https://orcid.org/0000-0002-4546-404X
Figures
Abstract
Chronic kidney disease (CKD) is commonly associated with vascular injury. To date, efficient tools for assessing microcirculatory changes in non-dialysis CKD patients remain limited. We conducted a retrospectively registered study to employed nailfold capillaroscopy as a non-invasive method to evaluate peripheral microcirculation in CKD. A total of 104 participants were enrolled, including 63 patients with non-dialysis CKD patients (CKD group) and 41 healthy controls (control group). Renal function assessment and nailfold microcirculation examinations were performed for all participants. We analyzed 20 microcirculatory parameters and further explored their associations with serum creatinine (Scr), blood urea nitrogen (BUN), cystatin C, estimated glomerular filtration rate (eGFR), CKD stage, and hemoglobin (Hb) within the CKD group. Results showed that serum creatinine, cystatin C, and CKD stage were independently and positively associated with the capillary number integral, whereas eGFR and hemoglobin were independently and negatively associated with the capillary number integral. In addition, serum creatinine, cystatin C, and CKD stage were independently and negatively associated with the subpapillary venular plexus integral, while eGFR was independently and positively associated with the subpapillary venular plexus integral. In summary, our findings suggest that several key renal function parameters are independently associated with capillary number integral and subpapillary venular plexus integral. These findings indicate that renal dysfunction may be associated with reduced capillary number and impaired subpapillary venous plexus relaxation in patients with non-dialysis CKD.
Citation: Li S, Liu Y, Yan H, Zhou X, Liu Q, Waheed YA, et al. (2026) Assessment of nailfold microcirculation in non-dialysis CKD: Capillaroscopic indicators correlated with renal dysfunction. PLoS One 21(9): e0359419. https://doi.org/10.1371/journal.pone.0359419
Editor: Diego Moriconi, University of Pisa, ITALY
Received: January 25, 2026; Accepted: September 14, 2026; Published: September 30, 2026
Copyright: © 2026 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: This study was supported by funding from the National Natural Science Foundation of China (82470726, 82270731, 82000703); The High-Level Hospital Construction Project of Jiangsu Province(LCZX202403);“Paired Assistance Scientific Research Project by The Affiliated Hospital of Xuzhou Medical University(SHJDBF2024104); The Open Project of Key Laboratory of Higher Education Institutions in Jiangsu Province (XZSYSKF2023019); Xuzhou Medical leading Talent training Project (XWRCHT20210038); the New Technology project of Affiliated Hospital of Xuzhou Medical University (2020301018) “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: CKD, Chronic kidney disease; Scr, serum creatinine; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HTN, hypertension; RAAS, renin-angiotension-aldosterone system
Introduction
The kidneys, as highly vascularized organs, play a crucial role in regulating blood flow. Kidney dysfunction and renal damage for more than three months can be replicated as CKD [1]. The leading causes of CKD include diabetes, hypertension (HTN), primary or secondary glomerulopathies, obstructive nephropathy, medications, and genetic disorders. Among these, HTN and diabetes are of particular concern [2,3]. Most CKD patients have a vascular injury, and traditional risk factors such as hyperlipidemia and hypertension, and non-traditional ones include uremia, disordered mineral-bone disease, inflammation, and oxidative stress participate in vascular lesion [4].
Studies indicate that abnormalities in microcirculatory structure and function can impair organ function and contribute to organ damage, as seen in diabetes, HTN, and kidney disease [5–7]. HTN, uremic toxin, mineral metabolic disorders, and others can also cause vascular injury in CKD patients, resulting in vascular structure changes and dysfunction [8–10]. Microvascular rarefaction has emerged as an early marker for assessing microvascular function and tissue perfusion, including that of the kidneys [11–13]. Skin microcirculation can be deliberated as the representative of the structure and function of systemic microcirculation [14,15]. The finger nailfold is the skin wrinkle covering the root of the nail [16]. Nailfold microcirculation is the circulation pathway consisting of nailfold capillaries, a typical peripheral circulation pathway. To a certain extent, nailfold capillaries can reflect changes of microcirculatory status and can be utilized as a window to evaluate microcirculatory status. To date, nailfold microcirculation research has primarily focused on rheumatic and immune diseases, with limited attention to kidney disease. Previous studies have demonstrated altered nailfold microcirculation in CKD patients undergoing dialysis, with a strong association between these changes and dialysis treatment [17,18].
The present study aimed to explore the relationship between nailfold capillary indexes and renal function, and to develop a novel, non-invasive, and efficient technique for assessing the microcirculatory status of non-dialysis CKD patients.
Methods
Ethical approval
The study was conducted at the Xuzhou Medical University Affiliated Hospital. Our study has been registered at Clinical Trials. gov (NCT03682952) and has been approved by the Clinical Trial Ethics Committee of Xuzhou Medical University Affiliated Hospital (XYFY2018-KL034–01) Helsinki and its later amendments or comparable ethical standards. All participants provided written informed consent prior to participation.
Subjects
We recruited 41 healthy individuals into the control group from Physical Examination Center of the Affiliated Hospital of Xuzhou Medical University. We recruited 68 non-dialysis CKD patients into the CKD group who accepted treatment in the Department of Nephrology of the Affiliated Hospital of Xuzhou Medical University. Following ethics committee approval, data were accessed for research purposes between 01/10/2018 and 31/12/2020. We had strict exclusion and inclusion criteria for CKD patients. Inclusion criteria: non-dialysis CKD patients with strict blood pressure control (systolic blood pressure ≤ 140 mmHg, diastolic blood pressure ≤ 90 mmHg). Exclusion criteria: Combined with other diseases that can affect systemic blood circulation and vascular function, including cardiovascular, cerebrovascular, respiratory, endocrine, rheumatic immune diseases, infection, shock, dehydration, urgent dialysis, and other emergencies. Among the CKD group, 5 CKD patients were excluded from the group. Those are as follows: blood pressure of 2 CKD patients did not reach up the criteria, nailfold microcirculation images of 2 CKD patients were affected by nailfold skin injury, and nailfold microcirculation result of 1 CKD patient was affected by the thickness of nailfold cutin. They were excluded from the CKD group. The remaining 63 CKD patients were included in the CKD group (Fig 1). We collected the medical history of the patients together with basic information. All members accepted hematological examination, including Scr, BUN, cystatin C, Hb. Also, we calculated eGFR according to the CKD-EPI formula. The detailed information regarding CKD etiology and the distribution of CKD stages are now presented in Tables 1 and 2.
We recruited non-dialysis CKD patients who accepted treatment in the Department of Nephrology of the Affiliated Hospital of Xuzhou Medical University, we exculuded the patients who were combined with other diseases that can affect systemic blood circulation and vascular function, including cardiovascular, cerebrovascular, respiratory, endocrine, rheumatic immune diseases, infection, shock, dehydration, urgent dialysis, and other emergencies, 68 non-dialysis CKD patients were included in the CKD group after informed consent, after relevant examinations, 5 patients were excluded, and ultimately 63 non-dialysis CKD patients were included in the CKD group.
Nailfold microcirculation examination
The nailfold microcirculation examination is a rapid, non-invasive, and quantitative technique to evaluate the nailfold capillary status using nailfold capillaroscopy. Before the examination, subjects were required to sit in a room for 15–20 minutes calm, their hands were needed to be warm, and the nailfold was uninjured, ensuring that we could clearly observe capillaries and blood flow. In the examination, pine and cypress oil were dripped on the skin of fourth finger nailfold. We evaluated morphology of capillaries, blood flow, and pericapillary state from the image (Fig 2a) pictured by nailfold capillaroscopy, which obtained 20 parameterized indexes. The 20 parameterized indexes such as clarity integral, capillary number integral, input branch diameter integral, output branch diameter integral, output branch diameter/input branch diameter, capillary top diameter integral, capillary length integral, crossed capillary number integral, abnormal capillary number integral, the velocity of blood flow integral, vascular motility integral, erythrocyte aggregation integral, white blood cell number integral, white microthrombus integral, the color of blood integral, perivascular exudation integral, capillary hemorrhage integral, subpapillary venular plexus integral, nailfold nipple integral and sweat gland catheter integral(Table 1). Our results showed that the image of nailfold microcirculation was clear, the nail fold capillaries were wavy, the capillary shape was normal, and the blood flow was good in the control group. However, with the progression of CKD, the image of nailfold microcirculation was blurred, the number of capillaries was reduced, the blood flow was poor, and in severe cases, the nail fold papillae were flat and the capillary morphology was abnormal in the CKD group (Fig 2b).
(b) In the control group, the image of nailfold microcirculation was clear, the nail fold capillaries were wavy, the capillary shape was normal, and the blood flow was good. In CKD group, with the progression of CKD, the image of nailfold microcirculation is blurred, the number of capillaries is reduced, the blood flow is poor, and in severe cases, the nail fold papillae are flat and the capillary morphology is abnormal.
Table 1 Nailfold microcirculation examination obtained 20 parameterized indexes, if the 20 parameterized indexes were not normal, the corresponding integral increased, resulting in abnormal comprehensive judgment.
Nailfold microcirculation examination analysis methods
We applied the Niu Tian integral method to assess and grade the status of nailfold microcirculation. According to the changes of the microcirculation indexes and weighted integral values, the comprehensive judgment can be divided into 5 degrees. The total integral is greater than or equal to 8, or one of the following changes occured, the comprehensive judgment is severely abnormal: a. the capillary number was reduced to 3 strips/mm, or the capillary number decreased by more than 80%; b. red blood cells accumulated heavily, the blood flow was slow or even completely stopped; c. most white microemboli in the blood flow were caused by non-local factors. d. in one nailfold, the number of capillary hemorrhage was greater than or equal to 7. The total integral is greater than or equal to 4, or two of the following changes occured, the comprehensive judgment is moderately abnormal: a. the capillary number decreased by 40% ~ 60%; b. the input branch diameter reduced by 20% to 60% or widened by 60%; c. the capillary length shortened by 80% or increased by more than 50%; d. the output branch diameter widened by more than 100%; e. perivascular exudation was obvious; f. most capillary blood flow is granular; g. in one nailfold, the number of capillary hemorrhage up to 3–6 strips; h. the color of blood was dark red; i. morphology of capillaries changed in a short time, the number of deformed and crossed capillaries up to 40%−60%; j. dermal papillae of nailfold is flat. The total integral is greater than 2, or two of the following changes occured, the comprehensive judgment is the comprehensive judgment is mildly abnormal: a. the input branch diameter, output branch diameter or capillary top diameter widened or narrowed up to 20%; b. the capillary length increased by 25%−50% or shortened by 20%; c. the number of deformed and crossed capillaries up to 40%; d. the blood flow is grained; e. in one nailfold, the number of capillary hemorrhage or perivascular exudation up to 1–2 strips; f. subpapillary venular plexus is obvious, dilated and thickened; g. the capillary is vague; h. the number of white blood cell is greater than 30 per 15 seconds or there is no white blood cell in blood flow; i. the number of sweat gland catheter in a nailfold is 3–4. The total integral is less than or equal to 2, the nailfold microcirculation is almost normal. The total integral is less than 1, the nailfold microcirculation is normal(Table 2).
Table 2 The comprehensive judgment of nailfold microcirculation examination can be divided into 5 degrees, if the total integral reached a certain level or there were abnormal changes in nail fold microcirculation, it directly affected the comprehensive judgment.
Statistical analysis
SPSS 22.0 statistical software was used to analyze the data. Under the normal distribution, the data were expressed by the mean ± standard deviation (x̄±s). Independent-samples t tests were used to compare the age, systolic pressure, diastolic pressure, cystatin C and Hb between the two groups. The data that do not accord with the normal distribution is expressed by the median (quartile). U tests were used to compare the Scr, BUN, and eGFR. The chi-square test was used to compare sex between the two groups. The correlations between Scr, BUN, eGFR, cystatin C, Hb, CKD stage, and meaningful indexes of nailfold microcirculation were analyzed by Spearman correlation analysis. Furthermore, adjusted multiple linear regression analyses were performed to evaluate the independent associations between renal function parameters and nailfold microcirculatory abnormalities. Separate models were constructed using the capillary number integral and subpapillary venular plexus integral as the dependent variables. Renal function parameters were entered as independent variables, with age, blood pressure, hemoglobin level, and CKD etiology included as covariates to adjust for potential confounding factors. P < 0.05 indicates a statistically significant difference.
Results
General data
We conducted statistical analysis on the sex, age, systolic blood pressure and diastolic blood pressure of CKD group and control group. No significant differences were observed between the two groups for these variables (Table 3, P > 0.05 for all).
Table 3 Sex, age, systolic blood pressure, and diastolic blood pressure were not significantly different between the control group and the CKD group. While Scr, BUN and cystatin C, eGFR and Hb were different between the control group and the CKD group. Scr, BUN and cystatin C of the control group were significantly lower than in CKD group, whereas eGFR and Hb were increased in the control group (P < 0.05).
Hematological indexes
We conducted statistical analysis on the scr, BUN, cystatin C, eGFR and Hb of CKD group and control group. Scr, BUN and cystatin C of the control group were significantly lower than in CKD group, whereas eGFR and Hb were increased in the control group(Table 3, P < 0.001 for all).
Nailfold microcirculation examination
Nailfold microcirculation examination has 20 parameterized indexes, we also conducted statistical analysis on the 20 parameterized indexes of CKD group and control group. Compared with the control group, we found that the capillary number integral, output branch diameter integral, capillary top diameter integral, crossed capillary number integral, the velocity of blood flow integral, erythrocyte aggregation integral, perivascular exudation integral, and capillary hemorrhage integral were increased in the CKD group, whereas the capillary length integral color of blood integral, and subpapillary venular plexus integral were decreased in the CKD group (Table 4, P < 0.05 for all).
*Indexes of nailfold microcirculation examination mentioned above named meaningful indexes.
Table 4 20 parameterized indexes of nailfold microcirculation examination were different between the control group and the CKD group. The capillary number integral, output branch diameter integral, capillary top diameter integral, crossed capillary number integral, the velocity of blood flow integral, erythrocyte aggregation integral, perivascular exudation integral, and capillary hemorrhage integral were increased in the CKD group (P < 0.05), whereas the capillary length integral color of blood integral, and subpapillary venular plexus integral were decreased in the CKD group (P < 0.05).
Correlation between renal function indexes and meaningful indexes in the CKD group
Based on the above results, we conducted statistical analysis on the correlation between renal function indexes and meaningful indexes in the CKD group. Scr, BUN, cystatin C, CKD stage had positive correlation with capillary number intergral(Table 5, P < 0.05 for all) (Fig 3a-d); eGFR had negative correlation with capillary number intergral(Table 5, P < 0.05) (Fig 3e); Scr, cystatin C, CKD stage had negative correlation with subpapillary venular plexus intergral(Table 5, P < 0.05 for all) (Fig 3f-h); eGFR had positive correlation with subpapillary venular plexus intergral(Table 5, P < 0.05) (Fig 3i).
(b) BUN has a positive correlation with the capillary number integral. (c) Cystatin C has a positive correlation with the capillary number integral. (d) The CKD stage has a positive correlation with the capillary number integral. (e) eGFR has a negative correlation with the capillary number integral. (f) Scr has a negative correlation with subpapillary venular plexus integral. (g) Cystatin C has a negative correlation with subpapillary venular plexus integral. (h) The CKD stage has a negative correlation with subpapillary venular plexus integral. (i) eGFR has a positive correlation with subpapillary venular plexus integral. (j) Hb has a negative correlation with the capillary number integral.
Table 5 Hematological indexes have connection with capillary number integral, subpapillary venular plexus integral. Scr, BUN, cystatin C, CKD stage had positive correlation with capillary number intergral (P < 0.05), while Scr, cystatin C, CKD stage had negative correlation with subpapillary venular plexus intergral (P < 0.05); eGFR, Hb had negative correlation with capillary number intergral (P < 0.05), while eGFR had positive correlation with subpapillary venular plexus intergral (P < 0.05).
Correlation between Hb and meaningful indexes of in the CKD group
We conducted statistical analysis on the correlation between Hb and meaningful indexes in the CKD group too. Hb showed a negative correlation with the capillary number integral (Table 3, P < 0.05) (Fig 3j) and positive correlations with the capillary top diameter integral and blood flow color integral (P = 0.047).
Adjusted multivariable linear regression analysis
Adjusted multivariable linear regression analyses were performed to evaluate the independent associations between renal function parameters and nailfold microcirculatory abnormalities after controlling for potential confounding factors. Age, blood pressure, hemoglobin level, and CKD etiology were included as covariates in the regression models. Serum creatinine, cystatin C, and CKD stage remained independently and positively associated with the capillary number intergral, whereas eGFR and hemoglobin remained independently and negatively associated with the capillary number intergral. Similarly, serum creatinine, cystatin C, and CKD stage remained independently and negatively associated with the subpapillary venular plexus intergral, while eGFR remained independently and positively associated with the subpapillary venular plexus intergral (Tables 6 and 7).
Discussion
This study mainly used nailfold capillaroscopy to investigate and evaluate various nailfold microcirculation indexes comprehensively. During the investigation, the present study suggested three findings. First, compared with healthy controls, patients with non-dialysis CKD exhibited significant nailfold microcirculatory abnormalities. Second, after adjustment for major clinical confounders, several key renal function parameters remained independently associated with nailfold microcirculatory abnormalities. Third, these findings support an independent association between renal dysfunction and nailfold microcirculatory impairment in non-dialysis CKD, although the cross-sectional design precludes any inference of causality.
Based on the data, we found that there are differences in most indexes between CKD group and control group. In CKD group, capillary number integral, output branch diameter integral, capillary top diameter integral, crossed capillary number integral, the velocity of blood flow integral, erythrocyte aggregation integral, perivascular exudation integral, and capillary hemorrhage integral were significantly higher than those in the control group. While the length integral, blood color integral, and subpapillary venular plexus integral of the CKD group were significantly lower than those in the control group. It exhibits that the alterations and changes of nailfold microcirculation were significantly different between both groups. These alterations were more severe in non-dialysis CKD patients compared with healthy individuals. Based on these findings, we hypothesize that the alterations and changes of nailfold microcirculation are strongly related to the chronic pathological process of a microvessel, which may be related to vascular damage, internal environment disturbance, hemodynamics changes, blood volume.
Alongside these investigations, we were also able to analyze the correlation between the nailfold microcirculation indexes and renal function indexes of the CKD group. The results showed that Scr, BUN, cystatin C and CKD stage had a positive correlation with capillary number integral. In contrast, the eGFR and Hb had a negative correlation with the capillary number integral. The Scr, cystatin C and CKD stage had a negative correlation with subpapillary venular plexus integral, while eGFR had a positive correlation. So with the deterioration of renal function, the number of nailfold capillaries was decreased. To further account for potential confounding factors, we performed adjusted multivariable linear regression analyses by including age, blood pressure, hemoglobin level, and CKD etiology as covariates. After adjustment, Scr, cystatin C, and CKD stage remained independently and positively associated with the capillary number intergral, whereas eGFR and hemoglobin remained independently and negatively associated with the capillary number intergral. Regarding the subpapillary venular plexus intergral, Scr, cystatin C, and CKD stage remained independently and negatively associated, while eGFR remained independently and positively associated. In contrast, blood urea nitrogen was no longer independently associated with either microcirculatory parameter after adjustment, and hemoglobin was not independently associated with the subpapillary venular plexus intergral These findings suggest that the associations between renal dysfunction and nailfold microcirculatory abnormalities are largely independent of major clinical confounding factors, thereby strengthening the robustness of our findings. Anemia led to the reduction of nailfold capillaries number too. Thang et al. discovered that the characteristic changes in skin capillaries of patients with advanced CKD are density reduction and dysfunction [19]. Furthermore, Edwards-Richards et al. revealed that nailfold capillary density of young CKD patients with hemodialysis was significantly decreased [20]. These were consistent with our finding. We know that the uremic state itself can lead to vascular endothelial growth factor production reduced, further affecting vascular regeneration, and repairment [21]. This may be related to the decrease of nailfold capillaries. Stroke is one of the death causes in CKD patients; in addition to that, CKD also has high cardiovascular morbidity and mortality [22–25]. This also indicated that the vascular condition of CKD patients was poor. Capillary rarefaction means two aspects, including structure and function, the structural aspect implies the reduction of capillary number, the functional aspect refers to the dysfunction of the capillary [11–13]. We also found that the deterioration of renal function caused the diastolic dysfunction of the subpapillary venular plexus. Stewart et al. mentioned that the microvascular results measured by non-invasive laser Doppler flowmetry correlate with coronary artery disease confirmed by coronary angiography [26]. This indicated that non-invasive microvascular examination can serve as a basis for assessing vascular sclerosis. CKD renin-angiotensin system- mediated angiotensin – II not only induces inflammatory factors but also leads to vascular fibrosis [27]. Endothelial cells are the primary barrier between blood and tissue whose structural damage and dysfunction are the beginning of vascular injury [28]. With CKD progression, the inflammation gradually increases, leading to endothelial dysfunction and ultimately causing vascular damage [29]. Oxidative stress can lead to atherosclerosis and cardiovascular time, and was also one of the main factors that damage blood vessels [30]. The above factors were present in the CKD, which may be related to the dysfunction of the subpapillary venular plexus.
We also found that Hb had negative correlation with capillary number intergral, Hb had positive correlation with capillary top diameter intergral and blood flow color intergral. The oxygen supplied to tissues or organs is related to the oxygen-carrying capacity of the blood. Reduced Hb levels lead to decreased blood oxygen content, impairing oxygen delivery to tissues. In end-stage renal disease, anemia significantly impacts blood flow and volume, altering cardiovascular structure and function [31–33]. In hypoxia, Hb can regulate blood flow by releasing vasodilators nitric oxide and adenosine triphosphate [34–36]. Hypoxia plays a vital role in physiological and pathological angiogenesis, which mainly promotes vascular growth factors [37–39]. However, in our study, the anemia caused a reduction of the nailfold capillary numbers in the CKD group.
Strengths and limitation
This study offers several key strengths. First, it utilizes nailfold capillaroscopy—a non-invasive, rapid, and repeatable technique—to assess peripheral microcirculation, making it well-suited for clinical use. Second, the quantitative analysis of 20 microcirculation indexes provides a detailed and objective evaluation of capillary alterations in CKD. Third, several key renal function parameters were found to be associated with selected nailfold microcirculatory indices, providing further evidence of the relationship between renal dysfunction and microcirculatory abnormalities in patients with non-dialysis CKD. Our findings suggest that nailfold capillaroscopy may serve as a promising tool for investigating microvascular abnormalities in patients with non-dialysis CKD. Further studies with larger sample sizes are needed to validate these findings and explore their clinical implications.
Although we adjusted for major clinical confounding factors, residual confounding from unmeasured variables cannot be completely excluded. Because antihypertensive treatment regimens varied among patients and detailed information regarding medication dosage and treatment duration was unavailable, the potential effects of different antihypertensive medications on nailfold microcirculation could not be fully adjusted for. In addition, our sample size was relatively small, which may limit the generalizability of the findings. Future prospective studies with larger cohorts and more comprehensive assessment of medication exposure are warranted to further validate these findings and clarify the clinical significance of nailfold microcirculatory abnormalities in patients with CKD.
Conclusion
To sum up our work, the study found that the nailfold microcirculation of non-dialysis CKD patients was altered and changed compared with healthy individuals. Several key renal function parameters were independently associated with nailfold capillary number and subpapillary venous plexus abnormalities in patients with non-dialysis CKD. These findings support an association between renal dysfunction and nailfold microcirculatory impairment. As a non-invasive, rapid, and quantitative technique, nailfold capillaroscopy may have potential research value for the rapid assessment of microvascular abnormalities in patients with non-dialysis CKD. Further studies with larger sample sizes are warranted to validate these findings.
References
- 1. Stevens PE, Levin A, Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: Improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825–30. pmid:23732715
- 2. Ameer R, et al. Hypertension in chronic kidney disease: What lies behind the scene. Journal of Clinical Hypertension. 2022.
- 3. Hanouneh M, Echouffo Tcheugui JB, Jaar BG. Recent advances in diabetic kidney disease. BMC Med. 2021;19(1):180. pmid:34399760
- 4. Schlieper G, Hess K, Floege J, Marx N. The vulnerable patient with chronic kidney disease. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2016;31(3):382–90.
- 5. Krishnan S, Suarez‑Martinez A, et al. Microvascular dysfunction and kidney disease: Challenges and opportunities? Microcirculation. 2020;28(3):e12661.
- 6. Bouman EJ, Smits MM, van Bommel EJ, Muskiet MHA, Hesp AC, Serné EH, et al. Skin microvascular function and renal hemodynamics in overweight patients with type 2 diabetes: A cross-sectional study. Microcirculation. 2021;28(6):e12700. pmid:33864418
- 7. Rizzoni D, Agabiti-Rosei C, Boari GEM, Muiesan ML, De Ciuceis C. Microcirculation in hypertension: A therapeutic target to prevent cardiovascular disease?. J Clin Med. 2023;12(15):4892. pmid:37568294
- 8. Konukoglu D, Uzun H. Endothelial dysfunction and hypertension. Advances in Experimental Medicine and Biology. 2017;956:511–40.
- 9. Chermiti R, Burtey S, Dou L. Role of Uremic Toxins in Vascular Inflammation Associated with Chronic Kidney Disease. J Clin Med. 2024;13(23):7149. pmid:39685608
- 10. Kaur R, Singh R. Mechanistic insights into CKD‑MBD‑related vascular calcification. Life Sci. 2022;311(Pt B):121148.
- 11. Chade AR. Renal vascular structure and rarefaction. Compr Physiol. 2013;3(2):817–31. pmid:23720331
- 12. Kida Y, Tchao BN, Yamaguchi I. Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease. Pediatr Nephrol. 2014;29(3):333–42. pmid:23475077
- 13. Struijker-Boudier HAJ, Rosei AE, Bruneval P, Camici PG, Christ F, Henrion D, et al. Evaluation of the microcirculation in hypertension and cardiovascular disease. Eur Heart J. 2007;28(23):2834–40. pmid:17942581
- 14. Lazaridis A, Triantafyllou A, Mastrogiannis K, Malliora A, Doumas M, Gkaliagkousi E. Assessing skin microcirculation in patients at cardiovascular risk by using laser speckle contrast imaging. A narrative review. Clin Physiol Funct Imaging. 2023;43(4):211–22. pmid:37020404
- 15. Barstow TJ, Wong BJ. Commentary on viewpoint: the human cutaneous circulation as a model of generalized microvascular function. J Appl Physiol (1985). 2008;105(1):376–89. pmid:18641219
- 16. Scioli MG, Bielli A, Arcuri G, Ferlosio A, Orlandi A. Ageing and microvasculature. Vasc Cell. 2014;6:19. pmid:25243060
- 17. Zoccali C, Mallamaci F, Tripepi G. Microcirculatory function deteriorates with advancing stages of chronic kidney disease independently of arterial stiffness and atherosclerosis. Nephrol Dial Transplant. 2020;35(4):713–20.
- 18. Schumann L, Korten G, Holdt B, Holtz M. Microcirculation of the fingernail fold in CAPD patients: preliminary observations. Perit Dial Int. 1996;16(4):412–6. pmid:8863336
- 19. Thang OH, Serné EH, Grooteman MP, et al. Capillary rarefaction in advanced chronic kidney disease is associated with high phosphorus and bicarbonate levels. Nephrol Dial Transplant. 2011;26(11):3529–36.
- 20. Edwards-Richards A, DeFreitas M, Katsoufis CP, Seeherunvong W, Sasaki N, Freundlich M, et al. Capillary rarefaction: An early marker of microvascular disease in young hemodialysis patients. Clin Kidney J. 2014;7(6):569–74. pmid:25859374
- 21. Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E, et al. Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res. 2000;86(12):1198–202. pmid:10864908
- 22. Seliger SL, Gillen DL, Longstreth WT, Kestenbaum B, Stehman-Breen CO. Elevated risk of stroke among patients with end-stage renal disease. Kidney Int. 2003;64(2):603–9. pmid:12846756
- 23. Grams ME, Yang W, Rebholz CM, Wang X, Porter AC, Inker LA, et al. Risks of adverse events in advanced CKD: The chronic renal insufficiency cohort (CRIC) Study. Am J Kidney Dis. 2017;70(3):337–46. pmid:28366517
- 24. Collins AJ, Li S, Gilbertson DT, Liu J, Chen S-C, Herzog CA. Chronic kidney disease and cardiovascular disease in the Medicare population. Kidney Int Suppl. 2003;(87):S24-31. pmid:14531770
- 25. van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey A, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int. 2011;79(12):1341–52. pmid:21307840
- 26. Stewart J, Kohen A, Brouder D, Rahim F, Adler S, Garrick R, et al. Noninvasive interrogation of microvasculature for signs of endothelial dysfunction in patients with chronic renal failure. Am J Physiol Heart Circ Physiol. 2004;287(6):H2687-96. pmid:15297253
- 27. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. The International Journal of Biochemistry & Cell Biology. 2003;35(6):881–900.
- 28. Xia T, Yu J, Du M, Chen X, Wang C, Li R. Vascular endothelial cell injury: Causes, molecular mechanisms, and treatments. MedComm (2020). 2025;6(2):e70057. pmid:39931738
- 29. Dane MJC, Khairoun M, Lee DH, van den Berg BM, Eskens BJM, Boels MGS, et al. Association of kidney function with changes in the endothelial surface layer. Clin J Am Soc Nephrol. 2014;9(4):698–704. pmid:24458084
- 30. Bolton CH, Downs LG, Victory JG. Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2001;16(6):1189–97.
- 31. Chen L, Xu R, Xu H, Yang Z, Zhang Y, Li Z, et al. Myocardial involvement in end-stage renal disease patients with anemia as assessed by cardiovascular magnetic resonance native T1 mapping: An observational study. Medicine (Baltimore). 2024;103(46):e39724. pmid:39560547
- 32. Io H, Muto M, Sasaki Y, Ishizaka M, Kano T, Fukuzaki H, et al. Impact of anemia treatment for left ventricular hypertrophy using long-acting erythropoietin-stimulating agents from the pre-dialysis to maintenance dialysis period in patients with chronic kidney disease, retrospective longitudinal cohort study. BMC Nephrol. 2023;24(1):74. pmid:36966289
- 33. Seliger SL, Ross DW, Himmelfarb J. Pathophysiological concepts and screening of cardiovascular disease in dialysis patients. Seminars in Dialysis. 2021;34(6):463–72.
- 34. Ellsworth ML. The red blood cell as an oxygen sensor: What is the evidence?. Acta Physiol Scand. 2000;168(4):551–9. pmid:10759592
- 35. Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003;9(12):1498–505. pmid:14595407
- 36. Jia L, Bonaventura C, Bonaventura J, Stamler JS. S-nitrosohaemoglobin: A dynamic activity of blood involved in vascular control. Nature. 1996;380(6571):221–6. pmid:8637569
- 37. Magar A, Morya VK, Kwak MK. A molecular perspective on HIF‑1α and angiogenic stimulator networks and their role in solid tumors: An update. Int J Mol Sci. 2024;25(6):3313.
- 38. Bakleh MZ, Al Haj Zen A. The distinct role of HIF‑1α and HIF‑2α in hypoxia and angiogenesis. Cells. 2025;14(9):673.
- 39. Zimna A, Kurpisz M. Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: Applications and therapies. BioMed Research International. 2015;2015:549412.