Italian experts map the size and care gaps of C3 glomerulopathy
C3 glomerulopathy remains one of nephrology’s least defined rare diseases, and this Italian Delphi exercise tries to put firmer contours around a disorder that has long sat at the edge of renal classification. The condition is driven by dysregulation of the alternative complement pathway, with glomerular injury linked to nephritic factors and genetic variants that stabilize C3 convertase and sustain complement activation. In practical terms, that means chronic immune-mediated injury in a disease where clinicians still lack robust national estimates, standardized endpoints, and clear management pathways.
The panel’s strongest agreement centered on the scale of the problem in Italy. Experts converged on an estimated 60–90 incident cases per year, with 94% agreement, and about 2,700 prevalent cases, with 82% agreement. Those numbers matter because they place C3 glomerulopathy in a category that is rare enough to fragment experience across centers, yet common enough to require organized recognition and follow-up. For a disease previously folded into membranoproliferative glomerulonephritis, that degree of definitional clarity is still relatively new.
One sentence captures the clinical tension: rapid diagnosis remains poor, and specific effective therapies remain scarce.
How the Delphi panel was built and why the process mattered
The consensus was developed through an online iterative modified Delphi study conducted between April 2024 and February 2025. Italian nephrologists with expertise in C3G were invited into a structured voting process that followed ACCORD guidance and used anonymity, iterative feedback, and prespecified thresholds for consensus. Twenty-three clinicians were invited. Two did not respond, and four did not meet eligibility criteria. The final voting panel included 17 Italian experts, all of whom completed both rounds once enrolled.
Eligibility was deliberately strict: participants had to have diagnosed, managed, or treated at least five patients with C3G in the previous five years. That threshold reflects the reality of ultra-rare disease care, where meaningful experience is often concentrated in a small number of centers and clinicians. It also explains why geographic representation was built into the selection process. Italian kidney care is highly regionalized, so the steering group aimed to capture perspectives from different parts of the country rather than a single referral network.
The steering committee itself combined clinical and methodological expertise: two nephrologists experienced in C3G, a biostatistician/epidemiologist, and a Delphi method specialist. Five domains shaped the questionnaire: epidemiology, patient characteristics, disease outcomes, treatment, and mixed issues such as unmet needs, quality of life, and the patient journey. The second round reused results from the first to test whether opinion would stabilize when participants could see how the group had responded.
eGFR stability and proteinuria emerged as the most meaningful response signals
The panel reached consensus on the disease and treatment outcomes that matter most in everyday care. Stabilization of estimated glomerular filtration rate and improvement in proteinuria rose to the top as key endpoints. In a disease caused by ongoing complement-mediated glomerular injury, that pairing is biologically coherent: eGFR reflects preservation of nephron mass, while proteinuria tracks glomerular barrier damage and ongoing inflammatory activity. When both move in the right direction, clinicians see a more credible signal that disease activity may be slowing rather than merely fluctuating.
This is also a reminder of how incomplete the C3G evidence base remains. In many chronic kidney diseases, surrogate endpoints such as eGFR slope and proteinuria reduction are already embedded in routine clinical thinking. In C3G, however, the evidentiary foundation for those endpoints is still relatively thin. The Delphi panel therefore did more than catalog opinion; it helped identify which measures are most likely to be useful when trials are small, follow-up is limited, and hard outcomes like kidney failure are too infrequent for frequent readouts.
The experts also agreed on the main unmet needs. Access to specific and effective treatments and rapid, correct diagnosis were identified as the most important gaps in care. Those two needs are tightly linked. A delayed diagnosis compresses the window for early intervention, while the absence of highly targeted therapy leaves clinicians managing a disease mechanism they can recognize but cannot yet reliably interrupt. In an ultra-rare disease, that combination can turn diagnostic delay into irreversible renal loss.
What the consensus adds to the C3G conversation in Italy
The study does not claim to replace epidemiologic registries or prospective cohorts. It cannot, by design, provide incidence calculations drawn from population surveillance or measure outcomes in treated patients. What it does provide is a disciplined snapshot of what experienced Italian nephrologists believe after years of caring for a disorder that remains undercounted and understandardized. For a disease without national prevalence data in Italy before this work, even a consensus estimate has value as a planning tool for referral pathways, diagnostic awareness, and research prioritization.
The findings also fit the disease biology. C3G is driven by sustained alternative complement activation, and that mechanism naturally points toward the need for targeted inhibition rather than broad immunosuppression alone. Yet the panel’s own priorities show how far clinical practice still has to travel before mechanism-based care becomes routine. The diagnosis still arrives too late in many cases, and the therapeutic options remain too limited to satisfy expert expectations.
The consensus threshold was set at 66.7%, with items categorized by focus level according to agreement and uncertainty. Two rounds were enough to stabilize the panel’s views. All 17 participants completed the second round, which strengthens the internal consistency of the exercise even if it does not solve the disease’s external evidence gaps.
Ultra-rare disease care still depends on expert coordination
C3G sits at an awkward intersection of rarity, pathology, and unmet therapeutic need. Electron microscopy can distinguish the major subtypes, C3 glomerulonephritis and dense deposit disease, but diagnosis still depends on a level of technical and clinical coordination that many patients never encounter early enough. The Italian consensus puts numbers and priorities on paper, yet the most consequential bedside challenge remains the same: identifying the disease before glomerular injury becomes fixed.
The article closes where much of C3G care currently stands: with a better map, but not the destination. Italy now has a first structured estimate of incidence and prevalence from expert consensus, along with a shared view of the endpoints and unmet needs that should guide future study. What remains unresolved is whether those estimates will be confirmed by registry-level data and whether truly effective, disease-specific treatments will become available soon enough to change the trajectory of patients who are still being diagnosed late.