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What are we missing in the clinical trials of focal segmental glomerulosclerosis?
Ladan Zand1, Richard J Glassock2, An S De Vriese3
1Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Abstract:
Focal segmental glomerulosclerosis (FSGS) is a lesion and not a disease. This conundrum is the crux of controversies regarding interventions to alter its natural history. In the broadest sense, the lesion can be primary (idiopathic), or secondary to a process originating outside the kidneys or to a genetic mutation. The organ-based target is the podocyte, and the mechanisms responsible for the podocytopathy are numerous and diverse. Recurrence of primary FSGS in renal allografts provides the best evidence for the existence of a circulating factor or factors, the nature of which remains uncertain. The separation of primary from secondary FSGS clinically and pathologically is challenging, but full-blown nephrotic syndrome and diffuse (universal) foot process effacement are strong signals for a primary form of FSGS. It is imperative that clinical trials designed to investigate therapeutic strategies for patients with a lesion of FSGS pay careful attention to the separation of primary from secondary forms of FSGS. This critical review provides a rationale and a process for helping to ensure that this is accomplished, such that clinical trials provide useful information and treatment responsiveness applicable to the primary forms of FSGS.
Insights
Focal segmental glomerulosclerosis (FSGS) is a lesion, not a disease, complicating treatment. Differentiating primary from secondary FSGS is crucial for effective clinical trials and therapies targeting podocytopathy.
Area of Science:
- Nephrology
- Pathology
- Clinical Trials
Background:
- Focal segmental glomerulosclerosis (FSGS) represents a kidney lesion, not a distinct disease, leading to therapeutic controversies.
- FSGS can be primary (idiopathic) or secondary to external factors or genetic mutations, targeting podocytes.
- The existence of a circulating factor in primary FSGS is suggested by its recurrence in renal allografts, though its nature is unknown.
Purpose of the Study:
- To address the diagnostic and therapeutic challenges posed by FSGS as a lesion.
- To provide a framework for distinguishing primary from secondary FSGS in clinical and pathological assessments.
- To guide the design of clinical trials for FSGS, ensuring focus on primary forms for relevant treatment strategies.
Main Methods:
- Review of existing literature on FSGS classification and pathogenesis.
- Analysis of clinical and pathological features differentiating primary and secondary FSGS.
- Discussion of the implications for designing targeted therapeutic interventions.
Main Results:
- Clinical and pathological separation of primary and secondary FSGS is challenging but essential.
- Nephrotic syndrome and diffuse podocyte foot process effacement are indicators of primary FSGS.
- Distinguishing FSGS types is critical for the validity and applicability of clinical trial outcomes.
Conclusions:
- Accurate differentiation between primary and secondary FSGS is imperative for advancing treatment strategies.
- Clinical trials must incorporate methods to ensure patient cohorts represent primary FSGS.
- This approach will yield more meaningful data on therapeutic responsiveness for primary FSGS.