Int Urol Nephrol (2014) 46:2191–2198 DOI 10.1007/s11255-014-0804-0

NEPHROLOGY - ORIGINAL PAPER

Ocular and systemic factors associated with glaucoma in chronic kidney disease patients Jasmina Djordjevic-Jocic • Rade Cukuranovic • Branka Mitic • Predrag Jovanovic Vidosava Djordjevic • Marija Mihajlovic • Aleksandar Veselinovic • Maja Zivkovic • Slavimir Veljkovic • Dragan Bogdanovic • Vladisav Stefanovic

•

Received: 19 February 2014 / Accepted: 17 July 2014 / Published online: 22 August 2014 Ó Springer Science+Business Media Dordrecht 2014

Abstract The goal of this study was to examine, the relationship between chronic kidney disease (CKD) and glaucomatous optic disc neuropathy in a cohort of patients from the south-east Serbia and to determine whether limited screening for glaucoma in specific subgroups of patients with CKD is reasonable and justifiable. This crosssectional study included 328 subjects with various stages of CKD. All patients had visited the Outpatient Department of the Nephrology Clinic, Clinical Center Nis, Serbia. All patients underwent routine ophthalmic examinations. Glaucoma diagnosis based on elevated intraocular pressure (IOP), the presence of excavation of the optic nerve head (C/D ratio), and characteristic glaucomatous visual field loss (MD—mean deviation, PSD—pattern standard deviation). CKD was defined as kidney damage or glomerular filtration rate (GFR) of \60 ml/min/1.73 m2 for [3 months. A total number of 328 CKD patients, 33 (10.1 %)

J. Djordjevic-Jocic
P. Jovanovic
A. Veselinovic
M. Zivkovic Clinic of Ophthalmology, Faculty of Medicine, University of Nis, Nis, Serbia

with primary open angle glaucoma and 28 (8.5 %) with ocular hypertension (OH), were included in the study. Patients with CKD and glaucoma had significantly higher mean values of C/D ratio (0.59), visual field mean deviations (dB)—MD (p \ 0.001), and visual field pattern standard deviations (dB)—PSD (p \ 0.001) than patients with CKD and OH. Stepwise multivariate linear regression analysis confirmed that the most significant factors related to IOP are age (p \ 0.05), AHT (p = 0.01), and eGFR (p = 0.001). Multivariate regression analysis also confirmed that the most significant factors related to cup-todisc ratio are number of years of smoking (p \ 0.05), AHT, and sCr (p \ 0.01). In conclusion, the prevalence of glaucoma among CKD patients in the cohort from southeast Serbia is 10.1 %. Patients with CKD and glaucoma, eGFR and current cigarette smoking are associated with IOP level, MD, and PSD of visual field and C/D ratio. Keywords Chronic kidney disease
Glaucoma
Optic disc neuropathy

Introduction R. Cukuranovic
B. Mitic
S. Veljkovic Clinic of Nephrology, Faculty of Medicine, University of Nis, Nis, Serbia V. Djordjevic Faculty of Medicine, Institute of Biochemistry, University of Nis, Nis, Serbia M. Mihajlovic
V. Stefanovic (&) Research Department, Faculty of Medicine, University of Nis, Blvd. Zorana Djindjica 81, 18000 Nis, Serbia e-mail: [email protected] D. Bogdanovic State University of Novi Pazar, Novi Pazar, Serbia

Chronic kidney disease (CKD) is a progressive loss of renal function over a period of months or years. Current literature reviews suggest that up to 10 % of the population may be affected by CKD [1, 2]. The global rise of CKD is primarily due not only to an increased ageing population, but also association with other chronic conditions, including cardiovascular disease, diabetes (DM), and cancer: [3– 5]. Recently, several types of ocular fundus pathologies have been shown to be associated with CKD, among them retinal microvascular abnormalities, age-related macular degeneration (ARMD), and increased intraocular pressure

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(IOP) [6, 7]. The precise relationships among CKD, IOP, and glaucoma, however, are unclear. Furthermore, although haemodialysis has been known to induce changes in the eye, its effect on IOP has yet to be completely defined [8–10]. Glaucoma is a multifactorial disease characterized by retinal ganglion cell loss, leading to distinctive damage to the optic nerve and visual field. Although IOP is considered to be the main risk factor for development of glaucoma and the only treatable parameter, there is sufficient evidence to suggest that glaucoma continues to progress despite lowering the IOP to target levels. The association between chronic renal failure (CRF) and ocular disease may occur via various prognostic factors accompanying CRF prognosis. These factors, which include metabolic changes, hypertension, anaemia, and haemodialysis treatment, may, in turn, continue through several mechanistic pathways, e.g. oxidative stress, inflammation, and endothelial dysfunction, all of which may contribute to the pathogenesis of glaucoma [11]. The rennin-angiotensin system, through its effects on aqueous humour production and drainage, may be implicated in glaucoma pathogenesis [12]. The aim of this study was to examine the ocular and systemic association with intraocular pressure (IOP) and glaucomatous optic disc neuropathy in patients with chronic kidney disease (CKD), a cohort of patients from south-east Serbia.

Materials and methods Patients Subject eligibility for inclusion in the study was reviewed and documented by a member of the investigational study team. In the cross-sectional study included were 328 subjects with various stages of chronic renal disease, all of whom had visited the Outpatient Department of the Institute for Nephrology and Hemodialysis, Clinical Center Nis, Serbia. CKD was defined as kidney damage or glomerular filtration rate (GFR) of \60 ml/min/1.73 m2 for [3 months. Over the course of the study period of 12 months, all patients underwent routine ophthalmic examinations in the Ophthalmology Clinic, Clinical Center, Nis. All subjects gave written informed consent before entering the study. Ethical approval was obtained from the local medical ethics committee of the Clinical Center, Nis. The study was designed and conducted in accordance with the tenets of the Declaration of Helsinki. During the interview process, subjects were asked about use of medications for hypertension, diuretics, and control of DM. Patients were also classified as current smokers, former smokers, or nonsmokers.

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Inclusion criteria Inclusion criteria: male or female subjects C40 years of age, evidence of persistent CKD—defined as a GFR of \60 ml/min per 1.73 m2. Patients signed informed consent indicating that the subject has been informed of the study details and goals. Exclusion criteria Exclusion criteria: history of recurrent fever, or clinical and laboratory signs of sepsis; severe acute or exacerbation of chronic systemic disease; any malignancy; proteinuria [10 g/day and/or serum albumin \20 g/l; history of congestive heart failure or stroke within the previous 3 months; or moderate liver function test abnormalities [1.5 times normal upper limit values.

Methods Each participant underwent a physical examination that included vital signs and height/weight measurements, the latter to determine body mass index (BMI). Systolic and diastolic blood pressures (BPs) were measured using an automated sphygmomanometer and standard protocol. After an overnight fast of at least 10 h, blood was collected to determine levels of serum glucose, glycosylated haemoglobin, total protein, urea, creatinine, and albumin, total cholesterol, high-density lipoprotein (HDL) cholesterol, and direct low-density lipoprotein (LDL) cholesterol, and serum highly sensitive C-reactive protein (hs-CRP). Serum creatinine was measured by enzymatic method on an Olimpus AU 680 (Tokio, Japan). Also determined was the estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) formula. Urine samples were collected for measurement of microalbuminuria, and creatinine levels, eGRF was calculated according to MDRD GFR. Clinical ophthalmic examinations included slit-lamp biomicroscopy of the anterior segment, slit-lamp gonioscopy, and direct slit-lamp Goldmann three-mirror gonioscopy of the anterior chamber angle. A Goldmann applanation tonometer, model BQ-900 (Haag-Streit; Haag Streit, Bern Switzerland) was used to obtain one reading of IOP from each eye. Prior to pupil dilation with tropicamide 1 %, a detailed high-magnification slit-lamp assessment of the pupillary margin was made. An ultrasound pachymeter was used to measure central corneal thickness (CCT). Visual field examination was performed using a Humphrey field analyser (Carl Zeiss Meditec, Dublin, CA, USA) for standard automated perimetry. The optic disc was examined through a 78 or 90 dioptre lens at 109

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magnification. Simultaneous colour stereo fundus photography, centred on the optic disc (30°), was achieved using a Nidek 3Dx/NM camera (Nidek). Horizontal and vertical disc diameters were determined in a masked manner by a glaucoma specialist. Ophthalmologic examination was performed by two glaucoma specialists in the Ophthalmology Clinic, Clinical Center Nis, Serbia. Glaucoma was diagnosed using two categories of surveys for prevalence of glaucoma, as suggested by Foster et al. [13] Category 1 requires the presence of glaucomatous visual field defects (GVFDs) as well as two or more of the following, based on optic nerve stereo photography: vertical cup-to-disc ratio (VCDR) in the 97.5th percentile ([0.7), focal glaucomatous disc change, and cup-to-disc asymmetry in the 97.5th percentile for difference between eyes ([0.2). Category 2, where visual field measurements were not possible, included two of three of the following: 99.5th percentile of VCDR ([0.8), 99.5th percentile difference between eyes ([0.3), and a focally glaucomatous disc. Ocular hypertension (OH) is a state in which the intraocular pressure (IOP) is [21 mmHg in the absence of optic nerve damage or visual field loss [13, 14]. The K/DOQI definition and classification of CKD were accepted [15]. CKD was defined as kidney damage or glomerular filtration rate (GFR) of \60 ml/min/1.73 m2 for [3 months. Classification of CKD by severity comprises: stage I: kidney damage with normal GFR (C90 ml/ min/1.73 m2), albuminuria, proteinuria, and haematuria; stage II: kidney damage with mild GFR (60–89 ml/min/ 1.73 m2), albuminuria, proteinuria, and haematuria; stage III: moderate decrease in GFR (30–50 ml/min/1.73 m2), chronic renal insufficiency, and early renal insufficiency; stage IV: severe reduction in GFR (15–29 ml/min/ 1.73 m2), chronic renal insufficiency, late renal insufficiency, and pre- end-stage renal disease (ESRD); and stage V: kidney failure (\15 ml/min/1.73 m2) or dialysis, renal failure/uraemia, and ESRD. Statistical analysis Data were analysed using version 2.2.1 ‘‘R,’’ (R Foundation for Statistical Computing, Vienna, Austria), a software language for statistical computing, and expressed as means (standard deviations) or numbers (percentages), as appropriate. One-way analysis of variance (ANOVA) and the Tukey–Kramer post hoc test were used to compare means between three or four groups. Chi-square and Fisher’s exact tests were used to compare categorical variables. Univariate and multivariate linear regression adjusted for eGFR analyses were performed to estimate associations among IOP, CCT, mean deviation, visual field pattern standard deviation, cup-disc ratio, and other factors of

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interest. Linear regression coefficients (B) are calculated with 95 % confidence intervals (95 % CI). p value \ 0.05 was considered statistically significant.

Results A total number of 328 CKD patients, 33 (10.1 %) with primary open angle glaucoma (POAG) and 28 (8.5 %) with OH, were included in the study. There was no statistically significant difference between groups with regard to average age or gender. Patient characteristics are shown in a Table 1. There were significantly more patients with DM in the group with glaucoma than in those with OH (p \ 0.05). Average HDL and triglyceride levels were significantly lower (p \ 0.01, p \ 0.05, respectively) in patients with no previous history of OH, compared with those with OH. CKD patients without glaucoma had significantly lower mean values of IOP (16.40 mmHg) than those with glaucoma (22.74 mmHg) (p \ 0.001) or those with OH (22.27 mmHg) (p \ 0.001). Compared with OH patients, those with glaucoma had significantly lower mean values of CCT (545.17:559.48) (p \ 0.001), whereas mean values of C/D ratio (0.59), visual field mean deviations (dB)—MD (8.29:2.72) (p \ 0.001) and visual field pattern standard deviations (dB)—PSD (6.54:2.43) (p \ 0.001) were significantly higher. Clinical ophthalmic parameters related to stage of renal disease did not show any significant difference (Tables 2, 3). In patients with no changes in IOP, those with stage II kidney disease had significantly lower mean values of IOP than did subjects with stage III (15.97:16.65) (p \ 0.01). OH patients with stage II kidney disease had significantly lower mean values of IOP (20.50) than those with stages III (22.8) (p \ 0.05) or IV (22.58) (p \ 0.05). In patients with glaucoma, there were no significant differences in IOP values among those with the various stages of kidney disease. Univariate regression analysis assessing the relationship between selected clinical/biochemical parameters and IOP, CCT, MD, PSD, and C/D ratio in the group with patients with CKD and glaucoma, confirmed that the significant factors related to increased values of IOP are age (B = 0.153, 95 % CI 0.056–0.250; p \ 0.01), AHT (B = 5.950, 95 % CI 2.919–8.981; p \ 0.001), kidney disease stage III (B = 1.156, 95 % CI 0.033–2.284; p \ 0.05), and serum creatinine values (sCr) (B = 0.017, 95 % CI 0.004–0.030; p \ 0.05), whereas a negative correlation with eGFR values (B = -0.092, 95 % CI -0.136 to 0.048; p \ 0.001) and HDL (B = -3.572, 95 % CI -7.011 to 0.133; p \ 0.01) was noted. (Table 4). MD and PSD shown negative correlation with DM (B = -1.920,

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Table 1 Demographic, clinical and biochemical characteristics of study participants Characteristic

Without n = 258

With OAG n = 33

With OH n = 28

Age, years, mean (SD)

63.8 (11.46)

65.59 (9.59)

141 (54.7 %)

13 (39.4 %)

16 (57.1 %)

n.s. n.s.

64.39 (9.38)

p n.s.

Gender, number (%) Males Females

117 (45.3 %)

20 (60.6 %)

12 (42.9 %)

Diabetes, number (%)

82 (31.8 %)

15 (45.5 %)

4 (14.3 %)

C*

Hypertension, number (%)

228 (88.4 %)

30 (90.9 %)

25 (89.3 %)

n.s.

Smoking status, number (%) Non-smokers

170 (65.9 %)

26 (78.8 %)

20 (71.4 %)

n.s.

Current smokers

49 (19.0 %)

5 (15.2 %)

3 (10.7 %)

n.s.

5 (17.9 %)

n.s.

Former smokers

39 (15.1 %)

2 (6.1 %)

Body mass index, kg/m2, mean (SD) CKD stage, number (%)

27.24 (4.53)

28.13 (3.94)

II

78 (30.2 %)

13 (39.4 %)

10 (35.7 %)

n.s.

III

133 (51.6 %)

16 (48.5 %)

12 (42.9 %)

n.s.

IV

34 (13.2 %)

3 (9.1 %)

5 (17.9 %)

n.s.

V

13 (5.0 %)

1 (3.0 %)

1 (3.6 %)

n.s.

Serum creatinine, lmol/l

158.37 (94.31)

143.27 (71.78)

150.43 (85.62)

n.s.

26.85 (5.16)

n.s.

Creatinine clearance, ml/min

48.92 (19.38)

51.78 (19.82)

50.69 (21.01)

n.s.

Total serum protein, mmol/l

75.13 (38.13)

73.73 (5.96)

71.23 (6.16)

n.s.

Serum albumin, g/l

38.82 (5.63)

39.90 (4.95)

38.49 (4.20)

n.s.

Total cholesterol, mmol/l

5.72 (1.59)

5.55 (1.65)

5.32 (1.29)

n.s.

HDL cholesterol, mmol/l

1.13 (0.30)

1.19 (0.28)

1.32 (0.43)

B 

LDL cholesterol, mmol/l

3.83 (3.18)

3.51 (1.29)

3.45 (1.26)

n.s.

Triglycerides, mmol/l

2.21 (1.62)

2.05 (1.10)

1.36 (0.59)

B*

Serum glucose, mmol/l

6.28 (2.07)

6.69 (2.19)

5.49 (0.89)

n.s.

HbA1c, %

44.42 (11.89)

47.66 (15.76)

High-sensitivity C-reactive protein, mg/l Urinary albumin, mg/l

6.85 (20.92) 279.94 (649.10)

4.48 (4.83) 210.83 (382.81)

Total urinary protein, mg/l

716.32 (1.802.41)

627.11 (876.20)

Urinary creatinine, mmol/l

6,213.86 (5.210.05)

5,347.25 (4.427.58)

Urinary albumin creatinine ratio, mg/mmol

54.24 (159.16)

Urinary protein creatinine ratio, mg/mmol

115.33 (386.03)

Visual acuity

0.84 (0.41)

0.78 (0.,25)

40.62 (5.89)

n.s.

10.25 (22.80) 124.43 (251.54)

n.s. n.s.

282.56 (392.23)

n.s.

6,262.91 (4.089.33)

n.s.

56.60 (157.21)

8.10 (12.93)

n.s.

190.01 (439.95)

171.05 (755.44)

n.s.

0.91 (0.18)

n.s.

Intraocular pressure—IOP

16.40 (2.15)

22.74 (3.92)

22.27 (1.97)

Central corneal thickness—CCT

555.3

545.17 (5.17)

569.48 (13.26)

D

C/D ratio: (horizontal and vertical cup-to-disc ratio) %

–

0.59 (0.08)

0.41 (0.05)

Cà

\0.4

–

4 (12.2)

14 (63.9)

D

0.5–0.7

–

23 (69.6)

8 (36.3)

Cà

0.8–1.0

–

6 (18.2)

Visual field medan deviation—MD (dB)

–

8.29 (5.52)

2.72 (0.65)

Cà

Visual field pattern standard deviation—PSD (dB)

–

6.54 (2.67)

2.43 (0.33)

Cà

–

A*, B*

Cà

A without changes versus glaucoma, B without changes versus OH, C glaucoma versus OH, D OH versus glaucoma, n.s. not significant * p \ 0.05;

 

p \ 0.01;

à

p \ 0.001

95 % CI -3.223 to -0.616; p \ 0.01) and serum glucose (B = -0.873, 95 % CI -1.487 to -0.259; p \ 0.01). In the same group, PSD demonstrated positive correlations with smoking (B = 1.159, 95 % CI 0.033–2.284;

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p \ 0.05), number of years smoking (B = 0.142, 95 % CI 0.049–0.235; p \ 0.01), and hs-CRP (B = 0.288, 95 % CI 0.010–0.567; p \ 0.05). The following significant factors were found to be associated with increased C/D ratio:

Int Urol Nephrol (2014) 46:2191–2198 Table 2 Clinical ophthalmic parameters related to the stages of renal disease

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Variable

Stage II n = 101

IOP mmHg

IOP intraocular pressure, CCT central corneal thickness, clinical optic head C/D estimation

IV n = 42

V n = 15

17.33 (3.66)

17.75 (3.25)

17.48 (3.22)

17.70 (3.47)

n.s.

554.47 (15.83)

551.52 (10.82)

553.50 (9.38)

550.0 (0.00)

n.s.

C/D ratio

0.42 (0.16)

0.41 (0.16)

0.40 (0.18)

0.43 (0.14)

n.s.

MD—mean deviation of visual field (dB)

5.47 (4.78)

6.28 (5.24)

4.82 (4.69)

4.17 (2.67)

n.s.

PDS—pattern standard of visual field (dB)

4.83 (2.92)

4.72 (2.92)

3.96 (2.60)

4.07 (2.2)

n.s.

Group

Stage II

Stage III

Stage IV

Stage V

Comparison

Without changes

15.97 (2.03)

16.65 (2.25)

16.34 (1.84)

16.73 (2.38)

A 

With glaucoma

21.31 (5.33)

23.22 (2.21)

25.33 (1.03)

26.00 (2.83)

n.s.

With OH

20.50 (1.61)

22.58 (1.38)

22.80 (2.99)

22.00 (0.00)

B*, C*

A stage III versus II, B stage IV versus II, C stage IV versus III, n.s. not significant  

III n = 161

CCT lm

Table 3 Relationship of intraocular pressure to stage of renal disease

* p \ 0.05;

Comparison

p \ 0.01

number of years smoking (B = 0.003, 95 % CI 0.0002–0.006; p \ 0.05), sCR (B = 0.0004, 95 % CI 0.0001–0.0007; p \ 0.01), and stage IV kidney disease (B = 0.069, 95 % CI 0.001–0.137; p \ 0.05), whereas serum albumin showed a negative correlation (B = -0.005, 95 % CI -0.009 to -0.001; p \ 0.05) (Table 4). Multivariate linear regression analysis in the group with CKD and glaucoma confirmed that the most significant factors related to IOP were age (B = 0.102, 95 % CI 0.015–0.189; p \ 0.05), AHT (B = 3.814, 95 % CI 0.935–6.693; p = 0.01), and eGFR (B = -0.073, 95 % CI -0.114 to -0.032; p = 0.001). The most significant factors related to MD and PSD were the number of years of smoking (B = 0.240, 95 % CI 0.160–0.321; p \ 0.001), eGFR (B = 0.227, 95 % CI 0.140–0.314; p \ 0.001), (B = 0.154, 95 % CI 0.089–0.210; p \ 0.001), and eGFR (B = 0.074, 95 % CI 0.012–0.135; p \ 0.05) respectively, while the factors associated with C/D were the number of years of smoking (B = 0.003, 95 % CI 0.002–0.005; p \ 0.01), AHT (B = 0.101, 95 % CI 0.002–0.201; p \ 0.05), and eGFR (B = 0.002, 95 % CI 0.0003–0.005; p \ 0.05) (Table 5).

Discussion In our study, in the group with CKD and glaucoma, multivariate regression analysis showed that the significant

Table 4 Univariate regression analysis Factor

B

Boundary values 95 % IP for B Lower

p

Higher

IOP Age

0.153

0.056

0.250

0.003

AHT

5.950

2.919

8.981

0.000

AHT duration

0.097

0.004

0.191

0.042

Serum creatinine, lmol/l

0.017

0.004

0.030

0.014

Creatinine clearance, ml min

0.092

0.136

-0.048

0.000

Third stage CKD

1.156

0.033

2.284

0.044

-3.572

-7.011

-0.133

0.042

-0.313

-0.567

-0.058

0.017

0.174

0.003

0.345

0.046

DM

-1.920

-3.223

-0.616

0.005

Serum glucose, mmol/l

-0.873

-1.487

-0.259

0.006

HDL, mmol/l CCT BMI Total urinary protein, mg/l VF MD (dB)

Urinare creatinine, mmol/l

0.0004

0.0001

0.0007

0.013

Current smoking

1.159

0.033

2.284

0.044

No. yrs smoking

0.142

0.049

0.235

0.003

-0.873

-1.487

-0.259

0.006

0.153

0.056

0.250

0.003

Current smoking

0.011

0.025

0.047

0.538

No. of years smoking

0.003

0.0002

0.006

0.046

Serum creatinine, lmol/l

0.0004

0.0001

0.0007

0.009

VF PSD (dB)

Serum glucose, mmol/l Highly sensitive C-reactive protein, mg/l C/D ratio

Fourth stage CKD Serum albumin, g/l

0.069

0.001

0.137

0.046

-0.005

-0.009

-0.001

0.023

Assessment of relationship between specific clinical/biochemical parameters and IOP, CCT, VF MD, VF PSD, and C/D in the group with patients with CKD and glaucoma IOP intraocular pressure, AHT arterial hypertension, HDL cholesterol serum level, CCT central corneal thickness, BMI body mass index, VF MD visual field, median deviation (dB), VF PSD visual field, pattern standard deviation (dB), DM diabetes mellitus, C/D ratio—cup-todisc ratio

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Table 5 Multivariate linear regression analysis Factor

B

Boundary values 95 % IP for B

p

Lower

Higher

16.318

9.976

22.660

0.000

0.102 3.814

0.015 0.935

0.189 6.693

0.022 0.010

IOP Constant Age AHT eGFR, ml/min

-0.073

-0.114

-0.032

0.001

-9.594

-14.371

VF MD Constant

-4.817

0.002

No. of years smoking

0.240

0.160

0.321

0.000

eGFR, ml/min

0.227

0.140

0.314

0.000

-5,225

1.478

0.233

VF PSD Constant

-1.873

No. of years smoking

0.154

0.089

0.210

0.000

eGFR, ml/min

0.074

0.012

0.135

0.024

Constant

0.441

0.333

0.550

0.000

No. yrs smoking

0.003

0.002

0.005

0.002

C/D ratio

AHT

0.101

0.002

0.201

0.047

eGFR, ml/min

0.002

0.0003

0.005

0.049

Correlation of specific factors with IOP, VF MD, VF PSD, and C/D ratio in patients with glaucoma in the group with patients with CKD and glaucoma IOP intraocular pressure, AHT arterial hypertension, eGFR estimated glomerular filtration rate, VF MD visual field median deviation (dB), VF PSD visual field pattern standard deviation (dB), C/D ratio—cupto-disc ratio

factors related to MD and PSD and C/D ratio in patients with CKD are reduced eGFR, increased AHT and current cigarette smoking. Assessment of glaucomatous optic neuropathy was based on monitoring morphological changes generated by C/D ratios, with functional changes assessed by visual field tests. The association detected between CKD and glaucoma in this investigation is supported in the literature by a number of studies. Several risk factors are well known to increase the likelihood of developing POAG, including increased IOP, older age, decreased corneal thickness, and positive family history [11]. However, a considerable number of systemic risk factors also influence the occurrence of glaucoma-related damage and, potentially, its unfavourable progression. Among the most frequently encountered systemic risk factors are systemic hypertension and hypotension; DM, the impact of which on the occurrence and course of glaucoma is still an issue with divided opinions; low perfusion pressure; dyslipidemia; and CKDs [12, 16]. Although most population-based and case–control studies have not reported any associations between smoking habits and glaucoma, one study did report such a

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relationship. However, there was consensus in examinations of the relationship of smoking to IOP [17]. Recent studies have attempted to delineate association between glaucoma and DM, but with conflicting results. Various studies have shown that diabetic patients have elevated IOP. As a risk factor for glaucoma, DM remains controversial, with some authors arguing that, far from contributing to glaucoma, DM has a protective effect [16]. The first such evidence of the protective effects of DM was published by the Ocular Hypertension Treatment Study [12]. Grundwald et al. [18] found that lower eGFRs were associated with an extremely high incidence of fundus pathology. The percentage of participants with some eye pathology was 60 % in those with eGFRs of \30 and 35 % in those with eGFRs of C50. Thus, the presence of fundus pathology, including glaucoma, in participants with CKD may provide important prognostic information regarding progression of renal disease. Nongpiur et al. [7] found, in their population-based study in Malay adults, that CKD is associated with higher IOP (15.8 vs. 15.3 mmHg, p \ 0.001), independent of age, diabetes, and glaucoma status. No association with glaucoma was found (OR (95 % CI) = 0.87(0.58–1.29). The pathophysiology of glaucoma has not been well characterized yet and suggests that the relationship between IOP and glaucoma progression is nonlinear, and other factors such as ischaemia and neuroprotective mechanisms influence the susceptibility of the optic nerve to pressure-related damage. In this study, we showed that patients with CKD had elevated values of IOP and glaucomatous optic disc neuropathy in higher stage of disease. Patients with stages III or IV kidney disease had higher IOP values compared with those with stage II kidney disease. However, patients in the glaucoma group showed no differences in IOP values related to stage of CKD, perhaps due to the fact that some patients had previously been diagnosed with glaucoma and had received anti-glaucoma therapy. The exact mechanism(s) by which CKD might be associated with higher IOP is not known. The major mechanisms that contribute to CKD are atherosclerosis, vascular remodelling, endothelial dysfunction, inflammation, and oxidative stress mechanisms that are also implicated in many systemic and eye disease. Angiotensin II induces inflammatory responses and endothelial dysfunction through the production of reactive oxygen species. In addition, it is involved in extracellular matrix remodelling, regulation of gene expression, and activation of multiple intraocular signalling pathways that lead to tissue injury. The rennin-angiotensin system, though its effects on aqueous humour production and drainage, may be implicated in glaucoma pathogenesis. Sodium homoeostasis in the ciliary blood vessels is thought to be the mechanism leading to reduced aqueous humour

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production with subsequent lowering of IOP [19]. Recent studies have shown that oxidative stress is associated not only with CKD but also with morphologic and physiologic changes in the aqueous outflow pathway [20, 21]. Possible mechanisms to explain increased IOP in CKD include breakdown in the homoeostasis of body fluids leading to fluid overload, accumulation of toxic metabolites, and impaired aqueous outflow through the trabecular meshwork [10]. Breakdown in the homoeostasis of body fluids, including aqueous humour, may result in fluid overload, causing an elevation of IOP. Several studies have revealed that impaired aqueous outflow facility through the trabecular meshwork may exist in the majority of patients with CKD [22, 23]. In the present study, univariate linear regression analysis confirmed the following significant factors to be related to increased C/D ratios: number of years smoking, sCr, and stage IV kidney disease. In the group of patients with CKD and glaucoma, those with decreased values of eGFR, AHT, and history of cigarette smoking had neuroretinal rim thinning. Several epidemiological studies have revealed that elevated systemic BP is associated with glaucoma optic neuropathy. The physiological meaning of the correlation between BP and IOP is speculative [24]. The relationship between BP and incidence of glaucoma progression remains controversial. In fact, systemic hypotension and antihypertensive treatment could induce hypotensive episodes, especially during the night. These, in turn, may cause impaired microcirculation, possibly due to excessive production of free radicals or other harmful molecules toxic to neurons and glial cells. A similar finding was reported to cause glomerular damage to the kidney [25]. Limitations of this study include the lack of data in control population with normal kidney function. For that, we should await data from a large epidemiological study of Serbian population. However, the literature data for white population are available and prevalence data for POAG, taken from eight population surveys, were published [26– 28]. The present study revealed a high prevalence of glaucoma among patients with CKD, a finding that highlights the importance of eye examinations for CKD patients. Such examinations would improve overall prognoses and quality of life. Early detection of glaucomatous optic neuropathy is of utmost importance, particularly for patients with CKD, to obviate development of glaucoma. However, since we did not sub-classify POAG or normal tension glaucoma (NTG), future large-scale prospective population-based studies are needed to elucidate these specific correlations. In conclusion, the prevalence of glaucoma among CKD patients in the cohort from south-east Serbia is 10.1 %. In patients with CKD and glaucoma, decreasing of eGFR

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associated with IOP level, MD and PSD of visual field and C/D ratio (p \ 0.001, p \ 0.001, p \ 0.05), respectively, as main factors to assessment of glaucomatous optic disc neuropathy. Acknowledgments This work was supported by a Grant No 175092 from the Ministry of Education, Science and Technological Development of Serbia. Conflict of interest

There are no conflicts of interest.

References 1. Hallan SI, Dahl K, Oien CM, Grootendorst DC, Aasberg A, Holmen J, Dekker FW (2006) Screening strategies for chronic kidney disease in the general population: follow-up of cross sectional health survey. BMJ 333(7577):1047 2. Vassalotti JA, Stevens LA, Levey As (2007) Testing for chronic kidney disease: a position statement from the National Kidney Foundation. Am J Kidney Dis 50(2):169–180 3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351(13):1296–1305 4. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS (2007) Prevalence of chronic kidney disease in the United States. JAMA 298(17):2038–2047 5. McClellan W, Warnock DG, McClure L, Campbell RC, Newsome BB, Howard V, Cushman M, Howard G (2006) Racial differences in the prevalence of chronic kidney disease among participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Study. J Am Soc Nephro l 7(6):1710–1715 6. Evans RD, Rosner M (2005) Ocular abnormalities associated with advanced kidney disease and hemodialysis. Semin Dial 18(3):252–257 7. Nongpiur ME, Wong TY, Sabanayagam C, Lim SC, Tai ES, Aung T (2010) Chronic kidney disease and intraocular pressure:the Singapore Malay Eye Study. Ophthalmology 117(3): 477–483 8. Jalel T, Faouzi H, Faten T, Abdellatif A, Mahdouani K (2005) Ocular complications in peritoneal haemodialysis. Tunis Med 83(10):617–621 9. Song WK, Ha SJ, Yeom HY, Seoung GJ, Hong YJ (2006) Recurrent intraocular pressure elevation during hemodialysis in a patient with neovascular glaucoma. Korean J Ophthalmol 20(2): 109–112 10. Tawara A, Kobata H, Fujisawa K, Abe T, Ohnishi Y (1998) Mechanism of intraocular pressure elevation during hemodialysis. Curr Eye Res 17(4):339–347 11. Cedrone C, Mancino R, Cerulli A, Cesareo M, Nucci C (2008) Epidemiology of primary glaucoma: prevalence, incidence, and blinding effects. Prog Brain Res 173:3–14 12. Wong CW, Wong TY, Cheng CY, Sabanayagam C. Kidney and eye diseases: common risk factors, ethiological mechanisms, and pathways. Kidney International advance online publication, December 2013 13. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ (2002) The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 86(2):238–242 14. Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Gordon MO (2002) The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or

123

2198

15.

16.

17.

18.

19.

20.

21.

prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 120(6):701–713 Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, De Zeeuw D, Hostetter TH, Lameire N, Eknoyan G (2005) Definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int 67(6):2089–2100 Nakamura M, Kanamori A, Negi A (2005) Diabetes mellitus as a risk factor for glaucomatous optic neuropathy. Ophthalmologica 219(1):1–10 Lee AJ, Rochtchina E, Wang JJ, Healey PR, Mitchell P (2003) Does smoking affect intraocular pressure? Findings from the Blue Mountains Eye Study. J Glaucoma 12(3):209–212 Grunwald JE, Alexander J, Maguire M, Whittock R, Parker C, McWilliams K, Lo JC, Townsend R, Gadegbeku CA, Lash JP, Fink JC, Rahman M, Feldman H, Kusek J, Ojo A, CRIC Study Group (2010) Prevalence of ocular fundus pathology in patients with chronic kidney disease. Clin J Am Soc Nephrol 5(5): 867–873 Vaziri ND (2004) Roles of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension. Curr Opin Nephrol Hypertens 3(1):93–99 Gabelt BT, Kaufman PL (2005) Changes in aqueous humor dynamics with age and glaucoma. Prog Retin Eye Res 24(5): 612–637 De Marchi S, Cecchin E, Tesio F (1989) Intraocular pressure changes during hemodialysis: prevention of excessive dialytic

123

Int Urol Nephrol (2014) 46:2191–2198

22.

23. 24.

25.

26. 27.

28.

rise and development of severe metabolic acidosis following acetazolamide therapy. Ren Fail 11(2–3):117–124 Konta T, Hao Z, Abiko H, Ishikawa M, Takahashi T, Ikeda A, Ichikawa K, Takasaki S, Kubota I (2006) Prevalence and risk factor analysis of microalbuminuria in Japanese general population: the Takahata study. Kidney Int 70(4):751–756 Costa VP, Arcieri ES, Harris A (2009) Blood pressure and glaucoma. Br J Ophthalmol 93(10):1276–1282 Dielemans I, Vingerling JR, Algra D, Hofman A, Grobbee DE, de Jong PT (1995) Primary open-angle glaucoma, intraocular pressure, and systemic blood pressure in the general elderly population: the Rotterdam Study. Ophthalmology 102(1):54–60 Kahn HA, Leibowitz HM, Ganley JP, Kini MM, Colton T, Nickerson RS, Dawber TR (1977) The Framingham eye study. I. Outline and major prevalence findings. Am J Epidemiol 106(1):17–32 Tuck MW, Crick RP (1998) The age distribution of primary open angle glaucoma. Ophthalmic Epidemiol 5(4):173–183 Hollands H, Johnson D, Hollands S, Simel DL, Jinapriya D, Sharma S (2013) Do findings on routine examination identify patients at risk for primary open-angle glaucoma? The rational clinical examination systematic review. JAMA 309(19): 2035–2042 Topouzis F, Wilson MR, Harris A, Anastasopoulos E, Yu F, Mavroudis L, Pappas T, Koskosas A, Coleman AL (2007) Prevalence of open-angle glaucoma in Greece: the Thessaloniki Eye Study. Am J Ophthalmo l44(4):511–519