Capillary rarefaction is broadly deﬁned as a reduction in vascular density. Capillary rarefaction in the kidneys is thought to promote hypoxia, impair hemodynamic responses and predispose to chronic kidney disease (CKD) progression and hypertension development. Various mechanisms have been suggested to play a role in the development of capillary rarefaction, including inﬂammation, an altered endothelial-tubular epithelial cell crosstalk, a relative deﬁciency in angiogenic growth factors, loss of pericytes, increased activity of Transforming growth factor -b1 and thrombospondin-1, vitamin D deﬁciency, a link to lymphatic neoangiogenesis and INK4a/ARF (Cylin-dependent kinase inhibitor 2a; CDKN2A). In this review, we summarize the tools available to monitor capillary rarefaction noninvasively in the clinic, the contribution of capillary rarefaction to CKD and hypertension, the known mechanisms of capillary rarefaction, and potential future strategies to attenuate capillary rarefaction and reduce its negative impact. Therapeutic strategies to be explored in more detail include optimization of antihypertensive therapy, vitamin D receptor activators, sirtuin 1 activators, Hypoxia inducible factor prolyl hydroxylase inhibitors and stem cell therapy. Key words: capillary, chronic kidney disease, hypertension, hypoxia-inducible factor, pericyte, rarefaction thought to promote hypoxia, impair hemodynamic responses Introduction and potentially predispose to chronic kidney disease (CKD) pro- Emerging evidence suggests that the kidney has considerable gression and hypertension development . In this review, we capacity to repair and regenerate. However, not all kidney cell summarize the tools available to monitor capillary rarefaction types have the same regenerative capacity. Unlike proximal noninvasively in the clinic, the role of capillary rarefaction in tubule cells, cells of the renal vasculature have a poor capacity the progression of CKD and the development of hypertension, for repair, which may lead to a persistent reduction in vascular the known mechanisms of capillary rarefaction, and potential density following an acute or chronic insult. The reduction in future strategies that attenuate capillary rarefaction and its vascular density is broadly termed ‘capillary rarefaction’ and is negative impact on CKD and hypertension. Received: July 11, 2017. Editorial decision: October 4, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 296 | B. Afsar et al. capillary rarefaction were observed before the onset of overt fib- Noninvasive in vivo assessment of capillary rosis and may be the earliest diagnostic and prognostic sign for rarefaction renal dysfunction. At histological level, CKD progression is asso- In kidney biopsy specimens, capillary rarefaction is assessed ciated with evidence of capillary injury, such as focal widening histologically. However, kidney biopsy is an invasive procedure, of the subendothelial space and higher numbers of endothelial not suitable for future clinical trials assessing the impact of vacuoles and caveolae, reduced numbers of endothelial fenes- therapeutic intervention on capillary rarefaction. Noninvasive trations and increased thickness of the cell soma and lamina quantitative analyses such as nailfold capillaroscopy a com- densa of the capillary basement membrane, and increased per- puted tomography (CT) are alternatives more suitable for meability . repeated assessment in the clinic, the latter marred by radiation and contrast use, but allowing direct quantification of kidney Capillary rarefaction and hypertension vascular rarefaction. Dermal capillaries represent an ‘open’ and representative Capillary rarefaction has also been implicated in the pathogenesis window for the in vivo study of the human microcirculation that of essential hypertension. The pathogenesis of capillary can be directly, repetitively and easily visualized by noninvasive rarefaction in hypertension is unknown, but it may involve a low- techniques such as nailfold capillaroscopy to show capillary rar- grade inflammatory response [18, 19]. In spontaneously hyperten- efaction [2, 3]. However, visual inspection of the capillaries is sive rats, there is rarefaction of arterioles and capillaries in skeletal limited by the depth of penetrance of light photons and pro- muscles . Additionally, the number of nailfold capillaries is vides only a one-dimensional analysis of a three-dimensional lower in patients with untreated essential hypertension than in problem. controls . In the non-renal population of hypertensive and nor- Functional in vivo micro-CT imaging has allowed accurate motensive individuals, capillary density significantly correlated assessment of vessel dysfunction in preclinical CKD . with high-density lipoprotein/low-density lipoprotein ratio, but Furthermore, small-caliber artery rarefaction (interlobular not with serum vascular endothelial growth factor (VEGF) or with artery and more distal branches) can be followed separately high-sensitivity C-reactive protein. An inverse association was from capillary rarefaction . In humans, contrast-enhanced CT found with body mass index, insulin levels and homeostasis angiography has also been used to assess kidney vascular rare- model assessment-insulin resistance . faction by quantifying renal blood volume. Renal blood volume In essential hypertension, capillary rarefaction was associated was lower in the cortex of CKD patients than in controls and with cardiovascular reactivity and exercise-induced rheological closely mirrored capillary rarefaction in the corresponding abnormalities. In all, 61 men with essential hypertension and nephrectomy specimens. In patients with follow-up CT angiog- capillary rarefaction (<80 capillaries per field), and 20 age- and raphy, reduction of renal function was paralleled by a decline in sex-matched controls underwent a strenuous cycle ergometer renal blood volume . test to monitor, during exercise and recovery, the blood pressure profile, the hemorheological pattern and other parameters. Capillary rarefaction and CKD progression Hypertensive men with <72 capillaries per field had an abnormal hemorheological profile before exercise. The physiological The major branches of the renal artery conduct more than 90% response to exercise was observed only in controls and in hyper- of renal blood flow directly to the glomerular capillary bed tensives with >73 capillaries per field. Abnormal responses to located in the kidney cortex . Then, the efferent arteriole exercise worsened as capillaries were more rarefied . branches into peritubular capillaries, which initially supply oxy- Finally, hypertension is a frequent side effect of anti- gen and nutrients to the highly metabolically active proximal angiogenesis therapy targeting VEGF receptor signaling in can- tubular cells. Less than 10% of the arterial blood flow is deliv- cer patients, to the point that development of hypertension ered to the medulla and then to more profound parts of the implies adequate VEGF inhibition and is associated with nephron. As a result, the cortex pO is between 30 and 50 improved tumor responses . In this regard, the receptor tyro- mmHg, while in the medulla and medullary rays it is 10–20 sine kinase sunitinib promoted dermal capillary rarefaction and mmHg, the lowest in the body [7, 8]. Thus, even under physio- this could be one of the mechanisms for hypertension develop- logical circumstances, tubular cells, especially in some parts of ment in these patients . the nephron, are relatively hypoxic. It is meaningful that erythropoietin-producing cells reside in the kidney, where they can sensitively detect hypoxia due to anemia. Under pathologi- Mechanisms of capillary rarefaction cal circumstances, the hypoxic areas may extend even into cor- Recent evidence has identified various mechanisms that con- tex region . In this regard, peritubular capillary rarefaction is tribute to the development of capillary rarefaction (Figure 1). a hallmark of CKD and of the acute kidney injury to CKD transi- These include inflammation, an altered endothelial-tubular epi- tion [10, 11]. Both acute and chronic kidney diseases result in thelial cell crosstalk, a relative deficiency in angiogenic growth capillary rarefaction in preclinical models and humans. Thus, factors, loss of pericytes, increased activity of TGF-b1 and unilateral ureteral obstruction , remnant kidney model , thrombospondin-1, vitamin D deficiency, a link to lymphatic chronic allograft rejection  Col4a3-deficiency  and glo- neoangiogenesis and INK4a/ARF (Cylin-dependent kinase inhib- merulonephritis  are characterized by peritubular capillary itor 2a; CDKN2A). loss associated with interstitial fibrosis and tubular atrophy. Although the sequence of events connecting peritubular capil- lary loss to fibrosis and tubular atrophy is still not completely Inflammation and crosstalk between tubular characterized, hypoxia due to peritubular capillary rarefaction epithelial cells and capillary endothelial cells is thought to be a primary event in CKD and peritubular capil- lary rarefaction has been associated with reduced kidney regen- There is a bidirectional relationship between tubular epithelial erative capacity . The functional micro-CT findings of cells and capillary endothelial cells. Primary tubular epithelial Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Capillary rarefaction and kidney | 297 Hypoxia resulting from peritubular capillary rarefaction pro- motes Hypoxia inducible factor (HIF) activation and the expres- sion of HIF-dependent genes such as VEGF, potentially favoring new capillary formation and thus offsetting capillary rarefac- tion [27, 35]. Thus, VEGF release could be considered a compen- satory response that enhances peritubular capillary density . Indeed, kidney-derived mesenchymal stem cells (MSCs) reduce peritubular capillary rarefaction via secretion of VEGF  and cobalt-induced HIF activation mitigated renal injury in a CKD model . However, in the remnant kidney model in adriamycin-induced CKD in mice, and in human CKD, a sponta- neous increased HIF-1a expression was not associated with increased tubular cell VEGF, suggesting an HIF-VEGF blockade in chronically injured tubules [39, 40]. Indeed, loss of tubular VEGF resulted in substantial reduction of peritubular capillary density . In this regard, a decreased renal expression of VEGF- A is associated with a reduction in peritubular capillary density in diabetic nephropathy . The late stages of the remnant kid- ney model are also characterized by loss of VEGF expression and VEGF administration preserved peritubular capillaries and improved tubulointerstitial injury [13, 42]. In addition, as CKD progresses, shear stress in the peritubular capillary decreases, leading to lower nitric oxide and VEGF availability and facilitat- ing Fas-FasL-mediated endothelial cell apoptosis . However, the biology of VEGF is complex and tightly regulated, since Fig. 1. Factors playing a role in capillary rarefaction. excess VEGF may also be deleterious. Excessive and uncon- trolled VEGF secretion may result in formation of leaky cell injury promotes capillary rarefaction  and capillary rare- and nonfunctional vessels, favoring inflammation, macrophage faction further promotes hypoxic tubular cell injury, thus creat- recruitment and fibrosis [36, 43]. Furthermore, the VEGF120 ing a vicious circle. and VEGF188 upregulated in preclinical CKD are dys-angiogenic There are several examples in which tubular injury precedes isoforms . Thus, the role of VEGF isoforms may have differ- capillary rarefaction. Chronic ureteral obstruction results in tub- ent impact on capillary rarefaction. There are various isoforms ular atrophy, tubulointerstitial fibrosis and peritubular capillary of VEGF such as VEGF121, VEGF165, VEGF189 or VEGF206 . rarefaction . Exposure of proximal tubular cells to plasma However, although these isoforms have been known for a long proteins, as in proteinuric conditions, results in release of period, their specific impact on capillary rarefaction has not inflammatory cytokines from tubular cells, which may drive been studied widely. In one study it was shown that impaired capillary rarefaction . Genetically modified mice have been adipose tissue angiogenesis is associated with overexpression used in conjunction with diphtheria toxin-induced sublethal of antiangiogenic isoform of VEGF-A165b . As also suggested injury specific to proximal tubular cells, thus demonstrating above, recent evidence showed that VEGF164 is proangiogenic, that proximal tubular cell injury is sufficient to elicit a strong whereas VEGF120 and VEGF188 were dys-angiogenic . peritubular inflammatory response with secondary interstitial Apparently, more studies are needed regarding VEGF isoforms fibrosis and peritubular capillary rarefaction . and capillary rarefaction. Additionally, capillary rarefaction decreases tubular blood and oxygen supply, promoting the loss of tubular cell viability Loss of pericytes and tubular atrophy and interstitial fibrosis. Hypoxia causes oxidative stress [29, 30] and increased expression of lethal Specific ablation of pericytes using a genetic model resulted in inflammatory cytokines such as FasL, interleukin-1b and tumor endothelial cell damage within 10 days and subsequent perma- necrosis factor a (TNF-a). Inflammatory factors and cells nent peritubular capillary rarefaction . An increase in the promote endothelial cell injury, including a pro-coagulant and distance between pericytes and endothelial cells, heralding pro-adhesive phenotype, leading to capillary occlusion by detachment of pericytes from capillaries, is an early feature of thrombosis, as well as to endothelial cell apoptosis. Impairment acute kidney injury . Pericyte detachment and loss leads to of blood flow decreases laminar shear stress on endothelial structural instability of blood vessels and to capillary rarefac- cells, resulting in further endothelial apoptosis and tubular tion [48–50]. Furthermore, detached pericytes are key precursors hypoxia as a vicious circle . This is especially striking in of myofibroblasts [51–53]. Pericytes-turned-myofibroblasts con- antibody-mediated rejection following kidney transplantation. tribute to interstitial fibrosis that leads to further capillary rare- During this type of rejection, endothelial cells become pro- faction . Additionally, pericytes serve as a local stem cell thrombotic, causing platelet and leukocyte adhesion, which population that replenish differentiated interstitial and vascular eventually leads to increased cell death . cells lost during aging . The loss of this reparative capacity in the toxic renal microenvironment after acute kidney injury or during CKD progression promotes cellular death of the unstable VEGF endothelium, with subsequent capillary rarefaction [54, 55]. VEGF promotes peritubular capillary formation and prolifera- A number of mediators are involved in the crosstalk between tion [33, 34] and, as discussed above, anticancer drugs targeting endothelial cells and pericytes via discontinuities in the capil- VEGF signaling promote dermal capillary rarefaction . lary basement membrane that helps maintain the normal Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 298 | B. Afsar et al. vessel structure and stability. platelet derived growth factor INK4a/ARF (CDKN2A) (PDGF)-b/PDGF receptor-beta (PDGFR-b) and angiopoietin-Tie2, Deletion of the INK4a/ARFlocus encoding p16 and p19 improved appear to be crucial for pericyte differentiation, recruitment and kidney regeneration and decreased capillary rarefaction after expansion during angiogenesis. Pericytes produce angiopoietin- renal ischemia-reperfusion . p16 and p19 play a role in tubu- 1, a growth factor that stabilizes the microvasculature by acti- lar atrophy and interstitial fibrosis by promoting apoptosis and vating the endothelial Tie2 receptor. After renal injury cell senescence. endothelium-derived angiopoietin-2, an antagonist of angiopoietin-1, increases, favoring capillary leakiness and peri- cyte loss . The endothelium and pericytes also communicate Potential implications for therapy and future via ephrinB2, TIMPs/matrix metalloproteinases and others . research TGF-b, VEGF, Notch and Sphingosine-1-phosphate also regulate Since there is evidence that capillary rarefaction plays an blood vessel stability . In addition, pericyte detachment and important role in CKD progression, tubular atrophy and intersti- myofibroblastic differentiation are associated with secretion of tial fibrosis and it contributes to the development of essential anti-angiogenic factors such as ADAMTS1 (a disintegrin and hypertension, prevention or treatment of capillary rarefaction metalloproteinase with thrombospondin motifs-1), which fur- may potentially halt the progression of CKD and hypertension. ther accelerate capillary regression induced by kallikrein . The potential for intervention includes the use of already avail- Bearing these issues in mind one may think that replace- able drugs (e.g. specific antihypertensive agents) or novel thera- ment of stem cells and pericytes, in particular, may attenuate peutic approaches. renal injury. However, it may not always be the case. For exam- ple, Kim et al. showed that administration of autologous MSCs resulted in rapid aggravation of preexisting renal insufficiency. Antihypertensive medication Renal biopsy findings at dialysis showed severe interstitial fib- An unresolved issue is the distinct effect of different antihyper- rosis and inflammatory cell infiltration. This highlights the tensive medications on capillary rarefaction. Angiotensin-con- potential nephrotoxicity of autologous MSC therapy in CKD verting enzyme inhibitors and angiotensin-1 receptor blockers patients . It was also concluded that regarding the results of may induce angiogenesis and reduce or even reverse microvas- the preliminary data about stem cell therapy, long-term follow- cular rarefaction . In rats with CKD, an angiotensin II antago- up data are not available and there is an absence of consensus nist for 10 weeks regenerated the kidney vasculature that had between therapeutic protocols . previously undergone rarefaction and this was associated with reduced apoptosis and increased endothelial cell proliferation TGF-b1 and thrombospondin-1 . Angiotensin-converting enzyme inhibitors also decreased both peritubular capillary rarefaction and lymphatic neoangio- During hypoxia, TGF-b1 stimulates angiogenesis indirectly by genesisin a rat renal allograft model . However, in observa- inducing VEGF-A expression . However, TGF-b1 directly tional cross-sectional human studies, dermal capillary density causes endothelial cell apoptosis and capillary pruning and this in treated hypertensive individuals has been reported to be negative effect predominates during renal fibrosis . lower than or higher than in control normotensive individuals Thrombospondin-1 could potentiate the fibrotic response [67, 68]. The reason for these seemingly contradictory findings by both activating TGF-b and exerting antiangiogenic actions, is unclear and may depend on the specific antihypertensive thus leading to capillary rarefaction . Inhibition of thrombo- agents, length of untreated or treated hypertension, or other spondin expression suppressed tubulointerstitial fibrosis by factors. Only prospective studies are likely to provide significant promoting VEGF production and restoring peritubular capillary insights. density . Vitamin D receptor activators (VDRA) Vitamin D deficiency The fact that vitamin D deficiency aggravates capillary rarefac- The role of vitamin D deficiency in tubulointerstitial damage tion does not necessarily imply that pharmacological vitamin D and peritubular capillary rarefaction following acute kidney doses of VDRA prevent kidney capillary rarefaction. We found injury induced by ischemia-reperfusion was studied in rats fed no report addressing this. However, in a randomized clinical vitamin D-free or standard diets for 35 days. On Day 28, rats trial, the VDRA paricalcitol slowed the progressive endothelial were randomized into four groups: control, vitamin D deficient, dysfunction of moderate CKD, pointing to potential endothelial bilateral kidney ischemia-reperfusion and a combination of preservation capabilities . Moreover, calcitriol prevented both. Vitamin D deficiency alone led to reduced capillary den- reduction of cardiac capillary density in rats with CKD . sity and it further exacerbated the capillary rarefaction induced by kidney ischemia-reperfusion . Sirtuin 1 activators Link to lymphatic neoangiogenesis A number of sirtuin 1 activators are known, most notably resver- atrol, although the pharmacokinetic properties of resveratrol are Peritubular capillary rarefaction may be associated with simul- suboptimal and additional sirtuin 1 (SIRT1) activators have been taneous proliferation of lymphatic vessels. Cortex and medulla microvascular density was lower in end-stage renal allografts developed to delay aging and age-related diseases . To our knowledge, these have not yet been tested for their preservation than in controls, while new lymphatic vessels were observed in the graft tubulointerstitium, but not in controls [62, 63]. The of kidney capillary density properties. However, sirtuin 1 may drivers of the divergent response of peritubular capillaries (rare- prevent capillary rarefaction. Sirtuin 1 is highly expressed in faction) and lymphatic capillaries (neoangiogenesis) should be endothelial cells and regulates angiogenesis signaling pathways explored in further studies, but there is some evidence for a role via its deacetylase activity . In mice with inactive Sirtuin 1, of angiotensin II . angiogenesis is compromised [73, 74]. Endothelial Sirtuin 1 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/295/4669820 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Capillary rarefaction and kidney | 299 dysfunction causes activation of endothelial Notch1 signaling, point to several potential therapeutic strategies. However, for which leads to enhanced apoptosis and senescence of peritubu- some mechanisms, it is still unclear whether the improvement lar capillary endothelial cells with impaired endothelial prolifera- in capillary rarefaction is a primary event, or an event secon- dary to the improvement in other factors such as tubular cell tion and expanded myofibroblast population, peritubular capillary rarefaction and fibrosis following kidney injury. injury or inflammation. Whether diminishing capillary rarefac- tion slows down the progression of CKD and the development Specifically, Sirtuin 1 mutant mice have more severe renal fibro- of hypertension remains to be defined in clinical trials. sis and renal function impairment than wild-type mice following induction of folic acid nephropathy . Compared with wild- type kidneys, SIRT1 mutant kidneys up-regulate Delta-like 4 Funding (DLL4, a potent Notch1 ligand), Hey1 and Hes1 (Notch target A.O. was supported by Intensificacion ISCIII and RETIC genes) and Notch intracellular domain-1 (NICD1, active form of REDINREN RD 016/0009 FEDER funds. Notch1) in microvascular endothelial cells post-injury. SIRT1 mutant primary kidney microvascular endothelial cells display lower motility and vascular assembly, and faster senescence Conflict of interest statement than wild-type cells . None declared. VEGF References Since VEGF is the major survival factor for capillary endothe- lium, it may attenuate capillary rarefaction. Administration of 1. Basile DP, Friedrich JL, Spahic J et al. Impaired endothelial recombinant VEGF-A121 decreased peritubular capillary rare- proliferation and mesenchymal transition contribute to vas- faction, improved renal function, lowered mortality and cular rarefaction following acute kidney injury. 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Clinical Kidney Journal – Oxford University Press
Published: Nov 28, 2017
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