Challenges in primary focal segmental glomerulosclerosis diagnosis: from the diagnostic algorithm to novel biomarkers

Abstract

Primary or idiopathic focal segmental glomerulosclerosis (FSGS) is a kidney entity that involves the podocytes, leading to heavy proteinuria and in many cases progresses to end-stage renal disease. Idiopathic FSGS has a bad prognosis, as it involves young individuals who, in a considerably high proportion (∼15%), are resistant to corticosteroids and other immunosuppressive treatments as well. Moreover, the disease recurs in 30–50% of patients after kidney transplantation, leading to graft function impairment. It is suspected that this relapsing disease is caused by a circulating factor(s) that would permeabilize the glomerular filtration barrier. However, the exact pathologic mechanism is an unsettled issue. Besides its poor outcome, a major concern of primary FSGS is the complexity to confirm the diagnosis, as it can be confused with other variants or secondary forms of FSGS and also with other glomerular diseases, such as minimal change disease. New efforts to optimize the diagnostic approach are arising to improve knowledge in well-defined primary FSGS cohorts of patients. Follow-up of properly classified primary FSGS patients will allow risk stratification for predicting the response to different treatments. In this review we will focus on the diagnostic algorithm used in idiopathic FSGS both in native kidneys and in disease recurrence after kidney transplantation. We will emphasize those potential confusing factors as well as their detection and prevention. In addition, we will also provide an overview of ongoing studies that recruit large cohorts of glomerulopathy patients (Nephrotic Syndrome Study Network and Cure Glomerulonephropathy, among others) and the experimental studies performed to find novel reliable biomarkers to detect primary FSGS.

Decoding the Mechanism behind the Pathogenesis of the Focal Segmental Glomerulosclerosis

“…Focal segmental glomerulosclerosis (FSGS) is a common glomerular disease, accounting for 40% of adult cases and 20% of children, with the major cause of the steroid-resistant nephrotic syndrome and end-stage renal disease [ 1 ]. The incidence of the disease has gradually increased in recent years and the prognosis is relatively poor, with 50% of patients gradually progressing to end-stage renal disease within 5 to 10 years, accounting for about 20% of dialysis patients [ 2 ]. In 1970, the international children's kidney disease research collaboration formally proposed FSGS as a separate clinicopathological syndrome [ 3 ].…”

A Specific Tubular ApoA-I Distribution Is Associated to FSGS Recurrence after Kidney Transplantation

“…Our data, together with the data presented in Clark’s study [ 6 ], clearly points to the possibility of using ApoA-I staining in the diagnosis process of primary FSGS, both in the native kidney [ 6 ] and in recurrence after kidney transplantation. This discovery can be relevant for the current clinical practice since primary FSGS diagnosis is not straightforward and, further, there are no verified plasmatic biomarkers associated with primary FSGS [ 22 ]. Urinary ApoA-Ib, a biomarker described by us, is highly specific to detect FSGS relapses [ 4 , 5 ], but its use is limited as it cannot be measured in anuric patients.…”

Defining diagnostic trajectories in patients with podocytopathies

“…identifying histologic lesions with specific disease entities) triggered off the concept that podocyte patterns of damage could represent the end result of diverse glomerular noxae with different mechanisms, prognosis and potentially specific therapeutic targets [ 1 , 2 ]. Indeed, podocytopathies encompass a broad spectrum of aetiologies, including genetic defects, permeability factor/s, immunologic dysfunction, vascular endothelial growth factor (VEGF) inhibition, infectious agents, drugs, malignancies and maladaptive responses, with different prevalence across infancy, adolescence and adulthood [ 2 , 6 ] (Fig. 1 ).…”

“…IL-1beta gene) in cultured podocytes. This could possibly be used as a diagnostic tool to distinguish podocytopathy relapse from other diseases [ 6 , 124 ]. Extending the use of SRM to kidney allograft biopsies, together with the implementation of innovative tools for the differential diagnosis of disease recurrence to other causes of graft failure (e.g.…”