Total Nephron Number

The human kidney is composed of approximately 1 million nephrons, and total nephron number is considered a fundamental determinant of renal function. Notably, the total number of nephrons varies significantly among individuals, even before the onset of kidney disease.1 This interindividual variation of nephron number can influence renal prognosis, despite similar clinical presentations at the time of specific kidney disease diagnosis.2 Consequently, developing reliable methods for estimating nephron number is of considerable clinical interest because it may enhance the ability to predict disease progression and tailor treatment strategies accordingly. To address this, several studies have attempted to establish methods for estimating nephron number in vivo.1 Denic et al.3 proposed a method that estimates total nephron number by combining contrast-enhanced computed tomography (CT)–based cortical volume measurements with glomerular density obtained from kidney biopsy specimens. This technique allowed for the estimation of nephron number in living individuals and demonstrated that lower nephron counts were associated with adverse kidney outcomes, including faster progression of CKD.4 Importantly, total nephron number is influenced by a complex interplay of congenital endowment, age-related nephron loss, and injury from kidney disease. Thus, it may serve as an integrative marker that captures aspects of renal health not fully explained by conventional clinical parameters such as eGFR, proteinuria, or histopathologic findings.3,5 IgA nephropathy (IgAN) is among the most common forms of chronic GN and is known for its variable clinical course. Approximately 20%–40% of IgAN patients progress to ESKD over a period of 20 years. As new therapeutic strategies have emerged on the basis of the pathophysiology of IgAN, risk stratification has become increasingly important in guiding treatment decisions.6 Although several clinical and pathologic markers, such as eGFR, proteinuria, and the Oxford classification score are currently used to assess disease severity, the potential role of total nephron number in predicting IgAN progression has not been thoroughly explored. Marumoto et al.2 previously reported significant interindividual differences in total nephron number among patients with IgAN who shared similar clinical and pathologic features. Their findings suggested that total nephron number might serve as a fundamental biologic parameter of renal capacity, offering additional insight beyond standard diagnostic metrics. To facilitate such evaluation in patients who cannot undergo contrast-enhanced imaging, the authors developed a modified method using unenhanced CT and stereological analysis of biopsy specimens, adapting the technique originally described by Denic et al.3,7 This approach allows estimation of total nephron number without the need for contrast agents, expanding its applicability in clinical settings. In this issue of Kidney360, Marumoto, et al.5 further investigated the relationship between total nephron number and disease progression in IgAN, using longitudinal follow-up data.5 The study's key finding was that higher nephron numbers were independently associated with a slower annual decline in eGFR, even after adjusting for traditional risk factors, including baseline eGFR, proteinuria, and histologic severity on the basis of the Oxford classification. Specifically, when dividing patients into tertiles according to nephron number, the authors observed a stepwise improvement in the eGFR slope: −1.35, −1.11, and −0.97 ml/min per 1.73 m2/year from the lowest to highest tertiles, respectively. Furthermore, the authors assessed the relationship between total nephron number and initiation of KRT, a definitive renal outcome. Using Cox proportional hazards models adjusted for confounders such as age, eGFR, and histologic findings, they found that each decrease of 100,000 nephrons was associated with a significantly higher risk of initiating KRT (hazard ratio, 1.42; 95% confidence interval, 1.18 to 1.71). These findings suggest that total nephron number may provide additive prognostic value in IgAN, complementing existing clinical and pathologic risk markers. While the study presents compelling data, several limitations must be considered. First, as acknowledged by the authors, the retrospective and single-center nature of the study introduces the potential for selection bias. Second, all participants were Japanese adults with a mean age of 42.7 years. It has been reported that total nephron number can vary significantly by race, with Japanese individuals having fewer nephrons on average compared with other populations.1,8 Thus, the generalizability of these findings to non-Japanese populations, children, and elderly individuals remains uncertain. Another critical consideration is the methodologic limitation of estimating total nephron number on the basis of kidney needle biopsies. Biopsy samples provide only a small portion of the kidney and contain a limited number of glomeruli, raising concerns about sampling bias.9 Although classical methods involving whole-kidney stereology in autopsy specimens yield more accurate total nephron numbers, they are not feasible for use in living patients. Recently, Denic et al.10 refined their nephron number estimation technique by addressing several biases, including glomerular tuft absence, lack of kidney capsule in core biopsies, partial glomeruli, and imaging resolution issues. They also introduced a more accurate tissue shrinkage factor because of formalin fixation and paraffin embedding. This revised approach resulted in total nephron number approximately 27% higher than earlier estimates.10 Nevertheless, even with improved methodologies, nephron number estimation in clinical practice remains less precise than autopsy-based assessments. Continued refinement and validation of these techniques are needed, ideally through multicenter studies with diverse patient populations. Marumoto et al.5 conducted the longitudinal study providing the first evidence of an independent association between total nephron number—estimated by CT imaging and biopsy-based stereology—and renal outcomes in IgAN, after adjusting for conventional risk factors. Total nephron number has long been recognized as a key determinant of renal function, yet its role in the progression of kidney diseases such as IgA nephropathy has remained underexplored. These findings underscore the potential clinical value of total nephron number as a prognostic biomarker and pave the way for future research. Further studies are warranted to establish standardized, accurate, and noninvasive methods for nephron number estimation and to validate its utility across broader populations and various types of kidney disease.