Why until just now? Undiscovered uniqueness of the human glomerulus!

Although many of us who teach courses on renal anatomy and histology, renal physiology, or nephrology assume that the blood is distributed equally to the individual glomerular capillaries as it enters the glomerulus, the elegant anatomic structures responsible for assuring that the glomerular capillaries are perfused at equivalent hydraulic pressures have not received our due attention. It is generally accepted that as the afferent arteriole enters the renal corpuscle, it branches into the various major capillaries that further subdivide into the lobules, and it is only sometimes mentioned that there exists a manifold-type structure that in turn gives rise to the filtering capillaries (1, 5). In rats and dogs, the afferent capillary branches from the manifold are known to filter immediately, and after decades of anatomic studies we have assumed that human glomeruli follow the same pattern while mostly ignoring the complexity of the physical principles involved. However, Neal et al. (7) have reported on a long overdue discovery, namely that the human glomerulus is structurally and functionally unique from that of experimental animals due to the presence of novel anatomic structures that may greatly affect the hemodynamics in the human glomerular vasculature.

Because the glomerular density is less in human kidneys than in experimental animals generally used (6), human afferent arterioles have a higher conductivity than those of rats and dogs, and they supply a disproportionately larger glomerular volume (7). It should not be surprising, although it has not been factually demonstrated, that the human glomerulus would employ an alternative mechanism to distribute flow throughout the glomerular capillary network. Neal et al. (7) investigated this issue in human glomeruli by perfusion fixation at physiological hydrostatic pressures using an oncotically appropriate solution to effectively fill the glomerular capillaries to their functional volume. Although confirmed in fresh tissue, the employment of perfusion fixation with an oncotically balanced solution was necessary for this study because the elastic vascular structures might collapse in the absence of physiological perfusion (10). Multiple imaging modalities were then employed to measure and characterize the architecture of the human glomerular vasculature.

Several novel hemodynamic structures in the human glomerulus were discovered, including a vascular chamber-like manifold arising from the afferent arteriole as it entered the renal corpuscle. Using electron microscopy, Neal et al. (7) determined that the chamber walls are rich in collagen I and III, which, in addition to mesangial support, allow the chamber to be resistant to collapse. This chamber in turn gives rise to approximately seven conduit vessels, each with quite similar diameter. These conduit vessels, also a novel finding, are so named due to their lack of podocyte cell bodies, indicating that they appear structurally phenotypically distinct, which may impinge on their filtering (functional) potential. The conduit vessels course almost directly to the glomerular edge, either on the surface or deep within mesangium, and from these conduit vessels, glomerular capillaries peel off into highly branched lobules. In turn, these capillaries coalesce to form efferent conduit vessels that form an efferent vascular chamber of smaller volume than its afferent analog, which is unsurprising given the smaller perfusion volume of the efferent glomerulus. These anatomic structures were present in juxtamedullary glomeruli as well as subcapsular glomeruli.

In addition to the anatomic study, Neal et al. (7) propose multiple theoretical hemodynamic consequences of these structures. It was found that Murray’s Law was not satisfied when comparing the diameter of the afferent arteriole to the afferent conduit vessels’ diameters. Murray’s Law is a mathematical relationship between the diameters of branching channels that minimizes the work of the blood flow through these bifurcations and is often encountered in cardiovascular anatomy (8). Breaking with Murray’s Law indicates the presence of disturbed flows and that, rather than minimizing the work of blood flow into the renal corpuscle, the capillary diameters force an even distribution of blood flow throughout the glomerular microvascular network. This hypothesis argues that these afferent vascular chambers act like plenum manifolds used in many engineering applications for even distribution of fluid in engines and other machines. Additionally, based on hemodynamic calculations, it became apparent that the afferent conduit vessels were at the highest risk of injury from hoop stress due to their relatively large radius and lack of mesangial support, an important finding in regard to the progression of injury in hypertensive diseases.

Although glomerular dynamics have been described by various mathematical models and principles over the years (1, 3, 4), far fewer studies have investigated the actual physical fluid forces and mechanics of the blood as it flows through and interacts with the walls of the glomerular capillaries. This is due primarily to the complex topology of the glomerular microvascular network in both rats (10) and humans (9), making it highly difficult to study these forces. Some mathematical models have investigated fluid flows through an anatomically accurate glomerular microvascular network (10). However, all of these studies have focused on the rat glomerular anatomy without a clear translation to the human case. The recent anatomic findings by Neal et al. (7) will provide for far more accurate modeling of human glomerular hemodynamics that take into account actual anatomic dimensions and functional capabilities of the human glomerular vasculature.

In addition to contributing crucial data for the development of theoretical models of glomerular hemodynamics, these findings bring to the forefront numerous questions regarding the hemodynamics within the glomerulus. It is possible, with the high velocity of blood from the afferent arteriole and the characteristic sharp bend of the afferent arteriole upon entering the renal corpuscle, that rotational flow and vortices form in the afferent vascular chamber. This rotational flow may play a significant role in the distribution of blood among the conduit vessels and may also cause or contribute to glomerular injury through exertion of oscillatory shear stresses on the chamber walls, especially when the arterial pressures are elevated and/or afferent arteriole autoregulatory capability is compromised. Additionally, it is unclear how hematocrit plays a role in these fluid dynamics and whether these vortices affect hematocrit distribution in the same manner as that of plasma. With recent gains in computational capabilities (2, 4), researchers may employ more computationally intensive mathematical modeling to more deeply investigate these questions to ultimately determine how these fluid dynamics affect glomerular function.

GRANTS

This work was supported by the National Institute of General Medical Sciences IDeA Program (CoBRE P30GM103337) (principal investigator: L. G. Navar) O. Richfield is a graduate student in the Tulane University Bioinnovation Program, supported by NSF IGERT Grant NSF DGE-1144646.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

L.G.N. and O.R. drafted manuscript; L.G.N. and O.R. edited and revised manuscript; L.G.N. approved final version of manuscript.