Response to: “Age-Related Differences in Anti-Glomerular Basement Membrane Disease: Distinct Biology or Distinct Timing of Presentation?”

The Author Replies:

We thank Upadhyay¹ for the thoughtful commentary on our study² and welcome the opportunity to address the points raised.

The concern regarding the retrospective, survey-based design is well taken and was acknowledged in our limitation. Anti-glomerular basement membrane disease — particularly in children — is sufficiently rare that prospective multicenter data collection presents substantial logistical challenges. Our multicenter European design was conceived to provide contemporary real-world data despite these inherent limitations.

Regarding the use of the Pottel equation we would like to point out that all participating centers in our study were located in European countries, and our cohort therefore consisted predominantly of Caucasian patients. Furthermore, we calculated estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration³ equation for adult patients and the revised Schwartz formula for pediatric patients.⁴ The age-related differences in estimated glomerular filtration rate at diagnosis and at last observation were fully reproduced, supporting the validity of our results irrespective of the estimation method used.

The question raised by the authors whether the marked female predominance in children (80%) reflects a pathophysiologically distinct entity rather than simply an earlier manifestation of adult disease, is of considerable interest. However, the observed pattern—better preserved renal architecture, lower interstitial fibrosis and tubular atrophy, and superior renal recovery in children—might reflect a more acute and florid disease course in the pediatric population, rather than a fundamentally distinct biological entity. A conceptually analogous pattern has been described in other immune-mediated glomerulonephritides, including IgA nephropathy and C3 glomerulopathy, where pediatric presentations tend to be more acutely inflammatory and adults more frequently exhibit chronic, smoldering disease with established irreversible damage at the time of diagnosis.^5,6

The discrepancy between the proportion of children with estimated glomerular filtration rate below 15 ml/min per 1.73 m² (28%) and those requiring dialysis (46%) may also underline a more acute course with fluid and electrolyte disturbances not fully captured by filtration-based metrics alone. On the other hand, pre-existing interstitial fibrosis and tubular atrophy in adults—potentially reflecting subclinical or delayed diagnosis as well as predamaged kidney parenchyma—may limit renal recovery regardless of treatment intensity.

We agree that stratified analyses by antineutrophil cytoplasmic antibodies dual positivity status could yield important mechanistic insights. In our dataset, such subgroup analyses were statistically limited by small case numbers, but remain an important priority for future, larger registries.

In conclusion, we propose that the superior outcomes observed in children with anti-glomerular basement membrane disease are best explained by earlier and more acute presentation with less irreversible renal damage, rather than by a distinct underlying biology. International prospective registries remain essential to further elucidate age-specific disease mechanisms and optimize treatment strategies.