Implications of the Concept of Nephron Loss on Precision Management of IgA Nephropathy

Introduction

The clinical trajectories of patients with IgA nephropathy often diverge markedly,¹ underscoring the substantial heterogeneity that defines this condition. Such inherent variability has long mandated an individualized therapeutic approach.

The Kidney Disease Improving Global Outcomes (KDIGO)  2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV) marks a major conceptual advance by explicitly incorporating nephron loss (i.e., a reduction in nephron number) into the therapeutic algorithm for IgA nephropathy.² This represents the first time that a quantitative structural parameter, reflecting the kidney's functional reserve, has been formally acknowledged within an international guideline for glomerular disease. By introducing this structural dimension, KDIGO makes explicit within the clinical algorithm what has long been implicitly reflected in eGFR. This approach recognizes that immunologic injury and nephron loss are inseparably linked, emphasizing that preserving nephron integrity is as essential as modulating immune activity.

Beyond Immunopathology: The Structural Dimension of IgA Nephropathy

IgA nephropathy has long been regarded as a glomerular disease driven by persistent immune complex deposition and chronic glomerular inflammation.³ The 2025 KDIGO guideline extends this view by recognizing nephron preservation as a therapeutic priority alongside immune modulation. It distinguishes between two complementary domains of care: strategies specific to IgA nephropathy that target immunological injury, and general CKD strategies that aim to maintain nephron structure and function (Figure 1). This dual emphasis acknowledges that immune modulation alone cannot prevent disease progression if the underlying structural reserve continues to decline. The explicit inclusion of nephron loss in a clinical algorithm formalizes what has been appreciated in kidney pathophysiology for decades: The kidney's ability to withstand injury depends directly on the number of remaining functional nephrons.

Figure 1.

Preventing nephron loss as a common goal of disease-specific and generic therapeutic strategies in IgA nephropathy at risk of kidney function decline. This figure illustrates the complementary therapeutic approaches for kidney protection in IgA nephropathy at risk of progression. The left circle shows disease-specific strategies targeting the underlying immunological mechanisms of nephron injury, including targeted-release budesonide, systemic corticosteroids, immunosuppressive agents, and tonsillectomy. The right circle depicts generic kidney-protective interventions addressing the maladaptive responses to nephron loss, such as lifestyle modification, renin-angiotensin system inhibitors, DEARA, and SGLT2 inhibitors. Both strategies ultimately aim at a common goal: preventing nephron loss, thereby maintaining kidney integrity and preventing progression to kidney failure. DEARA, dual endothelin angiotensin receptor antagonist; RAS, renin-angiotensin system; SGLT2, sodium-glucose cotransporter 2.

Determinants of Nephron Number at Diagnosis in IgA Nephropathy

Recent methodologic advances have enabled estimation of nephron number by combining imaging-derived cortical volume with biopsy-based stereology. Specifically, imaging-derived cortical volume is multiplied by biopsy-based glomerular density to estimate total nephron number.^4–6 Nevertheless, interpretation of the estimated nephron number at diagnosis requires consideration of multiple factors, including congenital nephron endowment, the interval between disease onset and diagnosis, and the patient's age at biopsy. This variability in nephron reserve at diagnosis is not merely background noise but a determinant of disease behavior in IgA nephropathy, shaping both clinical phenotype and therapeutic response.

Nephron number varies several fold among healthy individuals because of genetic and developmental factors.⁷ Such circumstances may likewise be present in patients with IgA nephropathy, potentially contributing to the variability observed at diagnosis. Because the diagnosis of IgA nephropathy relies exclusively on kidney biopsy, differences in the timing of biopsy, often reflecting subclinical disease progression and the extent of glomerulosclerosis, can substantially influence the number of functioning nephrons present at diagnosis.⁸ Aging introduces an additional dimension to the interpretation of nephron dynamics. In healthy individuals, nephron number decreases gradually with age, approximately 6000–7000 per kidney per year.⁴ In IgA nephropathy, however, this decline is markedly accelerated, reflecting the additive effect of immune-mediated injury on the background of physiological senescence.⁹ Therefore, an age-adjusted interpretation of nephron number may provide a more meaningful index of structural vulnerability than absolute counts, distinguishing normal aging from disease-driven attrition.

In IgA nephropathy, these lifelong multifactorial influences collectively determine the number of functioning nephrons at diagnosis. These factors, together with heterogeneity in the rate of nephron loss over time, likely contribute to the marked interindividual variability in progression rates.¹

Interplay of Immune Injury and Mechanical Stress in IgA Nephropathy

IgA-containing immune complex deposition in the mesangium initiates local inflammation and glomerular remodeling, ultimately resulting in glomerulosclerosis, the histologic hallmark of irreversible nephron loss. The consequences of this process depend critically on the baseline nephron reserve and the adaptive capacity of surviving nephrons. Thus, two patients with identical levels of proteinuria may represent biologically distinct states: one with many nephrons sharing a modest workload and another with few nephrons bearing excessive strain. This disproportionate workload increases intraglomerular pressure and drives compensatory hypertrophy, which initially sustain filtration but progressively induce podocyte stress, detachment, and glomerulosclerosis, establishing a self-perpetuating cycle of further nephron loss.¹⁰ In this sense, IgA nephropathy is an immune-mediated disease that unfolds within a nephron population whose size varies across individuals, where immunologic injury and mechanical stress interact to determine long-term kidney outcomes. A key point is that the disappearance of microscopic hematuria does not necessarily indicate cessation of IgA-containing immune complex deposition. IgA nephropathy can relapse, and resolution of hematuria alone does not confirm transition to a nonspecific CKD state or immunologic quiescence. Thus, nephron loss in IgA nephropathy cannot be cleanly separated into IgA nephropathy–specific and general CKD mechanisms, warranting continued vigilance in assessing disease course and management.

Clinical Implications

In biopsy-confirmed IgA nephropathy cohorts, our group and another group have reported that estimated nephron number, as well as derived single-nephron metrics, is independently associated with long-term kidney outcomes.^5,6 These findings indicate that nephron number provides incremental prognostic value beyond traditional clinical and histopathologic factors. Integrating structural reserve into clinical decision making may therefore complement existing risk tools and align with the dual-domain KDIGO concept. From a therapeutic perspective, structural reserve may inform the relative emphasis placed on upstream disease-modifying strategies versus interventions targeting downstream maladaptive responses. When nephron mass is relatively preserved, therapies directed at immunologic drivers of IgA nephropathy may help mitigate subsequent structural injury. By contrast, in the setting of advanced nephron loss, maladaptive hemodynamic and complement-mediated pathways may assume greater relevance and warrant therapeutic attention alongside appropriate immunomodulation.

Future Directions

Integrating quantitative data on nephron number at biopsy into routine evaluation could further refine risk classification beyond conventional clinical and pathologic metrics. For clinical trials, stratification by estimated nephron number may help distinguish treatment effects currently obscured by structural heterogeneity.

At present, these estimates rely on imaging and biopsy data and remain constrained by challenges inherent in nephron mass estimation, including limited biopsy sample size, sampling variability, and heterogeneity of glomerular distribution across cortical depth, yet simpler and less invasive methods are eagerly awaited to enable practical and reproducible assessment in clinical settings. Imaging-only cortical morphometrics may provide a less invasive and repeatable surrogate of structural reserve with potential prognostic value, pending independent validation.

Future technologic advances, including standardized volumetric imaging, reproducible stereological protocols, and validation in diverse populations, are required for methodologic robustness and future clinical translation. Artificial intelligence may further improve efficiency and scalability across centers.

Conclusion

The inclusion of nephron loss in the 2025 KDIGO guideline is more than a change in terminology; it signals a paradigm shift in how IgA nephropathy is conceptualized and managed. Although this conceptual update is transformative, it remains largely inferential rather than evidence based. Accordingly, the guideline's recognition of nephron loss therefore serves not only as a statement of principle but also as an invitation for empirical validation through future research. By embedding nephron preservation at diagnosis within the clinical decision algorithm, the guideline affirms that long-term kidney health depends as much on maintaining structural reserve as on modulating immunologic injury. IgA nephropathy can thus be viewed as an immune-mediated disease unfolding within a finite and progressively declining nephron population. Recognizing and protecting that structural substrate may ultimately become the cornerstone of precision management in IgA nephropathy.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F750.

Author Contributions

Conceptualization: Takaya Sasaki, Nobuo Tsuboi.

Funding acquisition: Nobuo Tsuboi.

Visualization: Nobuo Tsuboi.

Writing – original draft: Nobuo Tsuboi.

Writing – review & editing: Takaya Sasaki.

Funding

N. Tsuboi: JSPS KAKENHI (25K11551).