the superficial nephrons. The characteristic lesion is a segmental solidification of the glomerular tuft, usually in the perihilar region and sometimes in the peripheral areas, including the tubular pole. The extent of lesions varies in different portions of the kidney, ranging from normal unaffected glomerulus to segmental sclerosis and, eventually, global glomerulosclerosis as the disease evolves. Diffuse foot process fusion occurs, predominantly in the sclerotic segments, although partial effacement may be observed in normal-appearing lobules.

Many morphologic subsets, such as a cellular variant (endocapillary and extracapillary hypercellularity), a collapsing variant (FSGS with mesangial hypercellularity), and FSGS with tip lesions, have been described. Whether these diverse lesions reflect different pathogenesis or account for the differences in the prognoses in patients with FSGS is unclear. To better comprehend some aspects of pathogenesis, FSGS can be classified as follows.

• Primary (idiopathic) FSGS
  • FSGS with hyalinosis
  • Progression from minimal-change disease
  • Progression from immunoglobulin M (IgM) nephropathy
  • Progression from mesangial proliferative glomerulonephritis
  • Superimposed on other primary glomerulonephritis conditions (eg, membranous glomerulonephritis, immunoglobulin A [IgA] nephropathy)
  • Variants of primary FSGS
    • Collapsing form
    • Cellular variant (endocapillary and extracapillary hypercellularity)
    • FSGS with mesangial hypercellularity
    • FSGS with glomerular tip lesions
• Secondary FSGS
  • Drugs
    • Intravenous heroin
    • Analgesics
  • Viruses
    • Hepatitis B
    • HIV
    • Parvovirus
  • Hemodynamic factors - With reduced renal mass
    • Solitary kidney
    • Renal allograft
    • Renal dysplasia
    • Renal agenesis
    • Oligomeganephronia
    • Segmental hypoplasia
    • Vesicoureteric reflux
  • Hemodynamic causes - Without reduced renal mass
    • Massive obesity
    • Sickle cell nephropathy
    • Congenital cyanotic heart disease
  • Malignancies
    • Lymphomas
    • Other malignancies
  • Scarring - Postinflammatory in postinfectious glomerulonephritis
  • Miscellaneous
    • Hypertensive nephrosclerosis
    • Alport syndrome
    • Sarcoidosis
    • Radiation nephritis

In other words, factors as diverse as infections, inflammations, toxins, and intrarenal hemodynamic alterations can initiate injury and lead to glomerulosclerosis.

Frequency

United States

Typically, idiopathic FSGS is observed in persons aged 18-45 years, although no age group is exempt from the disease. In children with NS, FSGS is found in 7-10% of renal biopsies; incidence is much greater in those who are resistant to steroid and cyclophosphamide therapy. In adults, the lesion is more common in men and is observed in 20-30% of patients with NS. Incidence of FSGS is 3-7 times higher in young black men as compared to whites.

• The annual incidence of secondary FSGS in patients who are addicted to intravenous heroin is 30 times higher (611 cases per million population). In selected urban centers in the United States, heroin-associated FSGS accounted for 11.4% of end-stage renal disease (ESRD) patients in the 1970s and 1980s, although the disease has gradually disappeared in the 1990s. Most patients with HIV-associated FSGS are young black men (mean age, 33 y; male-to-female ratio, 10:1); 50% are intravenous drug abusers; and the remaining are either gay or bisexual men, heterosexual contacts of infected persons, or children with HIV infection. HIV-associated FSGS is distinctly rare in whites. In the United States and elsewhere, more than 95% of patients are black.

International

FSGS lesions are observed in about 10% of renal biopsies performed for the evaluation of proteinuria.

Mortality/Morbidity

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 ESRD is 6-8 years, although wide variations in the time course occur. One of the key factors that determines 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. The prognosis is much worse in blacks compared to whites. In the collapsing form of FSGS, the disease is marked by severe hypertension, more massive proteinuria, a very poor response to corticosteroids, and a much faster rate of progression to ESRD.

Race

The prevalence rate is much higher in blacks than in whites. In one large epidemiologic study, the annual incidence of FSGS in patients aged 18-45 years was 20 cases per million population in blacks, a rate 7 times higher than that of individuals who are not black. On the other hand, the annual incidence of secondary FSGS in patients addicted to intravenous heroin is 30 times higher (611 cases per million population). As previously noted, most subjects with HIV-associated FSGS are young black men.

Sex

In adults, the lesion is 3-4 times more common in men than women.

Age

Typically, idiopathic FSGS is observed in persons aged 18-45 years, although no age group is exempt from the disease. In children with NS, FSGS is found in 7-10% of renal biopsy specimens; incidence is much greater in those who are resistant to steroid and cyclophosphamide therapy.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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 nonresponders, the average time from the onset of proteinuria to ESRD is 6-8 years, although wide variations in the time course occur. The prognosis is much worse in blacks compared with whites. In the collapsing form of FSGS, the disease is marked by severe hypertension, more massive proteinuria, a very poor response to corticosteroids, and a much faster rate of progression to ESRD. In HIV-associated FSGS, the renal functional deterioration is rapid, leading to ESRD within a few weeks to 1 year. In recent times, with the introduction of highly active antiretroviral therapy (HAART), renal function is well preserved when the viral load decreases.

Physical

The most common clinical presenting feature is NS characterized by generalized edema, massive proteinuria, hypoalbuminemia, and hyperlipidemia. Common causes of nephrotic syndrome in adults include minimal change disease, membranous glomerulonephritis, systemic lupus erythematosus, focal sclerosis, HIV infection, IgA nephropathy, diabetes mellitus, and amyloidosis. In patients with primary (essential) hypertension and analgesic abuse, NS is not a common manifestation (although hypertension may be observed in patients with NS from all causes).

Occasionally, routine urinalysis may reveal proteinuria, prompting referral to a nephrologist. Less than a third of patients with FSGS present with nonnephrotic proteinuria along with microscopic hematuria and hypertension. Typically, edema develops over a few weeks, but the onset may be abrupt, with weight gain of 15-20 lb or more. Frequently, the onset of edema follows a recent upper respiratory tract infection.

Pleural effusion and ascites may be present; pericardial effusions are rare. Gross edema may predispose patients to ulcerations and infections in dependent areas (eg, lower extremities). 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 (ie, diastolic BP of 120 mm Hg or more) is not uncommon, especially in black patients with renal insufficiency. Rarely, patients experience severe renal failure with signs and symptoms of advanced uremia (eg, nausea, vomiting, bleeding, seizures) or altered mental status.

Causes

FSGS is considered primary or idiopathic when no etiology can be identified. Secondary FSGS is associated with illicit drug use, HIV and other viral infections, and many diverse factors, such as infections, inflammations, toxins, and intrarenal hemodynamic alterations. See Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Distinguishing FSGS from minimal-change disease, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, or membranous glomerulonephritis is clinically difficult. Rarely, NS may be the initial manifestation in patients with SLE. Young patients presenting with NS due to amyloidosis of the kidneys (except in rare familial forms) is very uncommon. Although hematuria is the most common presentation in whites with IgA nephropathy, NS and renal insufficiency may also be present.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urinalysis reveals large amounts of protein, along with hyaline and broad waxy casts, whereas RBC casts are generally absent. Broad casts may be observed in persons with advanced cases.
• Serum creatinine (SCr) concentration or creatinine clearance (CrCl) is usually within reference ranges in early stages.
• In patients with idiopathic FSGS, investigational findings for an underlying etiology, such as systemic lupus erythematosus (serum complement C4/C3 levels, antinuclear antibody/anti-DNA titers), hepatitis B or C infection, or vasculitis (antineutrophil cytoplasmic antibody titers, serum protein electrophoresis), are generally negative.
• In patients thought to have secondary FSGS, obtain HIV antibody, CD4, and viral load studies. FSGS can be considered in patients with proteinuria on the basis of NS; however, in young patients with an absence of RBC casts and negative serologic study findings, definitive diagnosis rests on a kidney biopsy.

Imaging Studies

• In the early stages, ultrasound examination reveals normal or large kidneys with increased echogenicity, suggesting diffuse intrinsic medical renal disease. In patients with advanced renal failure, kidneys are small and shrunken, indicating severe glomerular scarring and interstitial fibrosis.
• In HIV-associated FSGS, ultrasound generally reveals large echogenic kidneys.

Procedures

• Kidney biopsy is the most definitive way to establish the diagnosis.

Histologic Findings

The characteristic lesion in FSGS is segmental solidification of the glomerular tuft, usually in the perihilar region and sometimes in the peripheral areas, including the tubular pole. In the affected glomeruli, capillaries are segmentally obliterated by accumulation of acellular matrix and hyaline deposits, along with adhesion to the Bowman capsule. Coarsely granular deposits of IgM and C3 are often found in these areas.

Diffuse foot process fusion occurs, predominantly in the sclerotic segments, although partial effacement may be observed overlying normal-appearing lobules. Many morphologic subsets, such as a cellular variant (endocapillary and extracapillary hypercellularity), a collapsing variant (FSGS with mesangial hypercellularity), and FSGS with tip lesions, have been described. Whether these diverse lesions reflect different pathogeneses or can account for the differences in the prognoses in patients with FSGS is unclear.

In HIV-associated FSGS, electron microscopy of the kidney reveals tubulo-reticular complexes (TRC) in endothelial and mesangial cells, an indirect marker of viral disease.

Staging

The presence of interstitial fibrosis on an initial kidney biopsy specimen is a uniform predictor of poor renal prognosis. The collapsing variant is generally associated with a very rapid loss of renal function.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Treatment of FSGS can be divided into the following:
• • Nonspecific; nutritional management
  • Nonimmunosuppressive therapy - Diuretics for edema, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for reduction of proteinuria, other antihypertensive agents for hypertension, and lipid-lowering drugs for hyperlipidemia
• Nonspecific treatment goals in NS include maintenance of adequate nutrition, minimization or elimination of proteinuria, and prevention of complications resulting from edema. Control of hypertension is one of the most important aspects of overall management. Lowering of lipid levels is necessary to reduce cardiovascular risk and to possibly delay the progression of renal disease.
• • The mainstay of treatment is reduction in daily salt intake to 2 g of sodium (6 g of salt) and the use of diuretics in varying doses and combinations. A high level of protein intake may further aggravate proteinuria, adversely affecting renal function. Current recommendations call for an intake of 1-1.3 g of high biologic value protein per kilogram of body weight and a reduction of fat intake.
  • In most patients, loop diuretics (eg, furosemide) are needed to promote dieresis. Patients with massive edema with impaired oral absorption may require intravenous administration. In patients with refractory conditions, addition of other diuretics (eg, metolazone) and potassium-sparing agents (eg, spironolactone, triamterene) facilitates diuresis and prevents hypokalemia. Rarely, some patients (especially children) with intractable edema may need intravenous albumin and mannitol in a hospital setting to initiate diuresis. Protracted use of intravenous albumin should be discouraged because the regimen is both expensive and ineffective, as most of the infused albumin is lost in the urine.
  • Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are nonspecific agents that reduce proteinuria because of their antihypertensive and intrarenal hemodynamic effects of reducing glomerular capillary pressure and resistance. ACEIs and ARBs are effective in reducing protein loss even in normotensive patients. These agents do not eliminate proteinuria completely or reverse the primary glomerular disease process.
  • Since most patients with idiopathic FSGS develop hypertension, which further contributes to renal functional deterioration, meticulous attention must be paid to maintain BP in the reference range. All classes of antihypertensive agents, which effectively lower BP, have a beneficial effect in reducing proteinuria. In many patients, combination antihypertensive therapy may be needed to maintain normal blood pressure. Another nonspecific therapy uses lipid-lowering agents to control hyperlipidemia. The statin class of drugs is better tolerated than some of the older agents.
• Specific treatment
• • Idiopathic FSGS is a difficult disease to treat because of its highly variable clinical course. The specific treatment approach is still empirical, and no consensus has evolved because of a lack of prospective controlled trials.
  • Current evidence, mostly derived from retrospective analyses, favors prolonged corticosteroid therapy (6 mo or longer) to induce remission in patients with idiopathic FSGS.
  • Since long-term steroid therapy may lead to serious toxicity, patient counseling and close monitoring for adverse effects are essential before embarking on such a protracted regimen. The current approach calls for initiating therapy with prednisone in a dose of 1 mg/kg (60-80 mg/d) for 2-6 months or longer, depending on patient response as assessed by presence or absence of edema, 24-hour urine protein excretions, CrCl, SCr, serum albumin, and lipid levels.
  • Studies indicate that 30-60% of patients may undergo complete or partial remission to such a regimen, and relapses are frequent when steroids are discontinued. Complete remission is protein excretion of less than 200-300 mg/d, and partial response is excretion of 200-3500 mg/d, or a greater than 50% reduction in baseline proteinuria. In children, results from several studies show a remission of proteinuria in 11% of patients, persistence of NS with preservation of renal function in 31%, decline in the glomerular filtration rate in 23%, and development of ESRD in 21%. In adults, 10-year renal survival in nephrotic patients ranges from 25-55%, compared with 85-90% in patients with mild proteinuria.
  • Blacks and patients with collapsing FSGS are generally refractory to treatment and progress to renal failure. In responding patients, the goal is to titrate prednisone to the lowest dose needed to stop proteinuria and to prevent relapses. Use of steroids on alternate days can also reduce toxicity. The optimal treatment duration is uncertain; some authorities recommend the use of steroids indefinitely. In patients refractory to 2-3 months of prednisone therapy, the recommendation is to reduce the steroid dose and to add cyclophosphamide (2.5 mg/kg [150-200 mg/d]).
  • Monitor patients for bone marrow suppression, and encourage them to drink adequate fluids to prevent hemorrhagic cystitis.
  • Prolonged use of cyclophosphamide may lead to gonadal toxicity; therefore, persisting with cyclophosphamide beyond 3 months in patients who do not respond is unwise.
  • Randomized controlled trials and uncontrolled studies indicate that cyclosporine in a dose of 5-10 mg/kg/d may be beneficial in patients unresponsive to prednisone and cyclophosphamide. Few limited studies have employed tacrolimus. Since both of these calcineurin inhibitors can cause nephrotoxicity, the recommendation is to avoid them in patients with renal insufficiency.
  • Because of favorable results in other glomerular diseases, mycophenolate mofetil has also been evaluated in FSGS. Although the experience is limited, the suggested dose is 750-1000 mg twice daily in patients refractory to corticosteroids and in whom calcineurin inhibitors may not be appropriate.
  • Despite all attempts, some patients continue to deteriorate and progress to ESRD. Counsel patients and their families early regarding treatment choices for ESRD. A well-informed patient can choose among maintenance hemodialysis, continuous ambulatory peritoneal dialysis, or cadaver or living donor transplantation. FSGS may recur in the transplanted kidney, but most renal physicians do not consider this a contraindication for renal transplantation.
  • Management of secondary FSGS is directed toward the etiology or associated disorder. For example, in HIV-associated FSGS, HAART is associated with remission of proteinuria and preservation of renal function. In selected patients with HIV and FSGS, corticosteroid therapy is associated with a significant improvement and, in some patients, discontinuation of dialysis therapy. In heroin-associated FSGS, discontinuation of the drug may result in remission of proteinuria and improvement in renal function.

Diet

The mainstay of treatment is reduction in daily salt intake to 2 g of sodium (6 g of salt) and the use of diuretics in varying doses and combinations. Potassium supplementation may be needed in patients treated with diuretics who develop hypokalemia. High protein intake may further aggravate proteinuria, adversely affecting renal function. Current recommendations call for an intake of 1-1.3 g of high biologic value protein per kilogram of body weight and a reduction of fat intake.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to preserve renal function, to reduce morbidity, and to prevent complications.

Drug Category: Immunosuppressants

Current approach calls for initiating therapy with prednisone. In patients whose conditions are refractory to 2-3 mo of prednisone therapy, recommendations include reducing the steroid dose and adding cyclophosphamide. A recent prospective study indicates that 5-10 mg/kg/d of cyclosporine may be beneficial in patients unresponsive to prednisone and cyclophosphamide. Mycophenolate mofetil may be another alternative agent in patients with renal insufficiency in whom cyclosporine cannot be used. These powerful immunosuppressive agents need careful monitoring and are best used by specialists in the field.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients must be monitored for prednisone toxicity (eg, infections, hypertension, hyperglycemia). If cyclophosphamide is used, watch for leukopenia and hemorrhagic cystitis. During cyclosporine therapy, monitor BUN and SCr. Adjust diuretic doses according to fluid retention. Monitor WBC count and liver function during mycophenolate mofetil therapy. Patients receiving HAART will need periodic determination of viral load to assess the effectiveness of drugs used.

Complications

• Prednisone
  • Infections
  • Hypertension
  • Hyperglycemia
• Cyclophosphamide
  • Infections
  • Leukopenia
  • Hemorrhagic cystitis
• Cyclosporine
  • Renal insufficiency
  • Gingival hyperplasia
  • Infections

Prognosis

• 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. Average time from the onset of proteinuria to ESRD is 6-8 years, although wide variations in the time course occur. Prognosis is much worse in blacks compared with whites. In the collapsing form of FSGS, the disease is marked by severe hypertension, more massive proteinuria, poorer response to corticosteroids, and a much faster rate of progression to ESRD.

Patient Education

• Educate patients about renal failure, control of hypertension and lipids, and options for renal replacement therapy, such as peritoneal dialysis, hemodialysis, and renal transplantation.
• For further information, see Mayo Clinic - Kidney Transplant Information.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to distinguish FSGS from minimal-change disease, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, membranous glomerulonephritis, and IgA nephropathy.

Special Concerns

• FSGS is a common cause of NS in young adults, and its causes are diverse. FSGS is a nonspecific disorder, and glomerular damage may be due to immunologic, toxic, viral, or hemodynamic factors. The condition has a variable clinical course and responds poorly to corticosteroids and cytotoxic drugs. FSGS is an important contributor to ESRD, especially in young black men.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jan 30, 2007