Has the time come to change the treatment criteria for patients with chronic kidney disease? The “hypofiltering nephron” hypothesis

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"Personalized medicine" denotes the future of disease treatment. This implies that etiologically distinct entities, even if they converge on a common disease pathway, may benefit from differentiated treatments. Chronic kidney disease (CKD) is one example of this, as it has long been regarded as a sort of common container in which patients are treated similarly regardless of the underlying disease. In fact, all patients with CKD are treated as if they meet Bricker's "intact nephron" hypothesis [1]. This hypothesis, which was developed in the 1960s, assumes that the residual nephrons compensate for the reduction in the number of functioning nephrons because of kidney injury by increasing the fractional contribution of each nephron to the total excretion rate. This mechanism reduces the decline in total kidney function by causing a single intact nephron to hyperfilter, which occurs by increasing the glomerular blood hydrostatic pressure (↑ΔP) in conjunction with its hypertrophy [2].The current Kidney Disease: Improving Global Outcomes (KDIGO) CKD classification is based solely on estimated glomerular filtration rate (GFR) and albuminuria categories and does not distinguish between different patterns of nephron function [3]. As a result, mechanistically heterogeneous patients are grouped into the same prognostic category despite potentially distinct pathophysiological processes. The hyperfiltering nephron model has significantly influenced our understanding of CKD progression for decades. However, it fails to account for patients who experience a decline in GFR without the development of albuminuria, even in the presence of substantial vascular disease. To address this gap, we define a "hypofiltering nephron" as a structurally viable nephron with preserved filtration surface area but reduced single-nephron GFR (SNGFR) caused by increased preglomerular vascular resistance and hypoperfusion. This model complements, rather than contradicts, Bricker's paradigm and may help clarify a significant and poorly understood group of nonalbuminuric CKD patients.Hyperfiltration models suggest that increased ΔP, seen in conditions such as hypertensionrelated nephropathy, reduced kidney mass nephrectomy, albuminuric diabetes, or other CKD secondary to glomerulonephritis evolution, including obesity, results in mechanical stress on glomerular capillaries [4,5]. This mechanical stress activates complex molecular pathways that facilitate the elongation of capillaries and expand their surface area as a compensatory mechanism, ultimately leading to increased collagen synthesis and fibrosis [6]. Mechanical stress, together with inflammatory and oxidative signals, promotes podocyte injury and reduces podocyte density, compromising the filtration barrier. The resulting increase in the ultrafiltration coefficient (Kf), reflecting a larger effective filtration surface and higher permeability, leads to albuminuria, which further accelerates sclerosis in residual nephrons [7]. This pathogenesis justifies the use of treatments that lower glomerular hyperfiltration and reduce protein loss in the urine, which can slow the progression of kidney disease (see Figure 1).The "hypofiltering nephron" model proposes that vascular and tubulointerstitial dysfunction can occur without glomerular hyperfiltration [8]. A hypofiltering nephron remains structurally intact but is underperfused due to increased resistance before the glomerulus, resulting in a reduced SNGFR despite a preserved filtration surface area. This situation is distinct from (i) nephron loss, where filtration units are completely absent, and (ii) the failure of compensatory hyperfiltration in the remaining nephrons, as described by Bricker. Although these mechanisms may coexist throughout the progression of nonalbuminuric CKD, only the first mechanism truly reflects vascular-driven hypofiltration. A clear distinction between the two models is reported in Table 1.Accelerated vascular aging or systemic atherosclerosis can affect medium-sized intrarenal vessels, including interlobar and arcuate arteries. The increased resistance in these vessels leads to a reduced renal plasma flow and decreased total and single-nephron ultrafiltration coefficients (↓Kf), while the effect on glomerular capillary pressure (ΔP) remains uncertain in humans [9]. This process progresses without the onset of pathological albuminuria due to the absence of glomerular hyperfiltration in residual nephrons and defines "atherosclerotic nephropathy". In the aging as well as hypertensive kidney, nephrosclerosis is the most common finding, consisting of glomerulosclerosis, arteriosclerosis, tubular atrophy, and tubulointerstitial fibrosis [10]. In some instances of aging kidneys, the anticipated residual glomerular hypertrophy and hyperfiltering compensation do not develop to counteract the decrease in GFR as nephrosclerosis progresses [10]. Additionally, in cases of hypertension, arterial remodeling and atherosclerotic vascular dysfunction can lead to secondary chronic kidney ischemia and a further decline in GFR, even when there is no significant renal artery stenosis present [11]. Moreover, diabetic nephropathy, especially when associated with older age or cardiovascular risk factors, can progress without signs of hyperfiltration or albuminuria [12]. In our hypothesis, similar processes could explain the nonalbuminuric GFR decline and the evolution of "atherosclerotic nephropathy" [13], in which nephron hypoperfusion and failure to mount a hyperfiltration response may coexist and participate in nephron loss and CKD progression.Aging, hypertension and diabetes are major risk factors for atherosclerotic cardiovascular disease and share a common background of chronic oxidative stress that reduces nitric oxide bioavailability and disrupts endothelial-dependent vasodilation [14]. The resulting predominance of vasoconstrictor pathways, including endothelin-1 (ET-1) and angiotensin (Ang) II, promotes structural remodeling of the intrarenal vasculature, characterized by medial thickening, hyalinization and increased stiffness [15]. These changes narrow the lumen of interlobar and arcuate arteries, reducing renal plasma flow and glomerular perfusion pressure. In residual nephrons, this manifests as a reduction in SNGFR without increased permeability of the glomerular barrier. Progressive hypoperfusion also contributes to chronic hypoxia, which accelerates tubulointerstitial fibrosis and nephron loss [16].Atherosclerotic nephropathy is characterized by increased resistance in medium-sized preglomerular intrarenal arteries, which reduces renal plasma flow and leads to underperfusion of otherwise nonsclerotic nephrons, resulting in a hypofiltering, typically nonalbuminuric phenotype.Mechanistically, Carrara et al. found that in type 2 diabetes with hypertension and without albuminuria, a higher preglomerular/postglomerular resistance ratio was associated with a greater decline in GFR, indicating the significance of preglomerular vascular resistance and hypoperfusion in disease progression [17]. Clinically, the intrarenal Doppler-derived renal resistive index (RRI) serves as an effective indicator of nephrovascular hemodynamics. It increases with age and correlates with CKD progression and fibrosis, independent of albuminuria [18,19]. In our retrospective cohort of high cardiovascular-risk patients with nonproteinuric CKD, an elevated RRI was linked to an accelerated decline in GFR over five years and increased long-term mortality [13]. Additionally, the most significant decline in GFR was noted when proteinuria was present alongside elevated RRI [20]. These observations support the hypofiltering-nephron concept: increased intrarenal vascular resistance correlates with CKD progression regardless of albuminuria, and its association with proteinuria may indicate a more severe, dual-mechanism pathway (hypoperfusion and barrier injury). Future mechanistic studies are require

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