Risk factors for short-term all-cause mortality in patients with end stage renal disease: a scoping review.

OBJECTIVES: There is a lack of prognostic information to guide the prediction of short-term all-cause mortality in patients with end-stage renal disease (ESRD). The aim was to review the risk factors that influenced the risk of short-term all-cause mortality in patients with ESRD. METHODS: MEDLINE, Embase, PubMed, CINAHL, the Cochrane Library and Web of Science databases were searched for articles published between 2000 and 2020. Articles describing risk factors predicting short-term mortality (≤ 3 years) in patients with ESRD were included. Four reviewers independently performed title, abstract, full text screening and data extraction. Assessment of risk of bias was assessed using the Quality In Prognosis Studies (QUIPS) tool checklist. RESULTS: 20,840 articles were identified and 113 papers were included for this review. Of the 113 papers, 6.2% included only peritoneal dialysis (PD) patients, 67.3% included only hemodialysis (HD) patients, 20.4% included both PD and HD patients, with the remaining papers featuring patients on conservative management or awaiting renal transplant. Risk factors were categorised into 13 domains: 1)demographics/ lifestyle, 2) comorbidities 3)intradialytic blood pressure, 4)biomarkers, 5)cardiovascular measurements, 6)frailty status, 7)medications, 8)treatment related indicators, 9)renal related parameters, 10)health status, 11)cause of ESRD, 12)access to healthcare care/ information and, 13)proxy measures for poor health. C-reactive protein(CRP), age, and functional status were observed to have higher percentage of instances of being significantly associated with all-cause mortality. CONCLUSION: Commonly examined risk factors observed from this review may be used to build a general prognostic model for patients with ESRD, with specific treatment related risk factors added on to enhance the accuracy of the models.

Association between patient-reported functional measures and incident falls.

Lower extremity muscle strength, and functional limitations are important modifiable predictors of falls, but are often examined using performance based measures. We examined the association between self-reported physical function limitations, determined using Late-Life Function and Disability Instrument(LLFDI) and incident falls in community-dwelling elderly individuals. 283 older adults participants were included in this analysis. Physical function limitations were defined as a person's difficulty in completing items of the lower extremity function domain and composite scores of the LLFDI. Information on falls was obtained through a standardised questionnaire. At one-year follow-up, 15.2% (43) of the participants experienced their first fall. In the multivariable analysis, individuals who reported difficulties in items of lower extremity function domain were more likely to experience a fall (incidence rate ratio[IRR]: ranging between 2.43 and 7.01; all P ≤ 0.046). In addition, decreasing advanced lower extremity function scores (IRR: 1.70, 95% confidence interval[CI]): 1.04, 2.78) and overall function component score (IRR: 2.05, 95% CI: 1.22, 3.44) were associated with higher risk of incident falls. Physical function limitations, determined using LLFDI, were associated with incident falls. Our findings provide further evidence that the LLFDI function component has the potential to be used as a self-assessment tool for fall risk.

Retinal Vascular Imaging Markers and Incident Chronic Kidney Disease: A Prospective Cohort Study.

Retinal microvascular changes indicating microvascular dysfunction have been shown to be associated with chronic kidney disease (CKD) in cross-sectional studies, but findings were mixed in prospective studies. We aimed to evaluate the relationship between retinal microvascular parameters and incident CKD in an Asian population. We examined 1256 Malay adults aged 40-80 years from the Singapore Malay Eye Study, who attended both the baseline (2004-07) and the follow-up (2011-13) examinations and were free of prevalent CKD. We measured quantitative retinal vascular parameters (arteriolar and venular calibre, tortuosity, fractal dimension and branching angle) using a computer-assisted program (Singapore I Vessel Assessment, SIVA) and retinopathy (qualitative parameter) using the modified Airlie house classification system from baseline retinal photographs. Incident CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 + 25% decrease in eGFR during follow-up. Over a median follow-up period of 6 years, 78 (6.21%) developed CKD (70.5% had diabetes). In multivariable models, smaller retinal arterioles (hazards ratio [95% confidence interval] = 1.34 [1.00-1.78]), larger retinal venules (2.35 [1.12-5.94] and presence of retinopathy (2.54 [1.48-4.36]) were associated with incident CKD. Our findings suggest that retinal microvascular abnormalities may reflect subclinical renal microvascular abnormalities involved in the development of CKD.

Singapore Indian Eye Study-2: methodology and impact of migration on systemic and eye outcomes.

IMPORTANCE: Asian Indians are the fastest growing migration groups in the world. Studies evaluating the impact of migration on disease outcomes in this population are rare. BACKGROUND: We describe the methodology of the Singapore Indian Eye Study-2 (SINDI-2) aimed to evaluate the impact of migration status on diabetic retinopathy and other major age-related eye diseases in Asian Indians living in an urban environment. DESIGN: Population-based cohort study. PARTICIPANTS: A total of 2200 adults had participated in baseline SINDI (2007-2009, mean age [range] = 57.8 [42.7-84.1] years) and SINDI-2 (2013-2015, 56.5 [48.4-90.2] years). METHODS: Participants were classified as 'first generation' if they were Indian residents born outside of Singapore and as 'second-generation' immigrants (59.7% in SINDI vs. 63.6% in SINDI-2) if they were born in Singapore. MAIN OUTCOME MEASURES: Response rate, participant characteristics and prevalence of systemic diseases were stratified by migration status. RESULTS: Of the 2914 eligible SINDI participants invited to participate, 2200 participated in SINDI-2 (response rate of 75.2%). In both SINDI and SINDI-2, compared with first-generation immigrants, second-generation immigrants were younger, less likely to have income <1000 SGD, had lower levels of pulse pressure, higher levels of high-density lipoprotein cholesterol, had lower prevalence of hypertension and chronic kidney disease and had higher prevalence of current smoking and obesity (all P < 0.05). CONCLUSIONS AND RELEVANCE: In both SINDI and SINDI-2, second-generation immigrants had lower prevalence of cardiovascular risk factors except smoking and obesity compared with first-generation immigrants. The final report will confirm if these differences between generations are evident with regard to eye diseases.

Retinopathy Signs Improved Prediction and Reclassification of Cardiovascular Disease Risk in Diabetes: A prospective cohort study.

CVD risk prediction in diabetics is imperfect, as risk models are derived mainly from the general population. We investigate whether the addition of retinopathy and retinal vascular caliber improve CVD prediction beyond established risk factors in persons with diabetes. We recruited participants from the Singapore Malay Eye Study (SiMES, 2004-2006) and Singapore Prospective Study Program (SP2, 2004-2007), diagnosed with diabetes but no known history of CVD at baseline. Retinopathy and retinal vascular (arteriolar and venular) caliber measurements were added to risk prediction models derived from Cox regression model that included established CVD risk factors and serum biomarkers in SiMES, and validated this internally and externally in SP2. We found that the addition of retinal parameters improved discrimination compared to the addition of biochemical markers of estimated glomerular filtration rate (eGFR) and high-sensitivity C-reactive protein (hsCRP). This was even better when the retinal parameters and biomarkers were used in combination (C statistic 0.721 to 0.774, p = 0.013), showing improved discrimination, and overall reclassification (NRI = 17.0%, p = 0.004). External validation was consistent (C-statistics from 0.763 to 0.813, p = 0.045; NRI = 19.11%, p = 0.036). Our findings show that in persons with diabetes, retinopathy and retinal microvascular parameters add significant incremental value in reclassifying CVD risk, beyond established risk factors.

Comparison of Common Retinal Vessel Caliber Measurement Software and a Conversion Algorithm.

PURPOSE: To compare three commonly used retinal vessel caliber measurement software systems, and propose an algorithm for conversion between measurement systems. METHODS: We used 120 retinal photographs to evaluate the agreement between three commonly used software (Retinal Analysis [RA], Integrative Vessel Analysis [IVAN], and Singapore I Vessel Assessment [SIVA]). Bland-Altman plots were used to evaluate agreement of retinal arteriolar (central retinal artery equivalent, CRAE) and venular (central retinal vein equivalent, CRVE) calibers. Pearson's correlation was used to assess the associations between systemic factors and retinal vessel calibers, and Z-test was used to compare the strength of the correlation coefficients across the three software systems. An algorithm was created to convert measurements, with paired t-test performed to evaluate the differences between SIVA-measured retinal calibers and SIVA-approximates converted from RA- and IVAN-measurements using the algorithm. RESULTS: Differences between SIVA- and RA-measured calibers (CRAE: mean difference [MD] = -21.8 µm, 95% limits of agreement [LOA], -47.3 to 3.7 µm; CRVE: MD = -7.7 µm, 95% LOA, -28.0 to 12.6 µm), SIVA- and IVAN-measured calibers (CRAE: MD = -6.7 µm, 95% LOA, -23.8 to 10.4 µm; CRVE: MD = -18.2 µm 95% LOA, -36.7 to 0.4 µm) were large. However, the strength of correlations between systemic factors with SIVA-measured retinal calibers was not significantly different to that measured using RA and IVAN (P ≥ 0.332). SIVA-approximates converted from RA and IVAN measurements using the proposed algorithm was not significantly different from SIVA-measured calibers (P ≥ 0.20). CONCLUSION: Absolute measurements of retinal vessel calibers vary between three common software systems but associations with systemic factors were similar. TRANSLATIONAL RELEVANCE: The proposed algorithm allowed conversions of RA and IVAN measurements to SIVA-approximates. This conversion is important for future data pooling and establishment of normative values for retinal vascular caliber measurements.

Ten Emerging Trends in the Epidemiology of Diabetic Retinopathy.

PURPOSE: Diabetes is a major public health problem affecting 415 million people worldwide. With the increasing prevalence of diabetes, diabetic retinopathy (DR) is emerging as the leading cause of avoidable blindness worldwide. METHODS: We reviewed previous and recent literature to provide an overview of emerging trends on the burden, epidemiology, risk factors, and prevention of DR. RESULTS: First, there is clear evidence of a global increase in the prevalence of diabetes. Second, there is a decline in the incidence of blindness due to DR, particularly in developed countries. Third, diabetic macular edema (DME) rather than proliferative diabetic retinopathy (PDR) is the increasingly common cause of visual impairment. Fourth, DR awareness remains patchy and low in most populations. Fifth, hyperglycemia remains the most consistent risk factor for DR in type 1 diabetes across different studies and populations. Sixth, in contrast, blood pressure is an important risk factor for DR in type 2 diabetes. Seventh, the relationship between dyslipidemia and DR remains unclear, with inconsistent results from different studies and trials. Eighth, the utility of predictive models incorporating multiple risk factors for assessing DR risk requires evaluation. Ninth, photographic screening of DR using tele-ophthalmology platforms is increasingly recognized as being feasible and cost-effective. Finally, DR prevention in low-resource settings cannot follow models developed in high-resource countries and requires different strategies. CONCLUSIONS: The ten trends we observed in the current review may guide planning of public healthcare strategies for the management of DR and prevention of blindness.

Joint Effect of Early Microvascular Damage in the Eye &Kidney on Risk of Cardiovascular Events.

Microalbuminuria is associated with an increased risk of cardiovascular disease (CVD), but not all individuals require treatment. Retinal microvascular abnormalities and microalbuminuria reflect early systemic microvascular changes. We examined the joint effect of retinal abnormalities and microalbuminuria on CVD risk in an Asian cohort. We conducted a prospective, population-based study. Retinal abnormalities were defined as presence of retinopathy and/or retinal venular widening. Microalbuminuria was defined as urinary albumin: creatinine ratio between 30-300 mg/g. Incident CVD was defined as newly diagnosed clinical stroke, acute myocardial infarction or CVD death. Cox regression models were performed to determine the associations between retinal abnormalities and microalbuminuria with risk of CVD, while controlling for established risk factors. 3,496 participants (aged ≥ 40) were free of prevalent CVD. During the follow-up (5.8 years), 126 (3.60%) participants developed CVD. Persons presenting with both retinal abnormalities and microalbuminuria were 6.71 times (95% CI, 2.68, 16.79) as likely to have incident CVD compared with those without either abnormalities. There was a significant interaction effect between retinal abnormalities and microalbuminuria on incident CVD. Assessment of retinal abnormalities in patients with microalbuminuria may provide additional value in identifying persons at risk of developing CVD.

Relationship of Intraocular Pressure with Central Aortic Systolic Pressure.

PURPOSE: To examine the relationship between central aortic systolic pressure (CASP) and intraocular pressure (IOP), and to compare the strength of any association with that of peripheral blood pressure and IOP. METHODS: Adults ranging in age from 40 to 80 years were consecutively recruited from the population-based Singapore Chinese Eye Study. We measured CASP using arterial tonometry (BPro) and IOP using Goldmann applanation tonometry. All participants had a standardized examination including a complete ophthalmic and systemic examination. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using peripheral blood pressure cuff. Univariable and multiple linear regression analyses were performed to examine the relationship between CASP and IOP. Standardized regression coefficients (sß) were calculated to compare the associations between CASP and SBP with IOP. RESULTS: A total of 372 consecutive Chinese participants were analyzed. After adjusting for age, gender, body mass index, total cholesterol, use of antihypertensive medication and central corneal thickness, each 10 mmHg increase in CASP was associated with 0.32 mmHg of IOP elevation [95% confidence interval (CI): 0.10-0.53, sß = 0.160, p value = 0.004]. SBP also had a positive relationship with IOP (ß = 0.279, 95% CI: 0.079-0.479, sß = 0.152, p value = 0.006). Associations between IOP and CASP, SBP and DBP were similar in participants using antihypertensive medication to participant not using antihypertensives. CONCLUSIONS: Increased CASP, as measured by arterial tonometry, is associated with higher IOP. Our results strengthen the relationship between systemic blood pressure and IOP.

Retinal microvascular abnormalities and risk of renal failure in Asian populations.

BACKGROUND: Retinal microvascular signs may provide insights into the structure and function of small vessels that are associated with renal disease. We examined the relationship of retinal microvascular signs with both prevalent and incident end-stage renal disease (ESRD) in a multi-ethnic Asian population. METHODS: A total of 5763 subjects (aged ≥ 40 years) from two prospective population-based studies (the Singapore Malay Eye Study and the Singapore Prospective Study) were included for the current analysis. Retinopathy was graded using the modified Airlie House classification system. Retinal vascular parameters were measured using computer-assisted programs to quantify the retinal vessel widths (arteriolar and venular caliber) and retinal vascular network (fractal dimension). Data on ESRD was obtained by record linkage with the ESRD cases registered by National Registry of Diseases Office, Singapore. Multi-variable adjusted regression analyses were performed to assess the associations of baseline retinal vascular parameters and prevalent and incident ESRD. RESULTS: At baseline, 21(0.36%) persons had prevalent ESRD. During a median follow-up of 4.3 years, 33 (0.57%) subjects developed ESRD. In our analyses, retinopathy was associated with prevalent ESRD (multi-variable adjusted odds ratio [OR], 3.21, 95% confidence interval [CI]: 1.28-8.05) and incident ESRD (multi-variable adjusted hazard ratio [HR], 2.51, 95%CI: 1.14-5.54). This association was largely seen in person with diabetes (HR, 2.60, 95%CI: 1.01-6.66) and not present in persons without diabetes (HR, 1.65, 95%CI: 0.14-18.98). Retinal arteriolar caliber, retinal venular caliber and retinal vascular fractal dimension were not associated with ESRD. CONCLUSION: Retinopathy signs in persons with diabetes are related to an increased risk of ESRD; however, other microvascular changes in the retina are not associated with ESRD.

Reliability and determinants of retinal vessel oximetry measurements in healthy eyes.

PURPOSE: To assess the reliability and determinants of retinal vessel oximetry measurements with the Oxymap T1 Retinal Oximeter in normal Asian eyes. METHODS: Subjects older than 40 years without a history of stroke and heart disease were recruited from a community-based clinic. Subjects underwent standardized systemic and ocular examinations. Normal eyes were defined as eyes without major eye diseases such as age-related macular degeneration, glaucoma, or retinopathy. Retinal vessel oximetry levels were measured by using the Oxymap T1 Retinal Oximeter. Intra- and intergrader reliability of retinal vessel oximetry measurements were assessed by using 50 images. Intravisit repeatability of retinal vessel oximetry measurements was assessed by using 20 paired images. Univariable linear regression was performed to examine the associations between retinal vessel oximetry measurements and systemic determinants. RESULTS: A total of 118 retinal oximetry images were included in the final analysis. Intra- (intraclass correlation coefficient [ICC] values: 0.89-0.99) and intergrader (ICC values: 0.77-0.94) reliability, and intravisit (ICC values: 0.85-0.96) repeatability were both high. In the linear regression analysis, older age was associated with reduced overall retinal venular oximetry levels (ß: -2.61%; 95% confidence interval [CI]: -4.92 to -0.29) and reduced inferior-nasal retinal venular oximetry levels (ß: -3.53%; 95% CI: -6.07 to -0.99). CONCLUSIONS: The Oxymap Retinal Oximeter allows reliable and repeatable retinal vessel oximetry measurements. Age is the main factor that influences retinal venular oximetry levels and should be taken into account when retinal oximetry measurements are interpreted.

Prevalence, awareness, and control of hypertension among Asian Indians living in urban Singapore and rural India.

BACKGROUND: Hypertension is a major modifiable risk factor associated with cardiovascular morbidity and mortality. We compared the epidemiology of hypertension in South Asian Indians living in two geographic regions with vastly different socioeconomic settings (urban Singapore and rural India). METHODS: We analyzed data from two large population-based studies: the Singapore Indian Eye Study (SINDI, n = 3228, aged 40-80 years, 49.2% women) and the Central India Eye and Medical Study (CIEMS, n = 3591, aged ≥40 years, 52.6% women). Hypertension was defined as SBP at least 140 or DBP at least 90 mmHg or self-reported history/treatment for hypertension. RESULTS: The age-adjusted prevalence of hypertension in SINDI and CIEMS were 58.6 and 25.3%. After adjusting for potential confounders, increasing age, overweight/obese, and diabetes status showed a positive association and 'never drinking alcohol' showed a protective association with hypertension in both populations. Current smoking and being female showed a protective association and no formal education showed a positive association with hypertension in SINDI. Among those with hypertension in SINDI and CIEMS, 72.4 and 25.3% were aware of their condition of whom 85 and 31.6% were on treatment for hypertension. The blood pressure control was similar between the two populations (48.7% in SINDI and 46.9% in CIEMS). CONCLUSION: The prevalence of hypertension, the level of awareness, and treatment for hypertension was higher in Indians living in Singapore than in rural Indians. Socioeconomic and metabolic factors explain some of the observed differences between the two populations, which may provide insights to develop public health strategies.

A missense mutation in the murine Opa3 gene models human Costeff syndrome.

Opa3 mRNA is expressed in all tissues examined to date, but currently the function of the OPA3 protein is unknown. Intriguingly, various mutations in the OPA3 gene lead to two similar diseases in humans: autosomal dominant inherited optic atrophy and cataract (ADOAC) and a metabolic condition; type 3-methylglutaconic aciduria (MGA). Early onset bilateral optic atrophy is a common characteristic of both disorders; retinal ganglion cells are lost and visual acuity is impaired from an early age. In order to investigate the function of the OPA3 protein, we have generated a novel ENU-induced mutant mouse carrying a missense mutation in the OPA3 gene. The heterozygous mutation in exon 2, causes an amino acid change p.L122P (c.365T>C), which is predicted to alter tertiary protein structure. In the heterozygous state, the mice appear uncompromised however; in the homozygous state mice display some of the features of MGA. Visual function is severely reduced, consistent with significant loss of retinal ganglion cells and degeneration of axons in the optic nerve. In the homozygous optic nerve, there was evidence of increased mitochondrial activity, as demonstrated by the increased presence of mitochondrial marker Cytochrome C Oxidase (COX) histochemistry. Mice homozygous for the opa3(L122P) mutation also display a severe multi-systemic disease characterized by reduced lifespan (majority dying before 4 months), decreased weight, dilated cardiomyopathy, extrapyramidal dysfunction and gross neuro-muscular defects. All of these defects are synonymous with the phenotypic characteristics of Type III MGA found in humans. This model will be of major importance for future studies of the specific function of the OPA3 gene.

Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function.

OPA1 is a ubiquitously expressed, nuclear dynamin-related GTPase, targeted to the inner mitochondrial membrane, which plays a role in mitochondrial fusion. Mutations in the OPA1 gene on chromosome 3q28-qter are associated with autosomal dominant optic atrophy (ADOA), the most common inherited optic neuropathy, in which retinal ganglion cells (RGCs) are lost and visual acuity is impaired from an early age. We have generated a novel ENU-induced mutant mouse carrying a protein-truncating nonsense mutation in opa1 in order to explore the pathophysiology of ADOA. The heterozygous mutation, B6; C3-Opa1(Q285STOP), located in exon 8 immediately before the central dynamin-GTPase, leads to approximately 50% reduction in opa1 protein in retina and all tissues on western analysis. The homozygous mutation is embryonic lethal by 13.5 days post coitum, demonstrating the importance of Opa1 during early development. Fibroblasts taken from adult heterozygous mutant mice show an apparent alteration in morphology, with an increase in mitochondrial fission and fragmentation. Heterozygous mutants show a slow onset of degeneration in the optic nerve electron microscopy. Furthermore, they demonstrate a functional reduction in visual function on testing with the optokinetic drum and the circadian running wheel. These findings indicate that the opa1 GTPase contains crucial information required for the survival of RGCs and that Opa1 is essential for early embryonic survival. The Opa1 +/- mice described here provide a means to directly investigate the cellular pathophysiology of OPA1 ADOA.