Continuing Education Activity

Focal segmental glomerular sclerosis (FSGS) is histologically characterized by segmental scarring that involves a part of the glomerulus and only affects some but not all glomeruli sampled. Patients with this condition can present with the clinical manifestations of nephrotic and nephritic syndrome or renal insufficiency. The most common clinical manifestation of FSGS (in over 70% of patients) is nephrotic syndrome, presenting as generalized or dependent edema, fatigue, and appetite loss. Hypertension is another common feature and could be severe, with diastolic blood pressure over 120 mmHg. This activity reviews the evaluation and management of focal segmental glomerular sclerosis and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of focal segmental glomerular sclerosis.
• Describe the role of podocytes, epithelial cells, and basement membrane in the pathophysiology of focal segmental glomerular sclerosis.
• Outline the use of steroids and immunosuppressive therapies in managing focal segmental glomerular sclerosis.
• Summarize the importance of collaboration and communication among interprofessional team members to enhance care delivery for patients affected by focal segmental glomerular sclerosis.

Introduction

Focal segmental glomerular sclerosis (FSGS) is a frequently encountered cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children.[1] In FSGS, some (not all) glomeruli are sclerosed (focal), and each involved glomerulus is only partially affected (segmental).[2] FSGS is one of the commonest causes of primary glomerulopathy in adults.[3] FSGS can be broadly classified into primary (no known cause) or secondary. Causes of secondary FSGS include infections, drugs, hemodynamic adaptations in the kidney, and genetics.

Although clinical signs are suggestive, the confirmation of the diagnosis of FSGS is achieved only by histopathology findings.[4] Histologically, it is characterized by segmental scarring involving a part of the glomerulus. It 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.[5] Categorizing FSGS into primary and secondary forms carries prognostic and therapeutic implications.[6]

The most common clinical manifestation of FSGS (in over 70% of patients) is nephrotic syndrome, presenting as generalized or dependent edema, fatigue, and appetite loss. Hypertension is another common feature and could be severe, with diastolic blood pressure over 120 mmHg; this is common in patients of Afro-Caribbean origin, particularly those with kidney insufficiency.[7]

Etiology

Focal segmental glomerulosclerosis can be classified as primary (idiopathic), genetic, or secondary.

Primary (idiopathic) FSGS

Primary FSGS has been associated with the presence of circulating permeability factors/cytokines, which cause foot process effacement and proteinuria. These include corticotrophin-like cytokine factor 1, apoA1b, anti-CD40 Ab, and suPAR.[8][9][10] Primary (idiopathic) FSGS includes the following:

• FSGS with hyalinosis
• Progression from immunoglobulin M (IgM) nephropathy
• Progression from minimal-change disease
• Progression from mesangial proliferative glomerulonephritis
• Superimposed on other primary glomerulonephritis conditions (e.g., immunoglobulin A [IgA] nephropathy)

Variants of primary FSGS include the following:

• Collapsing form
• Cellular variant
• FSGS with mesangial hypercellularity
• FSGS with glomerular tip lesions

Genetic

Several genes encoding proteins of slit diaphragm, cell membrane, cytoskeleton, nuclear, mitochondrial, and lysosomal origin have been identified to be abnormal/mutated, causing the loss of integrity of glomerular filtration barrier resulting in FSGS.[11] Examples include NPHS1 and NHPS2 mutations that lead to the absence of essential slit diaphragm components, causing severe congenital nephrotic syndrome. Moreover, polymorphisms in the APOL1 gene are usually found in people of African descent, which markedly increases the risk for FSGS.[4][12] The mutations may occur in proteins such as nephrin, podocin, α-actinin-4, and β-integrin. Patients with the genetic form of FSGS may have a relevant family history, and they are often young.[13][12]

Secondary FSGS

A range of factors, including drugs, inflammations, infections, toxins, and intrarenal hemodynamic alterations, may initiate injury to podocytes and lead to glomerulosclerosis.

Drugs associated with FSGS include the following:[14][15][16]

• Intravenous heroin[17]
• Analgesics
• Pamidronate
• Lithium[18]
• Anabolic steroids
• Doxorubicin, daunomycin

Viruses associated with FSGS include the following:

• Hepatitis B and C
• HIV[19][20]
• Parvovirus B19[21]
• Cytomegalovirus
• SARS-CoV-2

Adaptive responses lead to glomerular hypertrophy. Histopathologically, these are characterized by large glomeruli, the predominance of perihilar scarring, and partial foot process effacement.[22][23] Hemodynamic factors in patients with decreased renal mass include the following:

• Solitary kidney
• Kidney allograft
• Renal dysplasia
• Renal agenesis
• Oligomeganephronia
• Segmental hypoplasia
• Vesicoureteral reflux

Hemodynamic causes in patients without decreased renal mass include the following:

• Obesity (especially morbid obesity)[24]
• Sickle cell nephropathy
• Congenital cyanotic heart disease

Lymphomas and other malignancies have an association with FSGS. Miscellaneous other conditions causing FSGS include the following:

• Hypertensive nephrosclerosis
• Alport syndrome
• Sarcoidosis
• Radiation nephritis

Epidemiology

The prevalence of focal segmental glomerulosclerosis seems to be increasing worldwide. The exact incidence and prevalence data of FSGS are difficult to ascertain due to significant racial and geographical differences.[25] The estimated incidence of FSGS is about 7 per 1 million, with a prevalence of 4%, as described by Kitiyakara et al. in 2003.[26]. In the United States, approximately 50% of nephrotic syndrome in AA is attributed to FSGS. However, 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 the development of therapy targeting mediators of such injury.

Australia has reported one of the highest incidences of FSGS, attributable to increased disease recognition due to a liberal kidney biopsy policy.[3] Typically, idiopathic FSGS is seen in persons aged 18-45; however, no age group is exempt. In the pediatric population, FSGS is found in 7 to 10% of all kidney biopsies; this incidence is much higher in those resistant to steroids and cyclophosphamide. In adults, FSGS is more common among men and is seen in 20-30% of nephrotic syndrome cases. FSGS is 3-7 times greater in young Black men than in Whites.[7] 

In one international literature review, the annual incidence of FSGS was observed between 0.2 and 1.8/100,000 population.[1] The yearly incidence of FSGS is 5 cases per million in Whites, as opposed to 24 cases per million in the Black population. In the US, ESRD due to FSGS was reported to be 1.9 per million population in Whites and 6.8 in Blacks.[26] This higher incidence is partly attributable to variants of two important podocyte proteins, apolipoprotein L1 (APOL1) and non-muscle myosin heavy chain-9, found in about 5% of White patients as opposed to 60% of African American patients.[27]

Mortality/Morbidity

The natural history of FSGS varies greatly. It involves edema, proteinuria refractory to steroids and other immunosuppressive agents, worsening hypertension, and progressively declining renal function.[28] In non-responsive cases, the average duration between the onset of gross proteinuria and ESRD is 6-8 years, although variations in the time course occur. Achievement of remission, whether spontaneous or induced, is associated with good renal outcomes.[29] The prognosis is much worse in the Black population compared with White patients. The collapsing form of FSGS is characterized by severe hypertension, a very poor response to corticosteroids, more massive proteinuria, and a much faster rate of progression to ESRD.

Pathophysiology

The pathogenesis of focal segmental glomerular sclerosis involves a complex interplay of several cell types, including podocytes, endothelial cells, and the basement membrane. Podocytes are terminally differentiated cells that provide structural support to the glomerulus and are essential in maintaining an intact glomerular filtration barrier essential to prevent nephrotic range proteinuria. Injury and loss of podocytes result in podocyte hypertrophy of remaining podocytes to cover the glomerular capillary surface resulting in effacement and protein loss.[30][31] Foot process effacement and the proliferation of mesangial, endothelial, and epithelial cells earlier in the course of illness, followed by collapse/shrinkage of glomerular capillaries, all result in scarring (glomerulosclerosis).[32]

The proposed mechanism for podocyte injury includes viral- or toxin-mediated insult and intrarenal hemodynamic alterations, such as high intraglomerular capillary pressure and glomerular hyperperfusion. Many morphologic subsets, such as a collapsing variant (FSGS with mesangial hypercellularity), a cellular variant (endocapillary and extracapillary hypercellularity), and FSGS with tip lesions, are known.[4]

Understanding the pathophysiology of FSGS has improved with the discovery that mutations in several proteins responsible for maintaining podocyte structure, function, or both not only result in FSGS but can predict disease characteristics, such as steroid responsiveness.[33] For instance, FSGS with mutations in NPHS2 or TRPC6 is challenging to treat with immunosuppressive therapy; however, when such patients undergo kidney transplantation, the disease does not usually recur. APOL1 G1/G2 variants have been associated with a poor renal prognosis and steroid resistance in nephrotic syndrome/FSGS.[34] 

Proposed circulating factors linked to the development of FSGS include candidate molecules, such as hemopexin, cardiotrophin-like cytokine 1, and vascular endothelial growth factor. One molecule that has been extensively studied is a form of urokinase receptor (suPAR).[35]

Histopathology

Histologically, focal segmental glomerular sclerosis (FSGS) is characterized by sclerosis, hyalinosis, and adhesions/synechiae formation, resulting in segmental obliteration of glomerular capillaries. On electron microscopy (EM), foot process effacement is the predominant finding without significant basement membrane abnormalities. Immunofluorescence shows staining for IgM and C3 in sclerotic areas. Juxtamedullary nephrons are affected first; hence, inadequate sampling may miss focal lesions.

Histologically, FSGS is classified into five variants: perihilar, tip, cellular, collapsing, and not otherwise specified (NOS).[6][36][37]

Perihilar: The sclerosing lesion is located at the vascular pole of the glomerulus. This is commonly seen in adaptive FSGS due to increased pressure in the glomerulus near the afferent arteriole. Foot process effacement is mild, resulting in subnephrotic proteinuria and relatively normal serum albumin levels. 

Tip: The segmental lesion involves the tubular pole of the glomerulus. This is commonly seen in Whites, presenting with diffuse foot process effacement and abrupt onset of nephrotic syndrome. These patients have lower baseline creatinine, an excellent response to treatment, and the lowest rate of progression.[38]

Cellular: This is the least common variant of FSGS, characterized by the hypercellular glomerulus, including endocapillary and glomerular epithelial cell hyperplasia. It presents with diffuse foot process effacement and full-blown nephrotic syndrome.[39]

Collapsing: This is characterized by hyperplasia and hypertrophy of visceral glomerular epithelial cells leading to the collapse of the glomerular tuft. This is commonly seen in viral (parvovirus B19, CMV, HIV) and drug-associated forms of FSGS (IFN, pamidronate) and presents with diffuse effacement of foot processes, heavy proteinuria with the lowest rate of remission, and the worst prognosis.[40][41][42]

NOS: This is the most common subtype of FSGS and does not fit into any other morphological forms of FSGS. It presents with a variable degree of effacement and proteinuria.

Histopathology may sometimes resemble nodular sclerosis, as in diabetes and other conditions.[43]

History and Physical

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

It is essential to obtain an extensive history, including birth history (low birth weight/premature birth, congenital renal malformations), family history, medical comorbidities, pre-existing renal disease, exposure to drugs/toxins, recent viral illnesses, and family history to identify secondary causes of FSGS.[44]

Generally, edema develops over a few weeks; however, the onset may be abrupt, with sudden weight gain of 15-20 lbs (6.8 to 9 kg) or more. Frequently, a recent upper respiratory tract infection precedes edema.

Pleural effusion and ascites could be present, although pericardial effusions are rare. Gross edema could predispose patients to infections and ulcerations in dependent areas, such as the lower extremities. Abdominal pain may be a sign of peritonitis, a common finding in children. Rarely, xanthomas may be seen in cases of severe hyperlipidemia. In many patients, physical examination is normal except for edema. Severe hypertension is not uncommon, particularly in Black patients with renal impairment.[7] Rarely do patients experience severe renal failure with features of advanced uremia, such as nausea, vomiting, seizures, bleeding, or altered mental status. Patients with FSGS secondary to conditions such as reflux nephropathy, massive obesity, and renal dysplasia/agenesis usually present with non-nephritic proteinuria. These patients may often experience worsening renal function over the course of months to years.

Evaluation

In patients with focal segmental glomerulosclerosis, urinalysis shows large amounts of protein and casts (hyaline and broad waxy), although red blood cell (RBC) casts are usually absent. In advanced cases, broad casts may be evident. Serum creatinine (SCr) and creatinine clearance (CrCl) are usually within the reference range in the early stages. Features of nephrotic syndrome (proteinuria >3.5 g/day, serum albumin <30 g/L, with or without edema) may or may not be present.

In idiopathic FSGS, investigations for an underlying etiology are usually negative. Such conditions include the following:

• Systemic lupus erythematosus (antinuclear antibody/anti-DNA titers, serum complement C4/C3 levels)
• Hepatitis B or C infection
• Vasculitis (serum protein electrophoresis, antineutrophil cytoplasmic antibody titers)

In patients suspected to have secondary FSGS, the following should be obtained:

• HIV antibody, CD4, and viral load
• Serology for hepatitis B and C
• Parvovirus testing

FSGS in morbidly obese patients is diagnosed by excluding other causes. The common features in obesity-related FSGS include glomerular hyperfiltration and activation of the renin-angiotensin-aldosterone system.[45] FSGS may be considered in patients with proteinuria; however, in younger patients with no RBC casts and negative serologic studies, the definitive diagnosis is made on a kidney biopsy.

Histologic Findings

A kidney biopsy is the most diagnostic modality in FSGS, like in many other glomerulopathies. The characteristic finding in FSGS is segmental solidification of the glomeruli, typically in the perihilar region and occasionally in the peripheral areas, such as the tubular pole.[46] In the diseased glomeruli, the accumulation of acellular matrix and hyaline deposits obliterates capillaries in a segmental fashion. Coarsely granular deposits of C3 and IgM are often seen in these areas. Diffuse foot process fusion is seen predominantly in the sclerotic segments, whereas partial effacement is observed overlying normal-appearing lobules. 

In HIV-associated FSGS, electron microscopy of the kidney shows tubuloreticular inclusions in mesangial and endothelial cells, an indirect indication of viral disease.[47]

Ultrasonography

Earlier in the course of illness, ultrasonography will reveal normal or enlarged kidneys with increased echogenicity, indicating diffuse intrinsic medical renal disease.[48] In advanced renal failure, kidneys are shrunken and small, suggesting severe interstitial fibrosis and glomerular scarring. In HIV-associated FSGS, ultrasound study generally reveals large echogenic kidneys.

Treatment / Management

Glucocorticoids (daily or every other day) are the first line of treatment in children and adults with focal segmental glomerular sclerosis (FSGS). Patients resistant or intolerant to steroids are treated with immunosuppressive therapy with calcineurin inhibitors (CNI), mycophenolate mofetil, or rituximab.[49][50][51]

Corticosteroids

High-dose corticosteroid therapy with prednisolone is started at an initial dose of 1 mg/kg/day daily single dose (maximum 80 mg) or alternate day dose of 2 mg/kg/day (maximum 120 mg) for at least four weeks and until complete remission is achieved or a maximum of 16 weeks treatment, whichever is earlier.[52][53] Patients with the potential to remit would likely show some decline in proteinuria before 16 weeks of high-dose steroid therapy. Hence, it is unnecessary to persist with high-dose steroids treatment until 16 weeks if proteinuria persists or worsens. This becomes more important in patients who are experiencing side effects of steroids.[54]

Tapering off steroids should start after at least four weeks of achieving remission with high-dose therapy or after two weeks of the disappearance of proteins, whichever is longer. Prednisolone is reduced by 5 mg every one to two weeks to complete a total duration of six months. If partial remission is achieved within eight to twelve weeks of high-dose steroid therapy, continue until 16 weeks to ensure complete remission. After that, the prednisolone dose is reduced by 5 mg every one to two weeks to complete a total six-month duration of 6 months.

Calcineurin Inhibitors

If the patient is steroid-resistant or develops adverse effects from steroids, alternative immunosuppression should be used, such as calcineurin inhibitors. The options include the following:

• Cyclosporine - 3 to 5 mg/kg/day (target trough levels 100 to 175 ng/ml)
• Tacrolimus - 0.05 to 0.1 mg/kg/day (target trough levels 5 to 10 ng/ml)[55]

Trough levels should be monitored to prevent drug toxicity. The duration of determining the efficacy of cyclosporin or tacrolimus is at least six months, after which the patient can be labeled CNI-resistant. CNIs should be continued for at least 12 months in patients with partial or complete remission to prevent relapses. The dose of CNIs is to be slowly tapered over 6-12 months as tolerated.

In patients resistant or intolerant to CNIs, there is a lack of evidence regarding any particular agent. Mycophenolate mofetil, high-dose dexamethasone, rituximab, and adrenocorticotropic hormone (ACTH) have been studied.[56] In addition, rituximab, mTOR inhibitors, and plasmapheresis have been tried in select patients with varied results.

In patients with subnephrotic proteinuria, adaptive FSGS, a trial of renin-angiotensin system (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. In addition, 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. Glucocorticoids are associated with a remission rate of approximately 30% compared to about 50% in patients treated with CNI.

Differential Diagnosis

In patients presenting with nephrotic syndrome, differentiating focal segmental glomerulosclerosis from other glomerulopathies, such as minimal change disease, membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, or membranous glomerulonephritis is clinically challenging. Therefore, the following differential diagnoses should be considered:

• Mesangial proliferative glomerulonephritis
• Membranoproliferative glomerulonephritis
• Nephrotic syndrome
• Systemic lupus erythematosus
• Diabetes mellitus
• IgA nephropathy
• Amyloidosis

Prognosis

Several features predict outcome in FSGS, including race (Blacks have worse outcomes), degree of proteinuria, presence of renal insufficiency, histological variant (tip variant had the best outcome and collapsing variant had the worst outcome), degree of IFTA (interstitial fibrosis/tubular atrophy) and response to treatment with patients attaining partial or complete remission having a better prognosis. Also, patients with primary FSGS did worse than those with adaptive/secondary causes of FSGS.[57][53]

Complications

Focal segmental glomerulosclerosis, like all other glomerulopathies, has the potential to lead to certain complications. The following is a list of potential complications of this disease:

• Uncontrolled high blood pressure
• Anemia
• Advanced renal failure
• Venous thromboembolism[58]
• Recurrent infections[59]
• Thrombotic microangiopathy[60]

Complications of prednisone therapy include:

• Infections
• Hypertension
• Hyperglycemia

Complications of cyclophosphamide therapy include:

• Infections
• Leukopenia
• Hemorrhagic cystitis[61]

Complications of cyclosporine therapy include:

• Renal insufficiency
• Gingival hyperplasia[62]
• Infections

Deterrence and Patient Education

Providers should educate patients about controlling hypertension and lipids, chronic kidney disease, and options for renal replacement therapy, such as hemodialysis, peritoneal dialysis, and kidney transplantation. Patients should be made aware of the signs and symptoms and when to seek medical help. Dietary modifications should also be advised to the patients. Salt intake should be restricted.[63] Daily intake should be decreased to 2 g of sodium (5 g of salt). Potassium supplements may be needed in patients managed with diuretics who develop hypokalemia.

As high protein intake could further aggravate proteinuria, affecting renal function, current guidance calls for an intake of 1 to 1.3 grams of high biologic-value protein/kg of body weight. In addition, reduction of fat intake could help with dyslipidemia.

Enhancing Healthcare Team Outcomes

Focal segmental glomerular sclerosis is a frequently encountered cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children.[1] Because of the numerous causes and varied presentations, the condition is best managed by an interprofessional team that includes a nephrologist, internist, pathologist, nurses, and pharmacist. The various clinicians will be the primary directors of care, and nurses will help coordinate activities between the different disciplines while assisting in patient evaluation and offering patient counsel. Pharmacists will verify appropriate dosing, perform medication reconciliation, provide patient counseling and answer questions about the medications they are on. Every team member must maintain accurate and updated patient records so that everyone involved in care can access the same information. Open communication lines between all team members are crucial to optimal outcomes in the interprofessional model. [Level 5]

Several features predict outcome in FSGS, including race (Blacks have worse outcomes), degree of proteinuria, presence of renal insufficiency, histological variant (tip variant had the best outcome and collapsing variant had the worst outcome), degree of IFTA (interstitial fibrosis/tubular atrophy) and response to treatment with patients attaining partial or complete remission having a better prognosis. Also, patients with primary FSGS did worse than those with adaptive/secondary causes of FSGS.[57][53] [Level 5]