Nephron number variability in Japanese subjects: an autopsy-based study and its implications for chronic kidney disease: clinical scientist award address 2024

Abstract

The number of nephrons is a key determinant of blood pressure regulation and chronic kidney disease (CKD) progression. Although traditional estimates suggest approximately one million nephrons per kidney, modern stereological approaches reveal substantial variability, that is influenced by ethnicity, birth weight, and other early life factors. This review evaluates the century-long evolution of nephron number research, variations across racial and ethnic groups, and explores how factors, such as body size, aging, and lifestyle risks, influence nephron endowment. Techniques for nephron quantification, from design-based stereology to emerging in vivo imaging, are also discussed. Recent research suggests markedly lower nephron counts in Japanese populations, especially among individuals with hypertension or CKD. The autopsy-based investigation in the present study included 27 middle-aged to older Japanese men (9 normotensive, 9 hypertensive, and 9 participants with CKD) who underwent dissector-fractionator stereology to quantify non-sclerosed glomeruli. Normotensive men had an average of approximately 640,399 non-sclerosed glomeruli. In contrast, the hypertensive participants had approximately 392,108 non-sclerosed glomeruli and those with CKD had only 268, 043. These findings underscore the potential influence of limited nephron reserves on hypertension and CKD in Japan. Current evidence suggests that nephron number estimates can guide therapeutic decisions and predict CKD outcomes, while advancements in real-time imaging offer potential avenues for non-invasive nephron assessment. Collectively, these developments highlight the central importance of nephron quantity in nephrology and enable targeted interventions aimed at preserving kidney function and mitigating the CKD burden.

Keywords: Chronic kidney disease; Glomerular density; Hyperfiltration; Hypertension; Nephron number.

Fig. 1

The progression of nephron reduction occurs through three key phases: intrauterine developmental programming, postnatal modification, and exacerbation. During intrauterine development, nephron endowment is influenced by multiple factors including genetic factors, maternal nutrition, birth weight, and environmental exposures. The postnatal phase involves continued modification of nephron structure and function, while the exacerbation phase establishes a self-reinforcing cycle where reduced nephron numbers lead to compensatory hyperfiltration by remaining glomeruli while simultaneously causing regional hypoperfusion. These aberrant hemodynamic patterns, characterized by excessive filtration pressure and inadequate blood flow, synergistically accelerate nephron loss and perpetuate a cycle of chronic kidney disease progression