1. bookVolumen 76 (2022): Edición 1 (January 2022)
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Evidence of retinal arteriolar narrowing in patients with autosomal-dominant polycystic kidney disease

Publicado en línea: 09 Mar 2022
Volumen & Edición: Volumen 76 (2022) - Edición 1 (January 2022)
Páginas: 82 - 90
Recibido: 03 Mar 2021
Aceptado: 17 Nov 2021
Detalles de la revista
License
Formato
Revista
eISSN
1732-2693
Primera edición
20 Dec 2021
Calendario de la edición
1 tiempo por año
Idiomas
Inglés
Abstract Introduction

The aim of this study was to examine retinal vessels in autosomal dominant polycystic kidney disease (ADPKD) patients with normal kidney function and without diabetes mellitus.

Materials and Methods

We enrolled 39 adult individuals with ADPKD and 45 gender- and age-matched individuals as controls. A full ophthalmologic examination, including retinal vessel caliber and reactions to flicker stimulation analysis and grading of hypertensive retinopathy according to the Keith-Wagener classification, was performed.

Results

Multivariable analysis of ADPKD patients and controls, adjusted for age, gender, estimated glomerular filtration rate (e-GFR) and the presence of hypertension, revealed that ADPKD was an independent factor associated with lower arteriovenous ratio (AVR) values (by 0.069 on average, β = −0.50, p < 0.0001). The severity of hypertensive retinopathy according to the Keith-Wagener classification appeared to be more advanced in the ADPKD group than in the controls, despite the lack of vascular abnormalities, such as retinal hemorrhages, exudates, cotton wool spots or papilledema, as well as microaneurysms, which are very characteristic signs of ADPKD in other vascular beds.

Conclusions

Lower AVR values could be a specific pathophysiological ocular manifestation of systemic vasculopathy in the course of ADPKD.

Keywords

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, with a prevalence of 1:400 to 1:1000 in Caucasians. It is caused by mutations in the PKD1 gene located on chromosome 16p13.3 [1] (in approximately 85% cases) as well as in the PKD2 gene on chromosome 4q13-23 [2]. These genes encode the polycystin-1 (PC-1) and polycystin-2 (PC-2) proteins [3]. PC-1 and PC-2 assemble in the plasma membrane to regulate the calcium (Ca2+) entry mechanism. The other biological functions of polycystins (PCs) are still under investigation [4].

The presence of kidney cysts is a characteristic feature in ADPKD patients and is necessary to establish the diagnosis [5]. Cystic pathology in the course of ADPKD is believed to be the result of abnormal cell proliferation and deregulated apoptosis [6]. Cysts may cause abdominal pain, hematuria and infection [7]. The number and diameter of cysts increases with age [8], which leads to progressive renal enlargement and subsequent loss of kidney function [9]. By the age of 60 years, half of ADPKD patients develop chronic end-stage kidney disease (ESRD), requiring kidney replacement therapy [10]. In developed countries, patients with ADPKD constitute 4–10% of all patients undergoing dialysis. In ADPKD, cyst generation and enlargement are associated with transformed vascular architecture: microvasculature tends to develop the regression of larger capillaries with flattened arterioles. It can be the result of reduced expression of the polycystins in the vasculature, where they are important for mechanosensation, fluid-shear stress sensing, signaling, and preserving structural integrity [11, 12, 13]. Vascular endothelial growth factor (VEGF) is an angiogenic cytokine playing pivotal roles in the maintenance of vascular networks; the VEGF family is chronically downregulated in ADPKD. Moreover, many cells in ADPKD aberrantly express VEGF, which in turn stimulates interstitial fibroblasts and endothelial cells, contributing to disease progression [14]. Abnormal kidney function due to polycystic kidney disease may result in systemic osmotic imbalances resulting from hyponatremia, which causes an osmotic gradient across the vascular interface. Interestingly, VEGF acting via VEGF receptor-2 can induce a release of glutamate from Müller cells, a type of retinal glial cell, which serve as support cells for retinal neurons, preventing cellular swelling of Müller glia in hypoosmotic stress [15]. Under prolonged osmotic stress conditions, the local production of reactive oxygen species (ROS) is induced, which is associated with the development of different chronic inflammatory retinal diseases, such as exudative age-related macular degeneration, diabetic retinopathy, uveitis, or atherosclerotic vascular retinal disorders [16, 17, 18].

In ADPKD patients, cardiovascular abnormalities are significantly more common than in the general population, including hypertension (HT), higher left ventricular mass or cardiac valvular defects, and intracranial and extracranial aneurysms [19]. Intracranial aneurysms occur in 4–8% of patients with ADPKD and in 25–50% may cause intracranial bleeding [20]. In ADPKD patients, especially 40–50-year-olds, subarachnoid bleeding occurs 5 times more often than in the general population and causes 5% of deaths among those patients [21]. In the general population, analysis of retinal vessels according to the Keith-Wagener classification [22] can serve as a predictive marker for the occurrence, clinical course, and prognosis of cerebrovascular and cardiovascular diseases. Retinal vessel analysis (RVA) is a modern methodological approach that is used to analyze retinal vessel caliber and vascular function in the retinal microcirculation [23]. The association of retinal vessel caliber abnormalities, such as arteriolar narrowing (AN) and a lower arteriovenous ratio (AVR), with HT and chronic kidney disease has been shown [24, 25, 26]. The width of the arterial vessels at the level of the retina depends on the age and gender, and as a person ages, the arterial vessels gradually narrow [27]. To date, no studies on the advancement of vascular changes have been performed in the retinal microcirculation of ADPKD patients.

The aim of this study was to analyze in detail the retinal vessel quality in ADPKD patients with normal kidney function and without concurrent diabetes mellitus (DM), using standard ophthalmological examination and RVA testing, and to compare it to a non-ADPKD control group. We also wanted to verify the hypothesis that retinal vessels in ADPKD patients may contain microaneurysms, as is are typical in the other vascular beds of ADPKD subjects, and to determine whether ADPKD may be a risk factor for retinal vascular abnormalities, independent of HT and kidney function.

Materials and methods

The study group included 39 adult individuals with ADPKD (15 males, 24 females), while the control group comprised 45 gender- and age-matched individuals (20 males, 25 females).

The following inclusion criteria were applied: the presence of cysts in both kidneys according to Ravine et al. criteria of the ADPKD phenotype [5], ADPKD in family history, serum creatinine concentration ≤1.35 mg/dL, and lack of developed DM. Individuals with a negative family history of ADPKD, an absence of cysts in the kidneys (Ravine's criteria not fulfilled), serum creatinine concentration ≤1.35 mg/dL, and no prior diagnosis of diabetes were enrolled for the control group.

Initially, both cohorts of patients qualified for prospective observation, according to the established inclusion criteria [28], as mentioned above. Since all examinations, including thorough ophthalmological examinations, were performed after 6 years of observation in both groups, at this time some of these initial inclusion criteria had already not been fulfilled. DM was not diagnosed in any patient from the ADPKD group, while it developed in five patients from the control group (DM type 2: four cases, DM type 1: one case; one patient treated exclusively with an anti-diabetic diet, two patients with oral anti-diabetic drugs, one with insulin therapy). The duration of diabetes at the time of the ophthalmological examination was approximately 2 years. Patients who developed DM were not excluded from the study due to its prospective, cohort nature, which requires monitoring of parameter changes in all patients in the study and control groups who met the specified inclusion criteria for the study at the beginning of the observation period. Additionally, the short duration of DM in these patients and its good control (HbA1C; 5.34 ± 0.56%) determine the low probability of developing diabetic retinopathy, the features of which were not found in the ophthalmological examination.

The study adhered to the tenets of the Declaration of Helsinki, and the study protocol was approved by the Local Research Bioethics Committee of the Pomeranian Medical University in Szczecin (decision BN-001/135/06). Each patient provided written informed consent for his/her involvement.

A full medical history review was obtained from the participants. The waist-hip ratio (WHR) was calculated as the proportion of the waist and hip circumferences, and the body mass index (BMI) was calculated as weight/height squared (kg/m2). The fasting venous blood sample of each participant was tested for glucose (the enzymatic-amperometric method (Cobas GLUC 800: 04,404,483,190 with a Super GL system, Diagnostic Systems, Germany)), insulin (microparticle enzyme immunoassay (Ax-Sym MEIA, Abbott Laboratories, Abbot Park, USA)), C-peptide (electrochemiluminescent method (Cobas 6000 system, Roche, Mannheim, Germany)), HbA1c (immunoturbidimetric method (Cobas HbA1c 150: 20753521322)). The measurements of serum creatinine, urea, uric acid, and lipid levels (total cholesterol (TC), LDL-cholesterol, HDL-cholesterol, triacylglycerol (TG)) were performed with a Bio-Autoanalyzer Cobas Integra 800 (Roche, Mannheim, Germany). Homeostatic model assessment (HOMA) indices of insulin action were analyzed. Insulin resistance in patients was expressed with the HOMA-% sensitivity (HOMA%S) formula, and pancreatic beta-cell function was expressed with the HOMA-% beta (HOMA%B) index [29]. The e-GFR was calculated from a single serum creatinine measurement with the chronic kidney disease epidemiology collaboration (CKD-EPI) equation [30].

Standard ophthalmological examination

A full ophthalmologic examination, including pupil reflexes, anterior segment and posterior segment, was performed in both eyes of 39 ADPKD patients and 45 healthy subjects. Visual acuity (VA) was evaluated before dilatation of the pupil. Fundus examination was performed using slit-lamp indirect ophthalmoscopy with noncontact slit-lamp lenses (90D double aspheric Volk lens; Shanghai, China) and normal fundus photography. The presence of the following abnormalities were noted and used to grade retinopathy: arteriolar narrowing or microaneurysms, arteriovenous crossings, retinal hemorrhages, cotton wool spots, exudates, and papilledema. Grading of the retinopathy was performed by an experienced ophthalmologist using the Keith-Wagener classification: Grade I – mild generalized retinal arteriolar narrowing or sclerosis; Grade II – definite focal narrowing and arteriovenous crossings, moderate-to-marked sclerosis of the retinal arterioles and exaggerated arterial light reflex; Grade III – retinal hemorrhages, exudates, and cotton wool spots, sclerosis and spastic lesions of the retinal arterioles; Grade IV – severe grade III and papilledema [22].

Intraocular pressure (IOP) measurement

The IOP was measured using a Pascal dynamic contour tonometer (DCT) (SMT Swiss Microtechnology AG, Port, Switzerland). Before the examination, topical anesthetic was instilled on the eye (Alcaine®; Alcon Laboratories Inc., Fort Worth, TX, USA). Additionally, the ocular pulse amplitude (OPA) and a quality score (Q) were presented with every measurement. The quality score ranges from Q1 to Q5, where Q1 and Q2 correspond to the most reliable results. Hence, only Q1 or Q2 results were included in the statistical analysis.

Accordingly, the actual arterial blood pressure (BP) was directly measured prior to ophthalmic examination in all subjects using a non-invasive blood pressure system with a manual aneroid manometer. The mean result from three measurements obtained with 5-minute resting intervals was calculated. A systolic/diastolic blood pressure ≥ 140/90 mmHg or the use of any anti-hypertensive drug qualified for the diagnosis of HT in the examined subjects. From the obtained BP data, the systemic mean arterial pressure (MAP) was calculated as follows: MAP = diastolic BP + 1/3 (systolic BP − diastolic BP) mmHg. Using the measured IOP and BP data for each examination session, the mean ocular perfusion pressure (MOPP) was analyzed as follows: MOPP = 2/3 × (MAP − IOP).

Retinal vessel analysis

Retinal vessel analysis (RVA) was performed in both eyes of 39 ADPKD patients and 45 healthy subjects. For static retinal vessel analysis (SVA), the FF450 plus fundus camera (Zeiss AG, Jena, Germany) was used, and 30° retinal photographs of each subject were collected and analyzed using VISUALIS and Vessel Map Software (IMEDOS Systems, Ltd, Jena, Germany), as described previously [31]. The standard parameters for this evaluation were as follows: central retinal arteriolar equivalent (CRAE), which relates to the diameter of the central retinal artery; central retinal venular equivalent (CRVE), which relates to the diameter of the central retinal vein; and AVR, which represents the CRAE/CRVE ratio.

The dynamic retinal vessel analysis (DVA) device and study protocol have been described elsewhere [32]. Briefly, in both eyes, mydriasis was induced using 0.5% tropicamide. After 20 minutes, DVA was conducted. The major temporal arterial and venous segments that were approximately 1.5 mm long were evaluated in each eye. The measurements were located 1 to 2 disc diameters from the optic disc. The selection criteria for the arterial and venous segment locations were as follows: no crossing or bifurcation in the measured segment, a curvature not exceeding 30°, a distance from the neighboring vessels of at least one vessel diameter, and sufficient contrast with the surrounding fundus. The standard program for flicker stimulation using DVA consisted of three consecutive optoelectronic flicker light cycles (12.5 Hz flicker frequency and 80-second observation each) and a total examination duration of 352 seconds. The response was measured as the difference between the mean vascular diameter for the last 10 seconds of flicker stimulation and the mean vascular diameter for the 30 seconds immediately preceding this flicker stimulation, divided by the latter value. The response was expressed as the mean of the calculations for the three flicker cycles. Only one artery and one vein were measured in each eye.

Statistical analysis

Since most of the analyzed quantitative parameters presented distributions significantly different from a normal distribution (Shapiro-Wilk test), the non-parametric Mann-Whitney U test was applied to compare values between groups, and the Spearman rank correlation coefficient (Rs) was used to measure the strength of the association between variables. Qualitative parameters were compared between groups with Fisher's exact test. Multivariable analysis of independent factors associated with retinal vessel parameters was performed with the general linear model (GLM). P < 0.05 was considered statistically significant. Statistical analysis was performed with Statistica 13 software.

Results

Both the ADPKD and control groups were comparable in terms of mean age (43.58 ± 11.6 vs 43.71 ± 9.1 years), gender distribution (36.8% vs 44.4% of males), and BMI. HT was observed more frequently in ADPKD patients, with both systolic blood pressure (SBP) and diastolic blood pressure (DBP) values significantly higher. The serum concentrations of creatinine, urea, and uric acid were significantly higher and the e-GFR was significantly lower in the ADPKD group than in the controls (Table 1). Fasting levels of the metabolic parameters (glucose, insulin, C-peptide, total cholesterol, HDL-cholesterol, LDL-cholesterol and triacylglycerol) were not significantly different between groups (Table 1).

Clinical and biochemical characteristics of the ADPKD and control groups. Data are presented as the mean ± SD (median) or number (percentage) of patients with a particular feature

Parameter ADPKD group (n=38) Control group (n=45) p-valuea
Age (years) 43.6 ± 11.6 (44) 43.71 ± 9.11(41) 0.87
Male gender (%) 14 (37%) 20 (44%) 0.51
BMI (kg/m2) 27.3 ± 5.3 (27.1) 25.7 ± 4.3 (25.4) 0.26
Hypertension 22 (67%) 7 (16%) <0.0001
SBP (mmHg) 135 ± 12.9 (132) 126±13.9 (125) 0.02
DBP (mmHg) 89 ± 9.34 (88) 82.6±10.7 (83.0) 0.018
MAP 104 ±9.043 (103.3) 97.04±10.9 (97) 0.006
TC (mg/dL) 219 ± 36.7 (222) 218 ±39.1 (212) 0.91
LDL (mg/dL) 133 ± 28.1 (129) 127 ± 37.4 (117.5) 0.26
HDL (mg/dL) 56.2 ± 11.5 (56) 58.02 ± 13.7 (58) 0.61
TG (mg/dL) 116 ± 56.4 (102) 120 ± 99.2 (97) 0.504
Fasting glucose (mg/dl) 92.6 ± 13.1 (89.5) 95.0 ± 13.6 (94) 0.22
Fasting insulin (μU/ml) 11 ± 10.5 (7.2) 12.1 ± 14.1 (7.9) 0.68
HbA1C (%) 5.2 ± 0.33 (5.2) 5.34 ± 0.56 (5.2) 0.77
HOMA%S 61.8 ± 40.3 (61.83) 69.6 ± 56.9 (53.65) 0.94
HOMA%B 132 ± 74.01 (109.4) 133 ± 115 (96) 0.26
Urea (mg/dL) 37.1 ± 16.9 (33.5) 28.2 ± 8.61 (27.5) 0.0078
Uric acid (mg/dL) 6.34 ± 1.94 (6.2) 5.43 ± 1.39 (5.35) 0.044
Creatinine (mg/dL) 1.084 ± 0.58 (0.97) 0.82 ± 0.12 (0.82) 0.00043
eGFRCKD EPI (mL/min/1.73m2) 81.3 ± 26.3 (84.05) 98.4 ± 11.6 (98.7) 0.002

Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; BMI, body mass index; CKD EPI, Chronic Kidney Disease Epidemiology Collaboration equation; DBP, diastolic blood pressure; e-GFR, estimated glomerular filtration rate; HDL, high density lipoprotein cholesterol; HbA1C, hemoglobin A1C; HOMA%B, homeostasis model assessment % beta; HOMA%S, homeostasis model assessment % sensitivity; LDL, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triacylglycerols. Bold data represent significant differences.

ADPKD group vs the control group; Fisher exact test for qualitative variables; Mann-Whitney test for quantitative variables

Outstandingly, the severity of hypertensive retinopathy appeared to be more advanced in the ADPKD group than in the control group. According to Keith-Wegener classification, retinal arteriolar narrowing (Grade I) and arteriovenous crossing (Grade II) were significantly more common in the ADPKD group in comparison to controls (Table 2). Importantly, in both study groups, we did not find vascular abnormalities such as retinal hemorrhages, exudates, cotton wool spots, sclerosis, spastic lesions of the retinal arterioles, or papilledema, or microaneurysms, which are very characteristic of ADPKD patients in other vascular beds.

Grading of retinopathy in ADPKD patients and control group according to the Keith-Wagener classification

Group ADPKD group (n=73 eyes) Control group (n=90 eyes) p-value*
No retinopathy 32 (44%) 75 (83%) reference
Grade I (AN) 33 (45%) 12 (13%) <0.00001
Grade II (AVC) 8 (11%) 3 (3%) 0.0070

Fisher's exact test in comparison to “No retinopathy” group. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; AN, arteriolar narrowing; AVC, arteriovenous crossing

Table 3 provides the values of ocular together with macro-and micro-retinal vessel parameters obtained in both investigated groups of patients. We observed that the AVR values were considerably lower in ADPKD patients than in controls (p < 0.0001). No significant difference in arterial and venous responses to flicker stimulation was identified between the eyes from the ADPKD and control groups. There was no difference in the values of the IOP and OPA between the investigated groups. We observed that the MOPP values were significantly higher (p < 0.0001) in the ADPKD group than in the controls and correlated positively with SBP and DBP. Interestingly, the OPA measurements were strongly related to the MOPP values. An increase in the MOPP was associated with lower OPA values (Rs = −0.39, p = 0.004 in the ADPKD group and Rs = −0.26, p = 0.02 in the control group).

The values of ocular and macro- and micro-retinal vessel parameters in ADPKD patients and the control group

Parameter ADPKD group (n=76 eyes) Control group (n=90 eyes) p-value*
AVR 0.806 ± 0.064 (0.81) 0.876 ± 0.056 (0.88) < 0.00001*
DVA A [%] 3.32 ± 2.15 (3.3) 3.37 ± 2.00 (3.2) 0.78*
DVA V [%] 3.72 ± 2.18 (3.3) 4.31 ± 2.38 (4) 0.096*
IOP values (mmHg) 17.2 ± 2.27 (17.4) 17.8 ± 0.98 (17.7) 0.35*
OPA (mmHg) 2.71 ± 1.017 (2.5) 2.93 ± 0.97(2.75) 0.18*
MOPP (mmHg) 52.11 ± 6.25 (52.03) 46.77 ± 7.43 (46.77) < 0.0001*

Mann–Whitney test; Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; AVR, arterio-venous ratio; IOP, intraocular pressure; DVA A, dynamic retinal vessel analysis of arteries; DVA V, dynamic retinal vessel of veins; MOPP, mean ocular perfusion pressure; OPA, ocular pulse amplitude. Bold data represent significant differences. Median value in parenthesis.

Significantly, the AVR measurements were dependent on the arterial blood pressure values. An increase in systolic blood pressure was associated with a lower AVR index (Rs = −0.25, p = 0.04 in the ADPKD group and Rs = −0.12, p = 0.29 in the control group). Similarly, diastolic blood pressure results correlated negatively with AVR values (Rs = −0.16, p = 0.20 in the ADPKD group and Rs = −0.25, p = 0.03 in the control group). Accordingly, the severity of hypertensive retinopathy according to the Keith-Wagener classification correlated positively with SBP values (Rs = +0.27, p = 0.03 in the ADPKD group and Rs = +0.27, p = 0.02 in the control group). Remarkably, the severity of hypertensive retinopathy positively correlated with participant age (Rs = +0,27; p = 0.02 in the ADPKD group and Rs = +0.28, p = 0.006 in the control group). A similar correlation was found in the ADPKD group between the arterial and venous responses to flicker stimulation and age (Rs = −0.35, p = 0.003 and Rs = −0.24, p = 0.045, respectively). This finding indicates that older patients have more advanced vascular changes than their younger counterparts.

Importantly, we also observed in univariate analysis that AVR values were lower in men than in women among controls (0.853 ± 0.051 vs 0.892 ± 0.054, p = 0.007) but not among ADPKD patients (0.804 ± 0.068 vs 0.808 ± 0.062, p = 0.84). The multivariate analysis of ADPKD patients and controls revealed that male gender was an independent factor significantly associated with lower AVR values (β = −0.171, p = 0.027). Finally, the multivariable analysis of ADPKD patients and controls (Table 4), adjusted for age, gender, e-GFR and the presence of HT, revealed that ADPKD was an independent factor associated with lower AVR values (by 0.069 on average, β = −0.50, p < 0.0001).

Multivariate analysis including AVR as dependent variable and group (ADPKD patients vs controls), age, gender, eGFR and presence of hypertension as independent variables

Independent variables Coefficient in regression equation Standardized beta p-value*
Group (ADPKD vs controls) −0.069 −0.502 <0.0001
Gender (male vs female) −0.24 −0.171 0.027
Age (years) 0.00056 0.083 0.37
Hypertension 0.0052 0.037 0.7
eGFRCKD EPI (mL/min/1.73m2) 0.0026 0.076 0.44

significance of each independent variable in the general linear model (GLM). Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; AVR, arteriovenous ratio; eGFR: estimated glomerular filtration rate; CKD EPI, Chronic Kidney Disease Epidemiology Collaboration equation

Discussion

Hypertension, arterial vasospasm, and extensive remodeling of small renal arteries and arterioles at early stages of cystic kidney disease result in cardiovascular complications that form the leading cause of death in ADPKD [19]. Therefore, verifiable detection of vascular changes in retinal vessels seems to be an important diagnostic task in subjects suffering from ADPKD. The early detection of vascular retinopathy signs is an important step in the risk stratification of patients with this chronic incurable illness for medical purposes and suitable treatment onset. In the present work, our effort was devoted to analyzing in detail the retinal vessel quality in non-diabetic ADPKD patients using selected, highly objective ophthalmological tests and comparing it to that of non-ADPKD subjects.

The quantitative measurement of different retinal vessel metrics, including the AVR, permits the objective detection of retinal microvascular changes. The AVR quantifies the change in diameter of retinal blood vessels, and it is basically the ratio of arteriole to venule diameter [33, 34]. To our knowledge, this is the first study exploring retinal vessel caliber and function using the RVA method in ADPKD patients with preserved normal kidney function. Here, we showed that ADPKD was an independent factor associated with a lower AVR irrespective of age and the presence of HT. We found no retinal hemorrhages, cotton wool spots, exudates, or papilledema, or microaneurysms in ADPKD patients.

High blood pressure primarily affects the blood vessels in the retina, altering the vessel caliber. Several study groups documented low AVR values in the course of HT [25, 27]. Despite numerous studies quantifying retinal vessel caliber in HT and other cardiovascular diseases, only a few analyzed retinal vascular measurements and AVR in the course of chronic kidney disease (CKD). Accordingly, Liu et al. observed that the retinal arteriole diameter was narrower in patients with CKD and that a low retinal arterial caliber was significantly associated with a lower e-GFR [35]. Baumann et al. [24] documented lower AVR in CKD patients than in controls. The higher age of non-diabetic CKD patients and their higher SBP independently predicted a lower retinal arteriolar diameter [24]. Similarly, in our study, AVR measurements were lower in ADPKD and dependent on the SBP values. Interestingly, we observed that male sex was an independent factor associated with lower AVR values. Likewise, Ponto et al. also observed that men had a lower AVR than women, and the decrease in AVR values with increasing age was steeper in men than in women [27].

It was previously shown in Pkd2+/− mice, which are the orthologous animal model of ADPKD, that the resistance arteries in their bodies present with enhanced vasoconstriction and increased arterial remodeling [36, 37]. Both of these processes may also be responsible for the increased risk of diverse vascular complications reported in ADPKD patients. Importantly, in the retinal microvasculature, we did not find microaneurysms, which are common in other vascular beds in ADPKD patients [20]. We hypothesize that mutations of either the PKD1 or PKD2 gene, encoding polycystins responsible for ADPKD, may participate in the mechanism leading to a decrease in AVR value through abnormalities of intracellular calcium ion (Ca2+) metabolism. Changes in the tone of the retinal arterioles are primarily achieved through changes in [Ca2+] within the smooth muscles of these vessels, which regulate muscle cell contraction and, subsequently, vascular constriction. Vascular smooth muscle cell (VSMC) contraction can be evoked by an increase in cytosolic [Ca2+] owing to transmembrane Ca2+ influx or sarcoplasmic reticulum (SR) Ca2+ release. Ca2+ influx across the plasma membrane can occur via a variety of Ca2+ channels, including voltage-gated, store-operated, and ligand-gated channels [38]. Ca2+ may also be released from intracellular stores via RyR- or IP3-R-gated channels in the SR membrane. Using high-speed confocal Ca2+ imaging, it has been demonstrated that the resulting signals are far from homogeneous, with spontaneous activity in retinal arterioles being characterized by both localized Ca2+ sparks and more global Ca2+ waves and oscillations [39, 40, 41]. PKD1 and PKD2 gene products (PC-1 and PC-2 proteins, respectively) form a subgroup of the transient receptor potential (TRP) superfamily, which consists of a large number of nonselective cation channels with variable degrees of Ca2+ permeability [42]. Recently, Yanda et al. [43] found that several key components of Ca2+ signaling are elevated in mouse PN (PC1 null) vs PH (PC1 containing) cells and proposed that elevated Ca2+ release from the SR is actually the key factor stimulating renal cyst growth. Qi Qian et al. [44], using an in vitro model, found decreased PC-2 expression in pkd2+/− vessels, roughly half of the wild-type level. Consistent with these observations, freshly isolated pkd2+/− VSMCs have significantly altered intracellular Ca2+ homeostasis. The resting [Ca2+]j was approximately 17% lower in pkd2+/− cells than in wild-type cells (p=0.0003), and the total SR Ca2+ stores were significantly decreased (p<0.0001). Pkd2+/− VSMCs have decreased resting [Ca2+] j and capacity of the SR Ca2+ store. PC-2 not only conducts Ca2+ from SR stores but is also intimately related to cytosolic Ca2+ levels, as they the open probability of PC-2. Low levels of Ca2+ (up to 1 μM) increase the open probability of PC-2, whereas high levels (>1 μM) are inhibitory, ultimately giving PC-2 a bell-shaped Ca2+ response [45]. The PC-2/PC-1 complex is important in maintaining proper signaling throughout the cell, thus explaining the requirement for both PCs in maintaining calcium homeostasis and how gene mutation in either polycystin can distinctly affect cell function. Interestingly, in our previous study [46], we found that ADPKD patients with preserved normal kidney function had higher Ca2+ concentrations in serum and erythrocytes than non-ADPKD controls, indicating the potential role of the polycystin complex as a putative membrane-based calcium channel and regulator of calcium homeostasis in different types of cells and in the retinal vasculature. This might also indicate that the natural course of ADPKD leads to disorders of intra- and extracellular calcium metabolism preceding the onset of renal failure. Based on our previous molecular observations in ADPKD patients, the results of our current study may indicate that dysfunction of the PC-1 and PC-2 in the SR membrane and in the cellular membrane, caused by mutation of PKD1 or PKD2 gene, interferes with Ca2+ flow through these membranes, leading to anomalous Ca2+ homeostasis, resulting in arteriole contraction, perhaps also in the human retina. In addition, Coban et al. showed that in patients with advanced stages of ADPKD, the arterial stiffness (AS) development, which contributes to endothelial dysfunction, was increased compared to patients at earlier stages or to healthy individuals [47]. Accordingly, results of Choi et al. suggest that the changes of AS in ADPKD patients may be caused by aberrant Ca2+ homeostasis [48].

On the other hand, inhibition of the endogenous glutamate receptor-dependent signal transduction cascade in the Müller cells of PKD21/703 transgenic rats with mutated polycystin-2 or pharmacological inhibition of purinergic P2Y1 and adenosine A1 receptors in Müller cells of wild-type retinas, results in swelling of these cells under hypo-osmotic conditions. Abrogation of osmotic-related adenosine-triphosphate (ATP) release through the glutamate signaling pathway might be glioprotective; that is, it may avoid cytotoxic Ca2+ overload due to overstimulation of P2Y1 receptors [49], prevent excessive release of different growth factors from the cells [50], or be neuroprotective through the upregulation of NTPDase1 in retinal Müller cells [15]. However, the loss of osmotic ATP release from Müller cells may also contribute to the development of cytotoxic retinal vasculature edema in PKD21/703 rats [15], affecting vessel caliber. Notwithstanding, further research is essential to determine the molecular mechanisms of osmotic ATP release from Müller cells and calcium metabolism in the retinal cells of transgenic animal models with polycystic kidney disease due to PC mutations.

Study limitations

Our study provides interesting results; it does not, however, lack drawbacks. The main limitation of our study is the rather low number of patients in the study group. This is associated with the rare occurrence of ADPKD in the Caucasian population (1:400–1:1000). Another factor contributing to the small size of the study group is the inclusion of patients with normal kidney function in the study – given that kidney failure is an element of ADPKD, this inclusion criterion thus affects the number of patients in the study group.

Conclusion

Overall, we suggest that a lower AVR value found in the retinal microcirculation, independent of HT, could be a specific pathophysiological ocular manifestation of the systemic vasculopathy that develops in the course of ADPKD. Increased awareness of retinal vascular symptoms and signs in ADPKD patients may provide an earlier diagnosis of retinal dysfunction and subsequent treatment before irreversible vision defects develop in the eyes of ADPKD patients.

Multivariate analysis including AVR as dependent variable and group (ADPKD patients vs controls), age, gender, eGFR and presence of hypertension as independent variables

Independent variables Coefficient in regression equation Standardized beta p-value*
Group (ADPKD vs controls) −0.069 −0.502 <0.0001
Gender (male vs female) −0.24 −0.171 0.027
Age (years) 0.00056 0.083 0.37
Hypertension 0.0052 0.037 0.7
eGFRCKD EPI (mL/min/1.73m2) 0.0026 0.076 0.44

The values of ocular and macro- and micro-retinal vessel parameters in ADPKD patients and the control group

Parameter ADPKD group (n=76 eyes) Control group (n=90 eyes) p-value*
AVR 0.806 ± 0.064 (0.81) 0.876 ± 0.056 (0.88) < 0.00001*
DVA A [%] 3.32 ± 2.15 (3.3) 3.37 ± 2.00 (3.2) 0.78*
DVA V [%] 3.72 ± 2.18 (3.3) 4.31 ± 2.38 (4) 0.096*
IOP values (mmHg) 17.2 ± 2.27 (17.4) 17.8 ± 0.98 (17.7) 0.35*
OPA (mmHg) 2.71 ± 1.017 (2.5) 2.93 ± 0.97(2.75) 0.18*
MOPP (mmHg) 52.11 ± 6.25 (52.03) 46.77 ± 7.43 (46.77) < 0.0001*

Grading of retinopathy in ADPKD patients and control group according to the Keith-Wagener classification

Group ADPKD group (n=73 eyes) Control group (n=90 eyes) p-value*
No retinopathy 32 (44%) 75 (83%) reference
Grade I (AN) 33 (45%) 12 (13%) <0.00001
Grade II (AVC) 8 (11%) 3 (3%) 0.0070

Clinical and biochemical characteristics of the ADPKD and control groups. Data are presented as the mean ± SD (median) or number (percentage) of patients with a particular feature

Parameter ADPKD group (n=38) Control group (n=45) p-valuea
Age (years) 43.6 ± 11.6 (44) 43.71 ± 9.11(41) 0.87
Male gender (%) 14 (37%) 20 (44%) 0.51
BMI (kg/m2) 27.3 ± 5.3 (27.1) 25.7 ± 4.3 (25.4) 0.26
Hypertension 22 (67%) 7 (16%) <0.0001
SBP (mmHg) 135 ± 12.9 (132) 126±13.9 (125) 0.02
DBP (mmHg) 89 ± 9.34 (88) 82.6±10.7 (83.0) 0.018
MAP 104 ±9.043 (103.3) 97.04±10.9 (97) 0.006
TC (mg/dL) 219 ± 36.7 (222) 218 ±39.1 (212) 0.91
LDL (mg/dL) 133 ± 28.1 (129) 127 ± 37.4 (117.5) 0.26
HDL (mg/dL) 56.2 ± 11.5 (56) 58.02 ± 13.7 (58) 0.61
TG (mg/dL) 116 ± 56.4 (102) 120 ± 99.2 (97) 0.504
Fasting glucose (mg/dl) 92.6 ± 13.1 (89.5) 95.0 ± 13.6 (94) 0.22
Fasting insulin (μU/ml) 11 ± 10.5 (7.2) 12.1 ± 14.1 (7.9) 0.68
HbA1C (%) 5.2 ± 0.33 (5.2) 5.34 ± 0.56 (5.2) 0.77
HOMA%S 61.8 ± 40.3 (61.83) 69.6 ± 56.9 (53.65) 0.94
HOMA%B 132 ± 74.01 (109.4) 133 ± 115 (96) 0.26
Urea (mg/dL) 37.1 ± 16.9 (33.5) 28.2 ± 8.61 (27.5) 0.0078
Uric acid (mg/dL) 6.34 ± 1.94 (6.2) 5.43 ± 1.39 (5.35) 0.044
Creatinine (mg/dL) 1.084 ± 0.58 (0.97) 0.82 ± 0.12 (0.82) 0.00043
eGFRCKD EPI (mL/min/1.73m2) 81.3 ± 26.3 (84.05) 98.4 ± 11.6 (98.7) 0.002

Baumann M, Schwarz S, Kotliar K, von Eynatten M, Trucksaess AS, Burkhardt K, Lutz J, Heemann U, Lanzl I. Non-diabetic chronic kidney disease influences retinal microvasculature. Kidney Blood Press Res. 2009; 32: 428–433. BaumannM SchwarzS KotliarK von EynattenM TrucksaessAS BurkhardtK LutzJ HeemannU LanzlI Non-diabetic chronic kidney disease influences retinal microvasculature Kidney Blood Press Res 2009 32 428 433 10.1159/00026465019996611 Search in Google Scholar

Brill AL, Ehrlich BE. Polycystin 2: A calcium channel, channel partner, and regulator of calcium homeostasis in ADPKD. Cell Signal. 2020; 66: 109490. BrillAL EhrlichBE Polycystin 2: A calcium channel, channel partner, and regulator of calcium homeostasis in ADPKD Cell Signal 2020 66 109490 10.1016/j.cellsig.2019.109490693542231805375 Search in Google Scholar

Cai Y, Anyatonwu G, Okuhara D, Lee KB, Yu Z, Onoe T, Mei CL, Qian Q, Geng L, Wiztgall R, et al. Calcium dependence of polycystin-2 channel activity is modulated by phosphorylation at Ser812. J Biol Chem. 2004; 279: 19987–19995. CaiY AnyatonwuG OkuharaD LeeKB YuZ OnoeT MeiCL QianQ GengL WiztgallR Calcium dependence of polycystin-2 channel activity is modulated by phosphorylation at Ser812 J Biol Chem 2004 279 19987 19995 10.1074/jbc.M31203120014742446 Search in Google Scholar

Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarten DA, Kenney PJ, King BF Jr, Glockner JF, et al. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int. 2003; 64: 1035–1045. ChapmanAB Guay-WoodfordLM GranthamJJ TorresVE BaeKT BaumgartenDA KenneyPJ KingBFJr GlocknerJF Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort Kidney Int 2003 64 1035 1045 10.1046/j.1523-1755.2003.00185.x12911554 Search in Google Scholar

Choi HM, Kwon YE, Kim S, Oh DJ. Changes in FGF-23, neutrophil/platelet activation markers, and angiogenin in advanced chronic kidney disease and their effect on arterial stiffness. Kidney Blood Press Res. 2019; 44: 1166–1178. ChoiHM KwonYE KimS OhDJ Changes in FGF-23, neutrophil/platelet activation markers, and angiogenin in advanced chronic kidney disease and their effect on arterial stiffness Kidney Blood Press Res 2019 44 1166 1178 10.1159/00050252631553973 Search in Google Scholar

Coban M, Inci A, Yılmaz U, Asilturk E. The association of fibroblast growth factor 23 with arterial stiffness and atherosclerosis in patients with autosomal dominant polycystic kidney disease. Kidney Blood Press Res. 2018; 43: 1160–1173. CobanM InciA YılmazU AsilturkE The association of fibroblast growth factor 23 with arterial stiffness and atherosclerosis in patients with autosomal dominant polycystic kidney disease Kidney Blood Press Res 2018 43 1160 1173 10.1159/00049224430064143 Search in Google Scholar

Curtis TM, Scholfield C, McGeown DJ. Calcium signaling in ocular arterioles. Crit Rev Eukaryot Gene Expr. 2007; 17: 1–12. CurtisTM ScholfieldC McGeownDJ Calcium signaling in ocular arterioles Crit Rev Eukaryot Gene Expr 2007 17 1 12 10.1615/CritRevEukarGeneExpr.v17.i1.1017341180 Search in Google Scholar

Ecder T. Cardiovascular complications in autosomal dominant polycystic kidney disease. Curr Hypertens Rev. 2013; 9: 2–11. EcderT Cardiovascular complications in autosomal dominant polycystic kidney disease Curr Hypertens Rev 2013 9 2 11 10.2174/157340211130901000223971638 Search in Google Scholar

Fu Z, Sun Y, Cakir B, Tomita Y, Huang S, Wang Z, Liu CH, Cho SS, Britton W, Kern TS, et al. Targeting neurovascular interaction in retinal disorders. Int J Mol Sci. 2020; 21: 1503. FuZ SunY CakirB TomitaY HuangS WangZ LiuCH ChoSS BrittonW KernTS Targeting neurovascular interaction in retinal disorders Int J Mol Sci 2020 21 1503 10.3390/ijms21041503707308132098361 Search in Google Scholar

Gieteling EW, Rinkel GJ. Characteristics of intracranial aneurysms and subarachnoid haemorrhage in patients with polycystic kidney disease. J Neurol. 2003; 250: 418–423. GietelingEW RinkelGJ Characteristics of intracranial aneurysms and subarachnoid haemorrhage in patients with polycystic kidney disease J Neurol 2003 250 418 423 10.1007/s00415-003-0997-012700905 Search in Google Scholar

Hanaoka K, Qian F, Boletta A, Bhunia AK, Piontek K, Tsiokas L, Sukhatme VP, Guggino WB, Germino GG. Co-assembly of polycystin-1 and −2 produces unique cation-permeable currents. Nature. 2000; 408: 990–994. HanaokaK QianF BolettaA BhuniaAK PiontekK TsiokasL SukhatmeVP GugginoWB GerminoGG Co-assembly of polycystin-1 and −2 produces unique cation-permeable currents Nature 2000 408 990 994 10.1038/35050128 Search in Google Scholar

Ikram MK, Ong YT, Cheung CY, Wong TY. Retinal vascular caliber measurements: Clinical significance, current knowledge and future perspectives. Ophthalmologica. 2013; 229: 125–136. IkramMK OngYT CheungCY WongTY Retinal vascular caliber measurements: Clinical significance, current knowledge and future perspectives Ophthalmologica 2013 229 125 136 10.1159/000342158 Search in Google Scholar

Joly D, Hummel A, Ruello A, Knebelmann B. Ciliary function of polycystins: A new model for cystogenesis. Nephrol Dial Transplant. 2003; 18: 1689–1692. JolyD HummelA RuelloA KnebelmannB Ciliary function of polycystins: A new model for cystogenesis Nephrol Dial Transplant 2003 18 1689 1692 10.1093/ndt/gfg256 Search in Google Scholar

Kaarniranta K, Kajdanek J, Morawiec J, Pawlowska E, Blasiak J. PGC-1α protects RPE cells of the aging retina against oxidative stress-induced degeneration through the regulation of senescence and mitochondrial quality control. The significance for AMD pathogenesis. Int J Mol Sci. 2018; 19: 2317. KaarnirantaK KajdanekJ MorawiecJ PawlowskaE BlasiakJ PGC-1α protects RPE cells of the aging retina against oxidative stress-induced degeneration through the regulation of senescence and mitochondrial quality control. The significance for AMD pathogenesis Int J Mol Sci 2018 19 2317 10.3390/ijms19082317 Search in Google Scholar

Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: Their course and prognosis. Am J Med Sci. 1974; 268: 336–345. KeithNM WagenerHP BarkerNW Some different types of essential hypertension: Their course and prognosis Am J Med Sci 1974 268 336 345 10.1097/00000441-193903000-00006 Search in Google Scholar

Kim K, Drummond I, Ibraghimov-Beskrovnaya O, Klinger K, Arnaout MA. Polycystin 1 is required for the structural integrity of blood vessels. Proc Natl Acad Sci USA. 2000; 97: 1731–1736. KimK DrummondI Ibraghimov-BeskrovnayaO KlingerK ArnaoutMA Polycystin 1 is required for the structural integrity of blood vessels Proc Natl Acad Sci USA 2000 97 1731 1736 10.1073/pnas.040550097 Search in Google Scholar

Kimberling WJ, Kumar S, Gabow PA, Kenyon JB, Connolly CJ, Somlo S Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13-q23. Genomics. 1993; 18: 467–472. KimberlingWJ KumarS GabowPA KenyonJB ConnollyCJ SomloS Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13-q23 Genomics 1993 18 467 472 10.1016/S0888-7543(11)80001-7 Search in Google Scholar

King BF, Torres VE, Brummer ME, Chapman AB, Bae KT, Glockner JF, Arya K, Felmlee JP, Grantham JJ, Guay-Woodford LM, et al. Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease. Kidney Int. 2003; 64: 2214–2221. KingBF TorresVE BrummerME ChapmanAB BaeKT GlocknerJF AryaK FelmleeJP GranthamJJ Guay-WoodfordLM Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease Kidney Int 2003 64 2214 2221 10.1046/j.1523-1755.2003.00326.x14633145 Search in Google Scholar

Kur J, McGahon MK, Fernández JA, Scholfield CN, McGeown JG, Curtis TM. Role of ion channels and subcellular Ca2+ signaling in arachidonic acid-induced dilation of pressurized retinal arterioles. Invest Ophthalmol Vis Sci. 2014; 55: 2893–2902. KurJ McGahonMK FernándezJA ScholfieldCN McGeownJG CurtisTM Role of ion channels and subcellular Ca2+ signaling in arachidonic acid-induced dilation of pressurized retinal arterioles Invest Ophthalmol Vis Sci 2014 55 2893 2902 10.1167/iovs.13-1351124699382 Search in Google Scholar

Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150: 604–612. LeveyAS StevensLA SchmidCH ZhangYL CastroAF3rd FeldmanHI KusekJW EggersP Van LenteF GreeneT CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) A new equation to estimate glomerular filtration rate Ann Intern Med 2009 150 604 612 10.7326/0003-4819-150-9-200905050-00006276356419414839 Search in Google Scholar

Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care. 1998; 21: 2191–2192. LevyJC MatthewsDR HermansMP Correct homeostasis model assessment (HOMA) evaluation uses the computer program Diabetes Care 1998 21 2191 2192 10.2337/diacare.21.12.21919839117 Search in Google Scholar

Li Y, Holtzclaw LA, Russell JT. Müller cell Ca2+ waves evoked by purinergic receptor agonists in slices of rat retina. J Neurophysiol. 2001; 85: 986–994. LiY HoltzclawLA RussellJT Müller cell Ca2+ waves evoked by purinergic receptor agonists in slices of rat retina J Neurophysiol 2001 85 986 994 10.1152/jn.2001.85.2.98611160528 Search in Google Scholar

Liew G, Wang JJ, Mitchell P, Wong TY. Retinal vascular imaging: A new tool in microvascular disease research. Circ Cardiovasc Imaging. 2008; 1: 156–161. LiewG WangJJ MitchellP WongTY Retinal vascular imaging: A new tool in microvascular disease research Circ Cardiovasc Imaging 2008 1 156 161 10.1161/CIRCIMAGING.108.78487619808533 Search in Google Scholar

Liu D, Wang CJ, Judge DP, Halushka MK, Ni J, Habashi JP, Moslehi J, Bedja D, Gabrielson KL, Xu H, et al. A Pkd1-Fbn1 genetic interaction implicates TGF-β signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2014; 25: 81–91. LiuD WangCJ JudgeDP HalushkaMK NiJ HabashiJP MoslehiJ BedjaD GabrielsonKL XuH A Pkd1-Fbn1 genetic interaction implicates TGF-β signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease J Am Soc Nephrol 2014 25 81 91 10.1681/ASN.2012050486387176624071006 Search in Google Scholar

Liu R, Jian W, Zhao Y, Lu X, Wu Y, Duan J. Retinal oxygen saturation and vessel diameter in patients with chronic kidney disease. Acta Ophthalmol. 2021; 99: e352–e359. LiuR JianW ZhaoY LuX WuY DuanJ Retinal oxygen saturation and vessel diameter in patients with chronic kidney disease Acta Ophthalmol 2021 99 e352 e359 10.1111/aos.1439832529722 Search in Google Scholar

Lorthioir A, Joannidès R, Rémy-Jouet I, Fréguin-Bouilland C, Iacob M, Roche C, Monteil C, Lucas D, Renet S, Audrézet MP, et al. Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans. Kidney Int. 2015; 87: 465–472. LorthioirA JoannidèsR Rémy-JouetI Fréguin-BouillandC IacobM RocheC MonteilC LucasD RenetS AudrézetMP Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans Kidney Int 2015 87 465 472 10.1038/ki.2014.24125029430 Search in Google Scholar

Machalińska A, Kawa MP, Babiak K, Sobuś A, Grabowicz A, Lejkowska R, Kazimierczak A, Rynio P, Safranow K, Wilk G, et al. Retinal vessel dynamic functionality in the eyes of asymptomatic patients with significant internal carotid artery stenosis. Int Angiol. 2019; 38: 230–238. MachalińskaA KawaMP BabiakK SobuśA GrabowiczA LejkowskaR KazimierczakA RynioP SafranowK WilkG Retinal vessel dynamic functionality in the eyes of asymptomatic patients with significant internal carotid artery stenosis Int Angiol 2019 38 230 238 10.23736/S0392-9590.19.04112-931112024 Search in Google Scholar

Machalińska A, Pius-Sadowska E, Babiak K, Sałacka A, Safranow K, Kawa MP, Machaliński B. Correlation between Flicker-induced retinal vessel vasodilatation and plasma biomarkers of endothelial dysfunction in hypertensive patients. Curr Eye Res. 2018; 43: 128–134. MachalińskaA Pius-SadowskaE BabiakK SałackaA SafranowK KawaMP MachalińskiB Correlation between Flicker-induced retinal vessel vasodilatation and plasma biomarkers of endothelial dysfunction in hypertensive patients Curr Eye Res 2018 43 128 134 10.1080/02713683.2017.135837229135307 Search in Google Scholar

Mao Z, Xie G, Ong AC. Metabolic abnormalities in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2015; 30: 197–203. MaoZ XieG OngAC Metabolic abnormalities in autosomal dominant polycystic kidney disease Nephrol Dial Transplant 2015 30 197 203 10.1093/ndt/gfu04424589722 Search in Google Scholar

Milenkovic I, Weick M, Wiedemann P, Reichenbach A, Bringmann A. P2Y receptor-mediated stimulation of Müller glial cell DNA synthesis: Dependence on EGF and PDGF receptor transactivation. Invest Ophthalmol Vis Sci. 2003; 44: 1211–1220. MilenkovicI WeickM WiedemannP ReichenbachA BringmannA P2Y receptor-mediated stimulation of Müller glial cell DNA synthesis: Dependence on EGF and PDGF receptor transactivation Invest Ophthalmol Vis Sci 2003 44 1211 1220 10.1167/iovs.02-026012601051 Search in Google Scholar

Milutinovic J, Fialkow PJ, Agodoa LY, Phillips LA, Rudd TG, Sutherland S. Clinical manifestations of autosomal dominant polycystic kidney disease in patients older than 50 years. Am J Kidney Dis. 1990; 15: 237–243. MilutinovicJ FialkowPJ AgodoaLY PhillipsLA RuddTG SutherlandS Clinical manifestations of autosomal dominant polycystic kidney disease in patients older than 50 years Am J Kidney Dis 1990 15 237 243 10.1016/S0272-6386(12)80768-2 Search in Google Scholar

Mosetti MA, Leonardou P, Motohara T, Kanematsu M, Armao D, Semelka RC. Autosomal dominant polycystic kidney disease: MR imaging evaluation using current techniques. J Magn Reson Imaging. 2003; 18: 210–215. MosettiMA LeonardouP MotoharaT KanematsuM ArmaoD SemelkaRC Autosomal dominant polycystic kidney disease: MR imaging evaluation using current techniques J Magn Reson Imaging 2003 18 210 215 10.1002/jmri.10347 Search in Google Scholar

Pei Y, Watnick T. Diagnosis and screening of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis. 2010; 17: 140–152. PeiY WatnickT Diagnosis and screening of autosomal dominant polycystic kidney disease Adv Chronic Kidney Dis 2010 17 140 152 10.1053/j.ackd.2009.12.001 Search in Google Scholar

Pietrzak-Nowacka M, Safranow K, Bober J, Olszewska M, Birkenfeld B, Nowosiad M, Ciechanowski K. Calcium-phosphate metabolism parameters and erythrocyte Ca2+ concentration in autosomal dominant polycystic kidney disease patients with normal renal function. Arch Med Sci. 2013; 9: 837–842. Pietrzak-NowackaM SafranowK BoberJ OlszewskaM BirkenfeldB NowosiadM CiechanowskiK Calcium-phosphate metabolism parameters and erythrocyte Ca2+ concentration in autosomal dominant polycystic kidney disease patients with normal renal function Arch Med Sci 2013 9 837 842 10.5114/aoms.2012.30834 Search in Google Scholar

Pietrzak-Nowacka M, Safranow K, Byra E, Bińczak-Kuleta A, Ciechanowicz A, Ciechanowski K. Metabolic syndrome components in patients with autosomal-dominant polycystic kidney disease. Kidney Blood Press Res. 2009; 32: 405–410. Pietrzak-NowackaM SafranowK ByraE Bińczak-KuletaA CiechanowiczA CiechanowskiK Metabolic syndrome components in patients with autosomal-dominant polycystic kidney disease Kidney Blood Press Res 2009 32 405 410 10.1159/000260042 Search in Google Scholar

Ponto KA, Werner DJ, Wiedemer L, Laubert-Reh D, Schuster AK, Nickels S, Höhn R, Schulz A, Binder H, Beutel M, et al. Retinal vessel metrics: Normative data and their use in systemic hypertension: Results from the Gutenberg Health Study. J Hypertens. 2017; 35: 1635–1664. PontoKA WernerDJ WiedemerL Laubert-RehD SchusterAK NickelsS HöhnR SchulzA BinderH BeutelM Retinal vessel metrics: Normative data and their use in systemic hypertension: Results from the Gutenberg Health Study J Hypertens 2017 35 1635 1664 10.1097/HJH.0000000000001380 Search in Google Scholar

Pose-Reino A, Gomez-Ulla F, Hayik B, Rodriguez-Fernández M, Carreira-Nouche MJ, Mosquera-González A, González-Penedo M, Gude F. Computerized measurement of retinal blood vessel calibre: Description, validation and use to determine the influence of ageing and hypertension. J Hypertens. 2005; 23: 843–850. Pose-ReinoA Gomez-UllaF HayikB Rodriguez-FernándezM Carreira-NoucheMJ Mosquera-GonzálezA González-PenedoM GudeF Computerized measurement of retinal blood vessel calibre: Description, validation and use to determine the influence of ageing and hypertension J Hypertens 2005 23 843 850 10.1097/01.hjh.0000163154.35577.8e Search in Google Scholar

Qian Q, Hunter LW, Li M, Marin-Padilla M, Prakash YS, Somlo S, Harris PC, Torres VE, Sieck GC. Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum Mol Genet. 2003; 12: 1875–1880. QianQ HunterLW LiM Marin-PadillaM PrakashYS SomloS HarrisPC TorresVE SieckGC Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells Hum Mol Genet 2003 12 1875 1880 10.1093/hmg/ddg190 Search in Google Scholar

Raina S, Honer M, Krämer SD, Liu Y, Wang X, ., Segerer S, Wüthrich RP, Serra AL. Anti-VEGF antibody treatment accelerates polycystic kidney disease. Am J Physiol Renal Physiol. 2011; 301: F773–F783. RainaS HonerM KrämerSD LiuY WangX SegererS WüthrichRP SerraAL Anti-VEGF antibody treatment accelerates polycystic kidney disease Am J Physiol Renal Physiol 2011 301 F773 F783 10.1152/ajprenal.00058.2011 Search in Google Scholar

Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet. 1994; 343: 824–827. RavineD GibsonRN WalkerRG SheffieldLJ Kincaid-SmithP DanksDM Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1 Lancet 1994 343 824 827 10.1016/S0140-6736(94)92026-5 Search in Google Scholar

Rübsam A, Parikh S, Fort PE. Role of inflammation in diabetic retinopathy. Int J Mol Sci. 2018; 19: 942. RübsamA ParikhS FortPE Role of inflammation in diabetic retinopathy Int J Mol Sci 2018 19 942 10.3390/ijms19040942 Search in Google Scholar

The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium. Cell. 1994; 77: 881–894. The European Polycystic Kidney Disease Consortium The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium Cell 1994 77 881 894 10.1016/0092-8674(94)90137-6 Search in Google Scholar

Triantafyllou A, Anyfanti P, Gavriilaki E, Zabulis X, Gkaliagkousi E, Petidis K, Triantafyllou G, Gkolias V, Pyrpasopoulou A, Douma S. Association between retinal vessel caliber and arterial stiffness in a population comprised of normotensive to early-stage hypertensive individuals. Am J Hypertens. 2014; 27: 1472–1478. TriantafyllouA AnyfantiP GavriilakiE ZabulisX GkaliagkousiE PetidisK TriantafyllouG GkoliasV PyrpasopoulouA DoumaS Association between retinal vessel caliber and arterial stiffness in a population comprised of normotensive to early-stage hypertensive individuals Am J Hypertens 2014 27 1472 1478 10.1093/ajh/hpu07424858306 Search in Google Scholar

Ureña J, Fernández-Tenorio M, Porras-González C, González-Rodríguez P, Castellano A, López-Barneo J. A new metabotropic role for L-type Ca2+ channels in vascular smooth muscle contraction. Curr Vasc Pharmacol. 2013; 11: 490–496. UreñaJ Fernández-TenorioM Porras-GonzálezC González-RodríguezP CastellanoA López-BarneoJ A new metabotropic role for L-type Ca2+ channels in vascular smooth muscle contraction Curr Vasc Pharmacol 2013 11 490 496 10.2174/157016111131104001223905643 Search in Google Scholar

Vogler S, Pannicke T, Hollborn M, Kolibabka M, Wiedemann P, Reichenbach A, Hammes HP, Bringmann A. Impaired purinergic regulation of the glial (Müller) cell volume in the retina of transgenic rats expressing defective polycystin-2. Neurochem Res. 2016; 41: 1784–1796 VoglerS PannickeT HollbornM KolibabkaM WiedemannP ReichenbachA HammesHP BringmannA Impaired purinergic regulation of the glial (Müller) cell volume in the retina of transgenic rats expressing defective polycystin-2 Neurochem Res 2016 41 1784 1796 10.1007/s11064-016-1894-027038933 Search in Google Scholar

Wong TY, Shankar A, Klein R, Klein BE, Hubbard LD. Retinal arteriolar narrowing, hypertension, and subsequent risk of diabetes mellitus. Arch Intern Med. 2005; 165: 1060–1065. WongTY ShankarA KleinR KleinBE HubbardLD Retinal arteriolar narrowing, hypertension, and subsequent risk of diabetes mellitus Arch Intern Med 2005 165 1060 1065 10.1001/archinte.165.9.106015883247 Search in Google Scholar

Xu HW, Yu SQ, Mei CL, Li MH. Screening for intracranial aneurysm in 355 patients with autosomal-dominant polycystic kidney disease. Stroke. 2011: 42: 204–206. XuHW YuSQ MeiCL LiMH Screening for intracranial aneurysm in 355 patients with autosomal-dominant polycystic kidney disease Stroke 2011 42 204 206 10.1161/STROKEAHA.110.57874021164130 Search in Google Scholar

Yanda MK, Liu Q, Cebotaru V, Guggino WB, Cebotaru L. Role of calcium in adult onset polycystic kidney disease. Cell Signal. 2019; 53: 140–150. YandaMK LiuQ CebotaruV GugginoWB CebotaruL Role of calcium in adult onset polycystic kidney disease Cell Signal 2019 53 140 150 10.1016/j.cellsig.2018.10.003634746430296477 Search in Google Scholar

Yu W, Ritchie BJ, Su X, Zhou J, Meigs TE, Denker BM. Identification of polycystin-1 and Gα12 binding regions necessary for regulation of apoptosis. Cell Signal. 2011; 23: 213–221. YuW RitchieBJ SuX ZhouJ MeigsTE DenkerBM Identification of polycystin-1 and Gα12 binding regions necessary for regulation of apoptosis Cell Signal 2011 23 213 221 10.1016/j.cellsig.2010.09.005299805920837139 Search in Google Scholar

Yue Z, Xie J, Yu AS, Stock J, Du J, Yue L. Role of TRP channels in the cardiovascular system. Am J Physiol Heart Circ Physiol. 2015; 308: H157–H182. YueZ XieJ YuAS StockJ DuJ YueL Role of TRP channels in the cardiovascular system Am J Physiol Heart Circ Physiol 2015 308 H157 H182 10.1152/ajpheart.00457.2014431294825416190 Search in Google Scholar

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