Clinical Features and Diagnosis

Proteinuria in FSGS is typically nonselective, consisting of both small and large proteins, including albumin. Edema, hypoalbuminemia, and hyperlipidemia are typically present in primary FSGS while less common in other forms. Hypertension is common, and decreased glomerular filtration rate (GFR) is noted in approximately one-third of patients at presentation. Microscopic hematuria may be present.

Various nosologies of FSGS have been presented over the years; all are somewhat arbitrary and depend on the judgments about where to split or combine categories. We have suggested that FSGS can be usefully classified into six forms and that making these distinctions can have clinical relevance ( Table 18.1 ). These forms are primary, adaptive, APOL1-associated, high-penetrance genetic, virus-associated, and medication-associated FSGS. Not listed here are cases that show a pattern of focal and segmental glomerular scarring that can result from a variety of inflammatory, proliferative, thrombotic, and hereditary conditions. There are situations where the proper diagnostic approach is unclear, including the case of an individual with diabetes with both classic changes of diabetic nephropathy and focal and segmental glomerular scars. We avoid the term secondary in this chapter, as it serves chiefly to distinguish primary disease (unknown cause) from other forms with known cause, although we recognize the term may have utility. Upon receiving a diagnosis of FSGS based on kidney biopsy findings, we believe that it is essential for the clinician to determine which form of FSGS his or her patient might have and to carry out additional diagnostic testing for this purpose.

The Six Focal Segmental Glomerulosclerosis Clinical Syndromes

Three FSGS syndromes are most common, with each of these accounting for approximately one third of FSGS in the United States; the distribution will differ in other countries. Distinction among these forms involves collecting clinical history and laboratory data and evaluating kidney biopsy findings ( Table 18.2 ).

Primary FSGS is the form that is least well understood. Many patients have nephrotic proteinuria, often as part of nephrotic syndrome. Primary FSGS is believed to be due to circulating factor(s), with evidence that it may recur following kidney transplant. The causative factor remains elusive, with candidates that include soluble plasminogen activator urokinase-type receptor (suPAR) and cardiotrophin-like cytokine 1.

Adaptive FSGS (perhaps more correctly termed postadaptive FSGS or maladaptive FSGS) arises from an imbalance between glomerular load (i.e., increased glomerular blood flow, arising from diverse factors) and glomerular capacity (i.e., the maximal effective glomerular capillary surface area), resulting in increased glomerular capillary pressures and thus placing podocytes under mechanical stress. Such maladaptive glomerular hemodynamic alterations can arise through (1) a reduction in the number of functioning nephrons (such as after unilateral renal agenesis, surgical ablation, oligomeganephronia, or any advanced primary kidney disease) or (2) mechanisms that place hemodynamic stress on an initially normal nephron population (as in morbid obesity, cyanotic congenital heart disease, and sickle cell anemia). In adaptive FSGS, proteinuria may be nephrotic range or subnephrotic. Plasma albumin concentration may be normal, even in the presence of nephrotic range proteinuria. Renin-angiotensin-aldosterone system antagonism, particularly when coupled with a diuretic and dietary sodium restriction, may have a particularly dramatic effect in reducing proteinuria in adaptive FSGS, and such a response may help confirm the diagnosis.

APOL1 FSGS is due to coding-region variants in the apolipoprotein L1 gene. These variants are termed G1 and G2 and are seen exclusively in individuals of sub-Saharan African descent. While some have advocated calling this entity APOL1-associated FSGS, recent work adds important evidence that the APOL1 kidney risk variants cause glomerular injury. The clinical picture of APOL1 FSGS is diverse and can mimic that of other forms of FSGS, which provides the rationale for having its own category. APOL1 FSGS is a specific form of genetic FSGS; APOL1 FSGS subjects often have a family history of FSGS, but given the requirement for an additional provocative factor for kidney disease to manifest, the inheritance pattern of clinical disease is highly variable and complex among families. Further, the high frequency of APOL1 FSGS (APOL1 is the cause of 72% of FSGS in African descent individuals in the United States and South Africa) sets it apart from other forms of genetic FSGS.

The clinical picture of APOL1 FSGS can mimic that of primary FSGS or adaptive FSGS, and it appears likely that the provocative factors that drive each of these two forms can also elicit perhaps accelerated glomerular scarring in individuals with two APOL1 risk alleles. APOL1 FSGS is also seen with virus-associated FSGS, augmenting risk for FSGS in this setting. Human immunodeficiency (HIV) infection is the most powerful interactor with APOL1 risk alleles, and carriage of a single APOL1 risk allele can associate with risk for FSGS, as shown by data from South Africa. APOL1 FSGS can present as a form of medication-associated FSGS, as interferon increases APOL1 gene expression and induces FSGS in genetically susceptible individuals. Finally, APOL1 FSGS can present in the setting of glomerulonephritides such as in lupus nephritis with collapsing glomerulopathy. At present, therapy for APOL1 FSGS should be based on whether the clinical presentation mimics primary FSGS, adaptive FSGS, virus-associated FSGS, or medication-associated FSGS. For this reason, APOL1 genetic testing is not clinically indicated at this time. In the future, that recommendation may change when precision therapies are developed that target cellular pathways activated by the APOL1 risk alleles.

Three other forms of FSGS are less common. High-penetrance genetic variants, with mendelian or mitochondrial inheritance patterns, manifest FSGS, often with a clinical picture that is neither classic for primary nor adaptive FSGS. There are now over 40 genetic loci implicated in FSGS, and more are identified annually. Several viruses cause FSGS. Uncontrolled HIV infection is associated with HIV-associated nephropathy, a form of collapsing FSGS. Infection with cytomegalovirus is a probable cause of FSGS, and parvovirus B19 and Epstein-Barr virus are possible causes. Certain medications also cause FSGS, including interferons (as mentioned above), anabolic androgenic steroids (likely a form of adaptive FSGS), bisphosphonates, and lithium.