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1.  Inpatient Coronary Angiography and Revascularisation following Non-ST-Elevation Acute Coronary Syndrome in Patients with Renal Impairment: A Cohort Study Using the Myocardial Ischaemia National Audit Project 
PLoS ONE  2014;9(6):e99925.
International guidelines support an early invasive management strategy (including early coronary angiography and revascularisation) for non-ST-elevation acute coronary syndrome (NSTE-ACS) in patients with renal impairment. However, evidence from outside the UK suggests that this approach is underutilised. We aimed to describe practice within the NHS, and to determine whether the severity of renal dysfunction influenced the provision of angiography and modified the association between early revascularisation and survival.
We performed a cohort study, using multivariable logistic regression and propensity score analyses, of data from the Myocardial Ischaemia National Audit Project for patients presenting with NSTE-ACS to English or Welsh hospitals between 2008 and 2010.
Of 35 881 patients diagnosed with NSTE-ACS, eGFR of <60 ml/minute/1.73 m2 was present in 15 680 (43.7%). There was a stepwise decline in the odds of undergoing inpatient angiography with worsening renal dysfunction. Compared with an eGFR>90 ml/minute/1.73 m2, patients with an eGFR between 45–59 ml/minute/1.73 m2 were 33% less likely to undergo angiography (adjusted OR 0.67, 95% CI 0.55–0.81); those with an eGFR<30/minute/1.73 m2 had a 64% reduction in odds of undergoing angiography (adjusted OR 0.36, 95%CI 0.29–0.43). Of 16 646 patients who had inpatient coronary angiography, 58.5% underwent inpatient revascularisation. After adjusting for co-variables, inpatient revascularisation was associated with approximately a 30% reduction in death within 1 year compared with those managed medically after coronary angiography (adjusted OR 0.66, 95%CI 0.57–0.77), with no evidence of modification by renal function (p interaction = 0.744).
Early revascularisation may offer a similar survival benefit in patients with and without renal dysfunction, yet renal impairment is an important determinant of the provision of coronary angiography following NSTE-ACS. A randomised controlled trial is needed to evaluate the efficacy of an early invasive approach in patients with severe renal dysfunction to ensure that all patients who may benefit are offered this treatment option.
PMCID: PMC4061061  PMID: 24937680
2.  Chronic kidney disease as a risk factor for acute community-acquired infections in high-income countries: a systematic review 
BMJ Open  2014;4(4):e004100.
A systematic review of the association of predialysis chronic kidney disease (CKD) with the incidence of acute, community-acquired infections.
We searched the MEDLINE, EMBASE and Cochrane databases (inception to 16 January 2014) for studies analysing the association of predialysis kidney disease with the incidence of acute, community-acquired urinary tract infection (UTI), lower respiratory tract or central nervous system infections or sepsis. Studies were required to include at least 30 participants with and without kidney disease.
Setting and participants
Community-based populations of adults in high-income countries.
Outcome measures
Acute, community-acquired UTI, lower respiratory tract or central nervous system infections or sepsis.
We identified 14 eligible studies. Estimates from two studies lacked 95% CIs and SEs. The remaining 12 studies yielded 17 independent effect estimates. Only three studies included infections managed in the community. Quality assessment revealed that probable misclassification of kidney disease status and poor adjustment for confounding were common. There was evidence from a few large high-quality studies of a graded association between predialysis CKD stage and hospitalisation for infection. One study found an interaction with age, with a declining effect of CKD on infection risk as age increased. There was evidence of between-studies heterogeneity (I2=96.5%, p<0.001) which persisted in subgroup analysis, and thus meta-analysis was not performed.
Predialysis kidney disease appears to be associated with increased risk of severe infection. Whether predialysis kidney disease increases the susceptibility to infections and whether age modifies this association remains unclear.
PMCID: PMC3996818  PMID: 24742975
Primary Care
3.  Incomplete Reversibility of Estimated Glomerular Filtration Rate Decline Following Tenofovir Disoproxil Fumarate Exposure 
Jose, Sophie | Hamzah, Lisa | Campbell, Lucy J. | Hill, Teresa | Fisher, Martin | Leen, Clifford | Gilson, Richard | Walsh, John | Nelson, Mark | Hay, Phillip | Johnson, Margaret | Chadwick, David | Nitsch, Dorothea | Jones, Rachael | Sabin, Caroline A. | Post, Frank A. | Ainsworth, Jonathan | Anderson, Jane | Babiker, Abdel | Chadwick, David | Delpech, Valerie | Dunn, David | Fisher, Martin | Gazzard, Brian | Gilson, Richard | Gompels, Mark | Hay, Phillip | Hill, Teresa | Johnson, Margaret | Kegg, Stephen | Leen, Clifford | Nelson, Mark | Orkin, Chloe | Palfreeman, Adrian | Phillips, Andrew | Pillay, Deenan | Post, Frank | Sabin, Caroline | Sachikonye, Memory | Schwenk, Achim | Walsh, John | Hill, Teresa | Huntington, Susie | Josie, Sophie | Phillips, Andrew | Sabin, Caroline | Thornton, Alicia | Dunn, David | Glabay, Adam | Orkin, C. | Garrett, N. | Lynch, J. | Hand, J. | de Souza, C. | Fisher, M. | Perry, N. | Tilbury, S. | Churchill, D. | Gazzard, B. | Nelson, M. | Waxman, M. | Asboe, D. | Mandalia, S. | Delpech, V. | Anderson, J. | Munshi, S. | Korat, H. | Poulton, M. | Taylor, C. | Gleisner, Z. | Campbell, L. | Babiker, Abdel | Dunn, David | Glabay, Adam | Gilson, R. | Brima, N. | Williams, I. | Schwenk, A. | Ainsworth, J. | Wood, C. | Miller, S. | Johnson, M. | Youle, M. | Lampe, F. | Smith, C. | Grabowska, H. | Chaloner, C. | Puradiredja, D. | Walsh, J. | Weber, J. | Ramzan, F. | Mackie, N. | Winston, A. | Leen, C. | Wilson, A. | Gompels, M. | Allan, S. | Palfreeman, A. | Moore, A. | Chadwick, D. | Wakeman, K. | Kegg, Stephen | Main, Paul | Mitchell,  | Hunter,  | Sachikonye, Memory | Hay, Phillip | Dhillon, Mandip
The Journal of Infectious Diseases  2014;210(3):363-373.
Background. Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy.
Methods. Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression.
Results. We observed declines in the eGFR during TDF exposure (mean slopes, −15.7 mL/minute/1.73 m2/year [95% confidence interval {CI}, −20.5 to −10.9] during the first 3 months and −3.1 mL/minute/1.73 m2/year [95% CI, −4.6 to −1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m2/year [95% CI, 8.9–16.1] during the first 3 months and 0.8 mL/minute/1.73 m2/year [95% CI, .1–1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy.
Conclusions. This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided.
PMCID: PMC4091582  PMID: 24585896
tenofovir; highly active antiretroviral therapy; eGFR; eGFR slopes; renal function; kidney
4.  Cognitive and Kidney Function: Results from a British Birth Cohort Reaching Retirement Age 
PLoS ONE  2014;9(1):e86743.
Previous studies have found associations between cognitive function and chronic kidney disease. We aimed to explore possible explanations for this association in the Medical Research Council National Survey of Health and Development, a prospective birth cohort representative of the general British population.
Cognitive function at age 60–64 years was quantified using five measures (verbal memory, letter search speed and accuracy, simple and choice reaction times) and glomerular filtration rate (eGFR) at the same age was estimated using cystatin C. The cross-sectional association between cognitive function and eGFR was adjusted for background confounding factors (socioeconomic position, educational attainment), prior cognition, and potential explanations for any remaining association (smoking, diabetes, hypertension, inflammation, obesity).
Data on all the analysis variables were available for 1306–1320 study members (depending on cognitive measure). Verbal memory and simple and choice reaction times were strongly associated with eGFR. For example, the lowest quartile of verbal memory corresponded to a 4.1 (95% confidence interval 2.0, 6.2) ml/min/1.73 m2 lower eGFR relative to the highest quartile. Some of this association was explained by confounding due to socioeconomic factors, but very little of it by prior cognition. Smoking, diabetes, hypertension, inflammation and obesity explained some but not all of the remaining association.
These analyses support the notion of a shared pathophysiology of impaired cognitive and kidney function at older age, which precedes clinical disease. The implications of these findings for clinical care and research are important and under-recognised, though further confirmatory studies are required.
PMCID: PMC3901795  PMID: 24482683
5.  Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis 
Wormser, David | Angelantonio, Emanuele Di | Kaptoge, Stephen | Wood, Angela M | Gao, Pei | Sun, Qi | Walldius, Göran | Selmer, Randi | Verschuren, WM Monique | Bueno-de-Mesquita, H Bas | Engström, Gunnar | Ridker, Paul M | Njølstad, Inger | Iso, Hiroyasu | Holme, Ingar | Giampaoli, Simona | Tunstall-Pedoe, Hugh | Gaziano, J Michael | Brunner, Eric | Kee, Frank | Tosetto, Alberto | Meisinger, Christa | Brenner, Hermann | Ducimetiere, Pierre | Whincup, Peter H | Tipping, Robert W | Ford, Ian | Cremer, Peter | Hofman, Albert | Wilhelmsen, Lars | Clarke, Robert | de Boer, Ian H | Jukema, J Wouter | Ibañez, Alejandro Marín | Lawlor, Debbie A | D'Agostino, Ralph B | Rodriguez, Beatriz | Casiglia, Edoardo | Stehouwer, Coen DA | Simons, Leon A | Nietert, Paul J | Barrett-Connor, Elizabeth | Panagiotakos, Demosthenes B | Björkelund, Cecilia | Strandberg, Timo E | Wassertheil-Smoller, Sylvia | Blazer, Dan G | Meade, Tom W | Welin, Lennart | Svärdsudd, Kurt | Woodward, Mark | Nissinen, Aulikki | Kromhout, Daan | Jørgensen, Torben | Tilvis, Reijo S | Guralnik, Jack M | Rosengren, Annika | Taylor, James O | Kiechl, Stefan | Dagenais, Gilles R | Gerry, F | Fowkes, R | Wallace, Robert B | Khaw, Kay-Tee | Shaffer, Jonathan A | Visser, Marjolein | Kauhanen, Jussi | Salonen, Jukka T | Gallacher, John | Ben-Shlomo, Yoav | Kitamura, Akihiko | Sundström, Johan | Wennberg, Patrik | Kiyohara, Yutaka | Daimon, Makoto | de la Cámara, Agustin Gómez | Cooper, Jackie A | Onat, Altan | Devereux, Richard | Mukamal, Kenneth J | Dankner, Rachel | Knuiman, Matthew W | Crespo, Carlos J | Gansevoort, Ron T | Goldbourt, Uri | Nordestgaard, Børge G | Shaw, Jonathan E | Mussolino, Michael | Nakagawa, Hidaeki | Fletcher, Astrid | Kuller, Lewis H | Gillum, Richard F | Gudnason, Vilmundur | Assmann, Gerd | Wald, Nicholas | Jousilahti, Pekka R | Greenland, Philip | Trevisan, Maurizio | Ulmer, Hanno | Butterworth, Adam S | Folsom, Aaron R | Davey-Smith, George | Hu, Frank B | Danesh, John | Tipping, Robert W | Ford, Charles E | Simpson, Lara M | Walldius, Göran | Jungner, Ingmar | Folsom, Aaron R | Demerath, Ellen W | Franceschini, Nora | Lutsey, Pamela L | Panagiotakos, Demosthenes B | Pitsavos, Christos | Chrysohoou, Christina | Stefanadis, Christodoulos | Shaw, Jonathan E | Atkins, Robert | Zimmet, Paul Z | Barr, Elizabeth LM | Knuiman, Matthew W | Whincup, Peter H | Wannamethee, S Goya | Morris, Richard W | Willeit, Johann | Kiechl, Stefan | Weger, Siegfried | Oberhollenzer, Friedrich | Wald, Nicholas | Ebrahim, Shah | Lawlor, Debbie A | Gallacher, John | Ben-Shlomo, Yoav | Yarnell, John WG | Casiglia, Edoardo | Tikhonoff, Valérie | Greenland, Philip | Shay, Christina M | Garside, Daniel B | Nietert, Paul J | Sutherland, Susan E | Bachman, David L | Keil, Julian E | de Boer, Ian H | Kizer, Jorge R | Psaty, Bruce M | Mukamal, Kenneth J | Nordestgaard, Børge G | Tybjærg-Hansen, Anne | Jensen, Gorm B | Schnohr, Peter | Giampaoli, Simona | Palmieri, Luigi | Panico, Salvatore | Pilotto, Lorenza | Vanuzzo, Diego | de la Cámara, Agustin Gómez | Simons, Leon A | Simons, Judith | McCallum, John | Friedlander, Yechiel | Gerry, F | Fowkes, R | Price, Jackie F | Lee, Amanda J | Taylor, James O | Guralnik, Jack M | Phillips, Caroline L | Wallace, Robert B | Kohout, Frank J | Cornoni-Huntley, Joan C | Guralnik, Jack M | Blazer, Dan G | Guralnik, Jack M | Phillips, Caroline L | Phillips, Caroline L | Guralnik, Jack M | Khaw, Kay-Tee | Wareham, Nicholas J | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Rothenbacher, Dietrich | Wennberg, Patrik | Jansson, Jan-Håkan | Nissinen, Aulikki | Donfrancesco, Chiara | Giampaoli, Simona | Woodward, Mark | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | D'Agostino, Ralph B | Vasan, Ramachandran S | Fox, Caroline S | Pencina, Michael J | Daimon, Makoto | Oizumi, Toshihide | Kayama, Takamasa | Kato, Takeo | Bladbjerg, Else-Marie | Jørgensen, Torben | Møller, Lars | Jespersen, Jørgen | Dankner, Rachel | Chetrit, Angela | Lubin, Flora | Svärdsudd, Kurt | Eriksson, Henry | Welin, Lennart | Lappas, Georgios | Rosengren, Annika | Lappas, Georgios | Welin, Lennart | Svärdsudd, Kurt | Eriksson, Henry | Lappas, Georgios | Bengtsson, Calle | Lissner, Lauren | Björkelund, Cecilia | Cremer, Peter | Nagel, Dorothea | Strandberg, Timo E | Salomaa, Veikko | Tilvis, Reijo S | Miettinen, Tatu A | Tilvis, Reijo S | Strandberg, Timo E | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Rodriguez, Beatriz | Dekker, Jacqueline M | Nijpels, Giel | Stehouwer, Coen DA | Hu, Frank B | Sun, Qi | Rimm, Eric B | Willett, Walter C | Iso, Hiroyasu | Kitamura, Akihiko | Yamagishi, Kazumasa | Noda, Hiroyuki | Goldbourt, Uri | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | Kauhanen, Jussi | Salonen, Jukka T | Kurl, Sudhir | Tuomainen, Tomi-Pekka | Poppelaars, Jan L | Deeg, Dorly JH | Visser, Marjolein | Meade, Tom W | De Stavola, Bianca Lucia | Hedblad, Bo | Nilsson, Peter | Engström, Gunnar | Verschuren, WM Monique | Blokstra, Anneke | de Boer, Ian H | Shea, Steven J | Meisinger, Christa | Thorand, Barbara | Koenig, Wolfgang | Döring, Angela | Verschuren, WM Monique | Blokstra, Anneke | Bueno-de-Mesquita, H Bas | Wilhelmsen, Lars | Rosengren, Annika | Lappas, Georgios | Fletcher, Astrid | Nitsch, Dorothea | Kuller, Lewis H | Grandits, Greg | Tverdal, Aage | Selmer, Randi | Nystad, Wenche | Mussolino, Michael | Gillum, Richard F | Hu, Frank B | Sun, Qi | Manson, JoAnn E | Rimm, Eric B | Hankinson, Susan E | Meade, Tom W | De Stavola, Bianca Lucia | Cooper, Jackie A | Bauer, Kenneth A | Davidson, Karina W | Kirkland, Susan | Shaffer, Jonathan A | Shimbo, Daichi | Kitamura, Akihiko | Iso, Hiroyasu | Sato, Shinichi | Holme, Ingar | Selmer, Randi | Tverdal, Aage | Nystad, Wenche | Nakagawa, Hidaeki | Miura, Katsuyuki | Sakurai, Masaru | Ducimetiere, Pierre | Jouven, Xavier | Bakker, Stephan JL | Gansevoort, Ron T | van der Harst, Pim | Hillege, Hans L | Crespo, Carlos J | Garcia-Palmieri, Mario R | Kee, Frank | Amouyel, Philippe | Arveiler, Dominique | Ferrières, Jean | Schulte, Helmut | Assmann, Gerd | Jukema, J Wouter | de Craen, Anton JM | Sattar, Naveed | Stott, David J | Cantin, Bernard | Lamarche, Benoît | Després, Jean-Pierre | Dagenais, Gilles R | Barrett-Connor, Elizabeth | Bergstrom, Jaclyn | Bettencourt, Richele R | Buisson, Catherine | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Trevisan, Maurizio | Hofman, Albert | Ikram, M Arfan | Tiemeier, Henning | Witteman, Jacqueline CM | Tunstall-Pedoe, Hugh | Tavendale, Roger | Lowe, Gordon DO | Woodward, Mark | Devereux, Richard | Yeh, Jeun-Liang | Ali, Tauqeer | Calhoun, Darren | Ben-Shlomo, Yoav | Davey-Smith, George | Onat, Altan | Can, Günay | Nakagawa, Hidaeki | Sakurai, Masaru | Nakamura, Koshi | Morikawa, Yuko | Njølstad, Inger | Mathiesen, Ellisiv B | Løchen, Maja-Lisa | Wilsgaard, Tom | Sundström, Johan | Ingelsson, Erik | Michaëlsson, Karl | Cederholm, Tommy | Gaziano, J Michael | Buring, Julie | Ridker, Paul M | Gaziano, J Michael | Ridker, Paul M | Ulmer, Hanno | Diem, Günter | Concin, Hans | Rodeghiero, Francesco | Tosetto, Alberto | Wassertheil-Smoller, Sylvia | Manson, JoAnn E | Marmot, Michael | Clarke, Robert | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimaki, Mika | Ridker, Paul M | Buring, Julie | Ford, Ian | Robertson, Michele | Ibañez, Alejandro Marín | Feskens, Edith | Geleijnse, Johanna M | Kromhout, Daan | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S | Angelantonio, Emanuele Di | Franco, Oscar H | Gao, Pei | Gobin, Reeta | Haycock, Philip | Kaptoge, Stephen | Seshasai, Sreenivasa R Kondapally | Lewington, Sarah | Pennells, Lisa | Rapsomaniki, Eleni | Sarwar, Nadeem | Thompson, Alexander | Thompson, Simon G | Walker, Matthew | Watson, Sarah | White, Ian R | Wood, Angela M | Wormser, David | Zhao, Xiaohui | Danesh, John
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
6.  Early-Life Overweight Trajectory and CKD in the 1946 British Birth Cohort Study 
Few studies have examined the impact of childhood obesity on later kidney disease, and consequently, our understanding is very limited.
Study Design
Longitudinal population-based cohort.
Setting & Participants
The Medical Research Council National Survey of Health and Development, a socially stratified sample of 5,362 singletons born in 1 week in March 1946 in England, Scotland, and Wales, of which 4,340 were analyzed.
Early-life overweight latent classes (never, prepubertal only, pubertal onset, or always), derived from repeated measurements of body mass index between ages 2 and 20 years.
Outcomes & Measurements
The primary outcome was chronic kidney disease (CKD), defined as creatinine- or cystatin C–based estimated glomerular filtration rate (eGFRcr and eGFRcys, respectively) <60 mL/min/1.73 m2 or urine albumin-creatinine ratio (UACR) ≥3.5 mg/mmol measured at age 60-64 years. Associations were explored through regression analysis, with adjustment for socioeconomic position, smoking, physical activity level, diabetes, hypertension, and overweight at ages 36 and 53 years.
2.3% of study participants had eGFRcr <60 mL/min/1.73 m2, 1.7% had eGFRcys <60 mL/min/1.73 m2, and 2.9% had UACR ≥3.5 mg/mmol. Relative to being in the never-overweight latent class, being in the pubertal-onset– or always-overweight latent classes was associated with eGFRcys-defined CKD (OR, 2.04; 95% CI, 1.09-3.82). Associations with CKD defined by eGFRcr (OR, 1.27; 95% CI, 0.71-2.29) and UACR (OR, 1.33; 95% CI, 0.70-2.54) were less marked, but in the same direction. Adjustment for lifestyle and health factors had little impact on effect estimates.
A low prevalence of CKD resulted in low statistical power. No documentation of chronicity for outcomes. All-white study population restricts generalizability.
Being overweight in early life was found to be associated with eGFRcys-defined CKD in later life. The associations with CKD defined by eGFRcr and UACR were less marked, but in the same direction. Reducing or preventing overweight in the early years of life may significantly reduce the burden of CKD in the population.
PMCID: PMC3719096  PMID: 23714172
Childhood obesity; chronic kidney disease; estimated glomerular filtration rate
7.  Polymorphisms in ARMS2/HTRA1 and Complement Genes and Age-Related Macular Degeneration in India: Findings from the INDEYE Study 
Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India.
Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1–3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center.
Of 3569 participants, 53.2% had no signs of AMD, 45.6% had features of early AMD, and 1.2% had late AMD. CFH (rs1061170), C2 (rs547154), or CFB (rs438999) was not associated with early or late AMD. In the ARMS2 locus, rs10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13–1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15–2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02–1.23; P = 0.02); rs10490923 was not associated with early or late AMD.
Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India.
We report results from a genetic association study of early AMD in an Indian population. Two variants in the ARMS/HTRA1 region were associated with early AMD but variants in C2, CFH, and CFB were not.
PMCID: PMC3490538  PMID: 23060141
8.  Differences in estimation of creatinine generation between renal function estimating equations in an Indian population: cross-sectional data from the Hyderabad arm of the Indian migration study 
BMC Nephrology  2013;14:30.
Creatinine based formulae for estimating renal function developed in white populations may be less valid in other ethnic groups. We assessed the performance of various estimating formulae in an Indian population.
917 subjects were recruited from the Hyderabad arm of the Indian Migration Study. Data were collected on comorbidity, serum creatinine and body composition from DXA scans. Renal function was compared using the modified Cockcroft-Gault, MDRD and CKD-EPI formulae. 24-hour creatinine production was derived from each estimate and the agreement with measured muscle mass examined. 24-hour creatinine production estimates were compared to that derived from a formula by Rule incorporating DXA measured muscle mass. Potential systematic biases were examined by age and eGFR. We assessed the association of renal function by each formula with hypertension and self-reported measures of vascular disease.
Mean modified Cockcroft-Gault eCCl was 98.8 ml/min/1.73 m2, MDRD eGFR 91.2 ml/min/1.73 m2 and CKD-EPI eGFR 96.3 ml/min/1.73 m2. MDRD derived 24-hour creatinine production showed the least age-related underestimation compared to the Rule formula. CKD-EPI showed a marked bias at higher eGFRs. All formulae showed similar strength associations with vascular disease and hypertension.
Our analyses support the use of MDRD for estimating renal function in Indian populations. Further work is required to assess the predictive value of formulae for incident disease and complications of CKD.
PMCID: PMC3599554  PMID: 23379609
Creatinine; Ethnicity; Muscle mass; Renal function
9.  Incidence of End-Stage Renal Disease in the Turkish-Cypriot Population of Northern Cyprus: A Population Based Study 
PLoS ONE  2013;8(1):e54394.
This is the first report of the incidence and causes of end-stage renal disease (ESRD) of the Turkish-Cypriot population in Northern Cyprus.
Data were collected over eight consecutive years (2004–2011) from all those starting renal replacement therapy (RRT) in this population. Crude and age-standardised incidence at 90 days was calculated and comparisons made with other national registries. We collected DNA from the entire prevalent population. As an initial experiment we looked for two genetic causes of ESRD that have been reported in Greek Cypriots.
Crude and age-standardised incidence at 90 days was 234 and 327 per million population (pmp) per year, respectively. The mean age was 63, and 62% were male. The age-adjusted prevalence of RRT in Turkish-Cypriots was 1543 pmp on 01/01/2011. The incidence of RRT is higher than other countries reporting to the European Renal Association – European Dialysis and Transplant Association, with the exception of Turkey. Diabetes is a major cause of ESRD in those under 65, accounting for 36% of incident cases followed by 30% with uncertain aetiology. 18% of the incident population had a family history of ESRD. We identified two families with thin basement membrane nephropathy caused by a mutation in COL4A3, but no new cases of CFHR5 nephropathy.
This study provides the first estimate of RRT incidence in the Turkish-Cypriot population, describes the contribution of different underlying diagnoses to ESRD, and provides a basis for healthcare policy planning.
PMCID: PMC3547872  PMID: 23349874
10.  Baseline Kidney Function as Predictor of Mortality and Kidney Disease Progression in HIV-Positive Patients 
Chronic kidney disease (CKD) is associated with increased all-cause mortality and kidney disease progression. Decreased kidney function at baseline may identify human immunodeficiency virus (HIV)-positive patients at increased risk of death and kidney disease progression.
Study Design
Observational cohort study.
Setting & Participants
7 large HIV cohorts in the United Kingdom with kidney function data available for 20,132 patients.
Baseline estimated glomerular filtration rate (eGFR).
Death and progression to stages 4-5 CKD (eGFR <30 mL/min/1.73 m2 for >3 months) in Cox proportional hazards and competing-risk regression models.
Median age at baseline was 34 (25th-75th percentile, 30-40) years, median CD4 cell count was 350 (25th-75th percentile, 208-520) cells/μL, and median eGFR was 100 (25th-75th percentile, 87-112) mL/min/1.73 m2. Patients were followed up for a median of 5.3 (25th-75th percentile, 2.0-8.9) years, during which 1,820 died and 56 progressed to stages 4-5 CKD. A U-shaped relationship between baseline eGFR and mortality was observed. After adjustment for potential confounders, eGFRs <45 and >105 mL/min/1.73 m2 remained associated significantly with increased risk of death. Baseline eGFR <90 mL/min/1.73 m2 was associated with increased risk of kidney disease progression, with the highest incidence rates of stages 4-5 CKD (>3 events/100 person-years) observed in black patients with eGFR of 30-59 mL/min/1.73 m2 and those of white/other ethnicity with eGFR of 30-44 mL/min/1.73 m2.
The relatively small numbers of patients with decreased eGFR at baseline and low rates of progression to stages 4-5 CKD and lack of data for diabetes, hypertension, and proteinuria.
Although stages 4-5 CKD were uncommon in this cohort, baseline eGFR allowed the identification of patients at increased risk of death and at greatest risk of kidney disease progression.
PMCID: PMC3657190  PMID: 22521282
Estimated glomerular filtration rate (eGFR); Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI); human immunodeficiency virus (HIV); chronic kidney disease; mortality; competing risk
11.  Clinical Disorders in a Post War British Cohort Reaching Retirement: Evidence from the First National Birth Cohort Study 
PLoS ONE  2012;7(9):e44857.
The medical needs of older people are growing because the proportion of the older population is increasing and disease boundaries are widening. This study describes the distribution and clustering of 15 common clinical disorders requiring medical treatment or supervision in a representative British cohort approaching retirement, and how health tracked across adulthood.
Methods and Findings
The data come from a cohort of 2661 men and women, 84% of the target sample, followed since birth in England, Scotland and Wales in 1946, and assessed at 60–64 years for: cardio and cerebro-vascular disease, hypertension, raised cholesterol, renal impairment, diabetes, obesity, hypothyroidism, hyperthyroidism, anaemia, respiratory disease, liver disease, psychiatric problems, cancers, atrial fibrillation on ECG and osteoporosis. We calculated the proportions disorder-free, with one or more disorders, and the level of undiagnosed disorders; and how these disorders cluster into latent classes and relate to health assessed at 36 years. Participants had, on average, two disorders (range 0–9); only 15% were disorder-free. The commonest disorders were hypertension (54.3%, 95% CI 51.8%–56.7%), obesity (31.1%, 28.8%–33.5%), raised cholesterol (25.6%, 23.1–28.26%), and diabetes or impaired fasting glucose (25.0%, 22.6–27.5%). A cluster of one in five individuals had a high probability of cardio-metabolic disorders and were twice as likely than others to have been in the poorest health at 36 years. The main limitations are that the native born sample is entirely white, and a combination of clinical assessments and self reports were used.
Most British people reaching retirement already have clinical disorders requiring medical supervision. Widening disease definitions and the move from a disease-based to a risk-based medical model will increase pressure on health services. The promotion of healthy ageing should start earlier in life and consider the individual's ability to adapt to and self manage changes in health.
PMCID: PMC3447001  PMID: 23028647
12.  Proteinuria and hypoalbuminemia are risk factors for thromboembolic events in patients with idiopathic membranous nephropathy: an observational study 
BMC Nephrology  2012;13:107.
Patients with nephrotic syndrome are at an increased risk of thromboembolic events (TEs). However, this association has not been thoroughly investigated in adult patients with idiopathic membranous nephropathy (IMN).
A retrospective analysis of all 101 consecutive adult patients with MN diagnosed at our centre during 1995 to 2008 was performed. Pertinent data including thromboembolic events and the risk factors for TEs were recorded.
The cohort was followed for 7.2 ± 3 years. Out of 78 patients with IMN, 15 (19.2%) had at least one TE. No TEs occurred six months after diagnosis. The incidence of TEs in the first 6 months of diagnosis was 7.69% (95%CI, 2.5-17.0) and all patients except one had venous TEs. At the time of diagnosis of MN, the patients with TEs had lower serum albumin (1.9 ± 0.5 vs. 2.4 ± 0.4 g/dl, TE vs. no TE; p < 0.01) and greater serum cholesterol (414 ± 124 vs. 317 ± 108 mg/dl, TE vs. no TE; p = 0.01) and 24-h proteinuria (10.7 ± 3 vs. 7.1 ± 4 g, TE vs. no TE; p < 0.01). Multivariate logistic regression adjusted for age, sex, cholesterol and creatinine revealed, an odds ratio of 0.8 (95% CI 0.7 – 0.96; p = 0.01) for every one g/dl increase in baseline serum albumin and, an odds ratio of 1.3 (95% CI 1.05-1.58; p = 0.01) for one gram increase in 24-h proteinuria, for TEs.
Our study finding confirms IMN as a prothrombotic state particularly in the first six months of diagnosis. Proteinuria, in addition to hypoalbuminemia, is a risk factor for TEs. These results have important implications for clinical care of patients with IMN, particularly with regards to initiation and duration of prophylactic anticoagulation.
PMCID: PMC3480900  PMID: 22963194
Membranous nephropathy; Thromboembolism; Proteinuria; Hypoalbuminemia
13.  Is Intergenerational Social Mobility Related to the Type and Amount of Physical Activity in Mid-Adulthood? Results from the 1946 British Birth Cohort Study 
Annals of Epidemiology  2012;22(7):487-498.
Greater levels of leisure-time or moderate-vigorous physical activity have consistently been found in those with greater socioeconomic position (SEP). Less is known about the effects of intergenerational social mobility.
We examined the influence of SEP and social mobility on mid-adulthood physical activity in the Medical Research Council National Survey of Health and Development. Two sub-domains of SEP were used: occupational class and educational attainment. Latent classes for walking, cycling, and leisure-time physical activity (LTPA) were used, plus sedentary behavior at age 36. Associations between types of physical activity and SEP were examined with the use of logistic or multinomial logistic regression.
Being a manual worker oneself or having a father who was a manual worker was, relative to nonmanual work, associated with lower levels of sedentary behavior and greater walking activity, but also with lower LTPA. Compared with those who remained in a manual occupational class, upward occupational mobility was associated with more sedentary behavior, less walking, and increased LTPA. Associations with downward mobility were in the opposite directions. Similar results were obtained for educational attainment.
This study found clear evidence of social differences in physical activity. Persistently high SEP and upward social mobility were associated with greater levels of LTPA but also increased sedentary behavior and less walking.
PMCID: PMC3383988  PMID: 22534178
Cohort Study; Education; Exercise; Leisure Activities; Occupation; Physical Activity; Social Mobility; Socioeconomic Position; CVD, cardiovascular disease; LCA, latent class analysis; LTPA, leisure-time physical activity; SEP, socioeconomic position
14.  EPHA2 Polymorphisms and Age-Related Cataract in India 
PLoS ONE  2012;7(3):e33001.
We investigated whether previously reported single nucleotide polymorphisms (SNPs) of EPHA2 in European studies are associated with cataract in India.
We carried out a population-based genetic association study. We enumerated randomly sampled villages in two areas of north and south India to identify people aged 40 and over. Participants attended a clinical examination including lens photography and provided a blood sample for genotyping. Lens images were graded by the Lens Opacification Classification System (LOCS III). Cataract was defined as a LOCS III grade of nuclear ≥4, cortical ≥3, posterior sub-capsular (PSC) ≥2, or dense opacities or aphakia/pseudophakia in either eye. We genotyped SNPs rs3754334, rs7543472 and rs11260867 on genomic DNA extracted from peripheral blood leukocytes using TaqMan assays in an ABI 7900 real-time PCR. We used logistic regression with robust standard errors to examine the association between cataract and the EPHA2 SNPs, adjusting for age, sex and location.
7418 participants had data on at least one of the SNPs investigated. Genotype frequencies of controls were in Hardy-Weinberg Equilibrium (p>0.05). There was no association of rs3754334 with cataract or type of cataract. Minor allele homozygous genotypes of rs7543472 and rs11260867 compared to the major homozygote genotype were associated with cortical cataract, Odds ratio (OR) = 1.8, 95% Confidence Interval (CI) (1.1, 3.1) p = 0.03 and 2.9 (1.2, 7.1) p = 0.01 respectively, and with PSC cataract, OR = 1.5 (1.1, 2.2) p = 0.02 and 1.8 (0.9, 3.6) p = 0.07 respectively. There was no consistent association of SNPs with nuclear cataract or a combined variable of any type of cataract including operated cataract.
Our results in the Indian population agree with previous studies of the association of EPHA2 variants with cortical cataracts. We report new findings for the association with PSC which is particularly prevalent in Indians.
PMCID: PMC3297613  PMID: 22412971
15.  Characterizing Longitudinal Patterns of Physical Activity in Mid-Adulthood Using Latent Class Analysis: Results From a Prospective Cohort Study 
American Journal of Epidemiology  2011;174(12):1406-1415.
The authors aimed to describe how longitudinal patterns of physical activity during mid-adulthood (ages 31–53 years) can be characterized using latent class analysis in a population-based birth cohort study, the Medical Research Council’s 1946 National Survey of Health and Development. Three different types of physical activity—walking, cycling, and leisure-time physical activity—were analyzed separately using self-reported data collected from questionnaires between 1977 and 1999; 3,847 study members were included in the analysis for one or more types of activity. Patterns of activity differed by sex, so stratified analyses were conducted. Two walking latent classes were identified representing low (52.8% of males in the cohort, 33.5% of females) and high (47.2%, 66.5%) levels of activity. Similar low (91.4%, 82.1%) and high (8.6%, 17.9%) classes were found for cycling, while 3 classes were identified for leisure-time physical activity: “low activity” (46.2%, 48.2%), “sports and leisure activity” (31.0%, 35.3%), and “gardening and do-it-yourself activities” (22.8%, 16.5%). The classes were reasonably or very well separated, with the exception of walking in females. Latent class analysis was found to be a useful tool for characterizing longitudinal patterns of physical activity, even when the measurement instrument differs slightly across ages, which added value in comparison with observed activity at a single age.
PMCID: PMC3276296  PMID: 22074812
adult; cohort studies; exercise; latent class; leisure activities; longitudinal studies; prospective studies
16.  Socioeconomic Status and Reduced Kidney Function in the Whitehall II Study: Role of Obesity and Metabolic Syndrome 
Previous US-based studies have found that chronic kidney disease (CKD) disproportionately affects those of more adverse social circumstances. Our aim was to show the association between socioeconomic status (SES) and decreased kidney function in a European context and explore the role of obesity and metabolic syndrome. We consider the potential confounding effect of lean muscle mass.
Study Design
Setting & Participants
White participants in the follow-up of the Whitehall II cohort: UK-based European population (age, 55-79 years; n = 5,533), of whom 4,066 men (73%) and 1,467 women (27%) with complete data were analyzed.
Self-reported occupational grade/salary range.
Estimated glomerular filtration rate (GFR) using the CKD-EPI (CKD Epidemiology Collaboration) equation.
Body mass index (BMI), serum lipid levels, blood pressure, Tanita TBF-300 body composition analyzer, impedance-derived lean mass index (LMI).
Participants in a lower compared with higher occupational grade were at increased odds of having decreased GFR (age- and sex-adjusted OR, 1.31; 95% CI, 1.12-1.53; P = 0.001). Socioeconomic disparity in LMI was evident in women, but not men. After further adjustment for BMI and components of metabolic syndrome, the odds of decreased GFR in whites with a lower compared with higher occupational grade was attenuated by 23.3% (OR, 1.23; 95% CI, 1.06-1.45; P = 0.008). Adjustment for LMI explained 15% of the association between SES and estimated GFR.
Cross-sectional design, missing data for subset of participants, no urinary data.
BMI and components of metabolic syndrome may explain up to a quarter of the association between low SES and decreased GFR, suggesting potential modifiable factors.
PMCID: PMC3192873  PMID: 21719176
Reduced kidney function; estimated glomerular filtration rate; lean body mass; obesity; serum lipids; socioeconomic status
17.  CKD and Hospitalization in the Elderly: A Community-Based Cohort Study in the United Kingdom 
We previously have shown that chronic kidney disease (CKD) is associated with cardiovascular and all-cause mortality in community-dwelling people 75 years and older. The present study addresses the hypothesis that CKD is associated with a higher rate of hospital admission at an older age.
Study Design
Cohort study.
Setting & Participants
15,336 participants from 53 UK general practices underwent comprehensive health assessment between 1994 and 1999.
Data for estimated glomerular filtration rate (eGFR, derived from creatinine levels using the CKD Epidemiology Collaboration [CKD-EPI] study equation) and dipstick proteinuria were available for 12,371 participants.
Hospital admissions collected from hospital discharge letters for 2 years after assessment.
Age, sex, cardiovascular risk factors, possible biochemical and health consequences of kidney disease (hemoglobin, phosphate, and albumin levels; physical and mental health problems).
2,310 (17%) participants had 1 hospital admission, and 981 (7%) had 2 or more. After adjusting for age, sex, and cardiovascular risk factors, HRs were 1.66 (95% CI, 1.21-2.27), 1.17 (95% CI, 0.95-1.43), 1.08 (95% CI, 0.90-1.30), and 1.11 (95% CI, 0.91-1.35) for eGFRs <30, 30-44, 45-59, and ≥75 mL/min/1.73 m2, respectively, compared with eGFRs of 60-74 mL/min/1.73 m2 for hospitalizations during <6 months of follow-up. HRs were weaker for follow-up of 6-18 months. Dipstick-positive proteinuria was associated with an increased HR throughout follow-up (HR, 1.29 [95% CI, 1.11-1.49], adjusting for cardiovascular risk factors). Dipstick-positive proteinuria and eGFR <30 mL/min/1.73 m2 were independently associated with 2 or more hospital admissions during the 2-year follow-up. Adjustment for other health factors and laboratory measurements attenuated the effect of eGFR, but not the effect of proteinuria.
Follow-up limited to 2 years, selection bias due to nonparticipation in study, missing data for potential covariates, and single noncalibrated measurements from multiple laboratories.
The study indicates that community-dwelling older people who have dipstick-positive proteinuria and/or eGFR <30 mL/min/1.73 m2 are at increased risk of hospitalization.
PMCID: PMC3392651  PMID: 21146270
Chronic kidney disease; cohort study; dipstick proteinuria testing; general population; hospitalization; older people
18.  30 Year Patterns of Mortality in Tobago, West Indies, 1976-2005: Impact of Glucose Intolerance and Alcohol Intake 
PLoS ONE  2011;6(1):e14588.
To determine the main predictors of all-cause and cardiovascular (CV) mortality in a rural West Indian population in Plymouth, Tobago over 30 years.
Questionnaire survey for CV risk factors and alcohol consumption patterns administered at baseline in 1976 with 92.5% response rate. 831/832 patients were followed up until 2005 or death.
Hypertension (>140/90 mm Hg) was prevalent in 48% of men and 44% of women, and 21% of men and 17% of women had diabetes. Evidence showed most predictors for all cause and cardiovascular mortality having the main effects at ages <60 years, (p-value for interaction<0.01) but no risk factors having sex-specific effects on mortality. The main predictors of all-cause mortality at age <60 years in the fully adjusted model were high sessional alcohol intake (hazard ratio (HR) 2.04, 95% CI 1.10-3.80), severe hypertension >160/95 mm Hg (HR 1.68, 95% CI 1.09-2.60), diabetes (HR 3.28, 95% CI 1.89-5.69), and BMI (HR 1.04, 95% CI 1.00-1.07). The main predictors of cardiovascular mortality were similar in the fully adjusted model: high sessional alcohol intake (HR 2.47 95% CI 1.10-5.57), severe hypertension (HR 2.78 95% CI 1.56-4.95), diabetes (HR 3.68 95% CI 1.77-7.67) and additionally LVH, (HR 5.54 95% CI 1.38-22.26), however BMI did not show independent effects. For men, high sessional alcohol intake explains 27% of all cause mortality, and 40% of cardiovascular mortality at age <60 yrs. In adults aged <60 years, the attributable risk fraction for IGT/Diabetes and all cause mortality and cardiovascular mortality is 28% in women vs. 11% in men, and 22% in women vs. 6% in men respectively.
In this Afro-Caribbean population we found that a major proportion of deaths are attributable to high sessional alcohol intake (in males), diabetes, and hypertension and these risk factors primarily operate in those below 60 years.
PMCID: PMC3026774  PMID: 21283617
19.  Multiple New Loci Associated with Kidney Function and Chronic Kidney Disease: The CKDGen consortium 
Köttgen, Anna | Pattaro, Cristian | Böger, Carsten A. | Fuchsberger, Christian | Olden, Matthias | Glazer, Nicole L. | Parsa, Afshin | Gao, Xiaoyi | Yang, Qiong | Smith, Albert V. | O’Connell, Jeffrey R. | Li, Man | Schmidt, Helena | Tanaka, Toshiko | Isaacs, Aaron | Ketkar, Shamika | Hwang, Shih-Jen | Johnson, Andrew D. | Dehghan, Abbas | Teumer, Alexander | Paré, Guillaume | Atkinson, Elizabeth J. | Zeller, Tanja | Lohman, Kurt | Cornelis, Marilyn C. | Probst-Hensch, Nicole M. | Kronenberg, Florian | Tönjes, Anke | Hayward, Caroline | Aspelund, Thor | Eiriksdottir, Gudny | Launer, Lenore | Harris, Tamara B. | Rapmersaud, Evadnie | Mitchell, Braxton D. | Boerwinkle, Eric | Struchalin, Maksim | Cavalieri, Margherita | Singleton, Andrew | Giallauria, Francesco | Metter, Jeffery | de Boer, Ian | Haritunians, Talin | Lumley, Thomas | Siscovick, David | Psaty, Bruce M. | Zillikens, M. Carola | Oostra, Ben A. | Feitosa, Mary | Province, Michael | Levy, Daniel | de Andrade, Mariza | Turner, Stephen T. | Schillert, Arne | Ziegler, Andreas | Wild, Philipp S. | Schnabel, Renate B. | Wilde, Sandra | Muenzel, Thomas F. | Leak, Tennille S | Illig, Thomas | Klopp, Norman | Meisinger, Christa | Wichmann, H.-Erich | Koenig, Wolfgang | Zgaga, Lina | Zemunik, Tatijana | Kolcic, Ivana | Minelli, Cosetta | Hu, Frank B. | Johansson, Åsa | Igl, Wilmar | Zaboli, Ghazal | Wild, Sarah H | Wright, Alan F | Campbell, Harry | Ellinghaus, David | Schreiber, Stefan | Aulchenko, Yurii S | Rivadeneira, Fernando | Uitterlinden, Andre G | Hofman, Albert | Imboden, Medea | Nitsch, Dorothea | Brandstätter, Anita | Kollerits, Barbara | Kedenko, Lyudmyla | Mägi, Reedik | Stumvoll, Michael | Kovacs, Peter | Boban, Mladen | Campbell, Susan | Endlich, Karlhans | Völzke, Henry | Kroemer, Heyo K. | Nauck, Matthias | Völker, Uwe | Polasek, Ozren | Vitart, Veronique | Badola, Sunita | Parker, Alexander N. | Ridker, Paul M. | Kardia, Sharon L. R. | Blankenberg, Stefan | Liu, Yongmei | Curhan, Gary C. | Franke, Andre | Rochat, Thierry | Paulweber, Bernhard | Prokopenko, Inga | Wang, Wei | Gudnason, Vilmundur | Shuldiner, Alan R. | Coresh, Josef | Schmidt, Reinhold | Ferrucci, Luigi | Shlipak, Michael G. | van Duijn, Cornelia M. | Borecki, Ingrid | Krämer, Bernhard K. | Rudan, Igor | Gyllensten, Ulf | Wilson, James F. | Witteman, Jacqueline C. | Pramstaller, Peter P. | Rettig, Rainer | Hastie, Nick | Chasman, Daniel I. | Kao, W. H. | Heid, Iris M. | Fox, Caroline S.
Nature genetics  2010;42(5):376-384.
Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 Caucasian individuals from 20 population-based studies to identify new susceptibility loci for reduced renal function, estimated by serum creatinine (eGFRcrea), cystatin C (eGFRcys), and CKD (eGFRcrea <60 ml/min/1.73m2; n = 5,807 CKD cases). Follow-up of the 23 genome-wide significant loci (p<5×10−8) in 22,982 replication samples identified 13 novel loci for renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2, and SLC7A9) and 7 creatinine production and secretion loci (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72, BCAS3). These results further our understanding of biologic mechanisms of kidney function by identifying loci potentially influencing nephrogenesis, podocyte function, angiogenesis, solute transport, and metabolic functions of the kidney.
PMCID: PMC2997674  PMID: 20383146
genome-wide association; renal disease; population-based; genetics; chronic kidney disease
20.  An Ecological Correlation Study of Late Age-Related Macular Degeneration and the Complement Factor H Y402H Polymorphism 
Based on published data, this ecological correlation study showed evidence to support the hypothesis that variation in the risk allele frequency of the Y402H polymorphism across ethnicities explains variation in prevalence of late AMD when data on people of African ancestry are excluded.
To investigate whether variation in the distribution of the risk allele frequency of the Y402H single-nucleotide polymorphism (SNP) across various ethnicities and geographic regions reflects differences in the prevalence of late age-related macular degeneration (AMD) in those ethnicities.
Published data were obtained via a systematic search. Study samples were grouped into clusters by ethnicity and geographic location and the Spearman correlation coefficient of the prevalence of late AMD and risk allele frequencies was calculated across clusters.
Across all ethnicities, AMD prevalence was seen to increase with age. Populations of European descent had both higher risk allele frequencies and prevalence of late AMD than did Japanese, Chinese, and Hispanic descendants. Results for African descendants were anomalous: although allele frequency was similar to that in European populations, the age-specific prevalence of late AMD was considerably lower. The correlation coefficient for the association between allele frequency and AMD prevalence was 0.40 (95% confidence interval [CI] = −0.36 to 0.84, P = 0.28) in all populations combined and 0.71 (95% CI = 0.02–0.94, P = 0.04) when people of African descent were excluded.
Evidence was found at the population level to support a positive association between the Y204H risk allele and the prevalence of AMD after exclusion of studies undertaken on persons of African ancestry. Data in African, Middle Eastern, and South American populations are needed to provide a better understanding of the association of late AMD genetic risk across ethnicities.
PMCID: PMC2868481  PMID: 20042653
21.  Survival of patients from South Asian and Black populations starting renal replacement therapy in England and Wales 
Nephrology Dialysis Transplantation  2009;24(12):3774-3782.
Background. South Asian and Black ethnic minorities in the UK have higher rates of acceptance onto renal replacement therapy (RRT) than Caucasians. Registry studies in the USA and Canada show better survival; there are few data in the UK.
Methods. Renal Association UK Renal Registry data were used to compare the characteristics and survival of patients starting RRT from both groups with those of Caucasians, using incident cases accepted between 1997 and 2006. Survival was analysed by multivariate Cox's proportional hazards regression split by haemodialysis and peritoneal dialysis (PD) due to non-proportionality, and without censoring at transplantation.
Results. A total of 2495 (8.2%) were South Asian and 1218 (4.0%) were Black. They were younger and had more diabetic nephropathy. The age-adjusted prevalence of vascular co-morbidity was higher in South Asians and lower in Blacks; other co-morbidities were generally common in Caucasians. Late referral did not differ. They were less likely to receive a transplant or to start PD. South Asians and Blacks had significantly better survival than Caucasians both from RRT start to Day 90 and after Day 90, and for those on HD or PD at Day 90. Fully adjusted hazard ratios after Day 90 on haemodialysis were 0.70 (0.55–0.89) for South Asians and 0.56 (0.41–0.75) for Blacks.
Conclusion. South Asian and Black minorities have better survival on dialysis. An understanding of the mechanisms may provide general insights for all patients on RRT.
PMCID: PMC2781153  PMID: 19622573
ethnic minorities; haemodialysis; peritoneal dialysis; survival
22.  A structured approach to modelling the effects of binary exposure variables over the life course 
Background There is growing interest in the relationship between time spent in adverse circumstances across life course and increased risk of chronic disease and early mortality. This accumulation hypothesis is usually tested by summing indicators of binary variables across the life span to form an overall score that is then used as the exposure in regression models for health outcomes. This article highlights potential issues in the interpretation of results obtained from such an approach.
Methods We propose a model-building framework that can be used to formally compare alternative hypotheses on the effect of multiple binary exposure measurements collected across the life course. The saturated model where the order and value of the binary variable at each time point influence the outcome of interest is compared with nested alternative specifications corresponding to the critical period, cumulative risk or hypotheses about the effect of changes in environment. This framework is illustrated with data on adult body mass index and socioeconomic position measured once in childhood and twice in adulthood from the Medical Research Council National Survey of Health and Development, using a series of liner regression models.
Results We demonstrate how analyses that only consider the association of a cumulative score with a later outcome may produce misleading results.
Conclusion We recommend comparing a set of nested models—each corresponding to the accumulation, critical period and effect modification hypotheses—to an all-inclusive (saturated) model. This approach can provide a formal and clearer understanding of the relative merits of these alternative hypotheses.
PMCID: PMC2663717  PMID: 19028777
Longitudinal studies; social class; body mass index; critical period; social mobility; regression analysis
23.  How good is probabilistic record linkage to reconstruct reproductive histories? Results from the Aberdeen children of the 1950s study 
Probabilistic record linkage is widely used in epidemiology, but studies of its validity are rare. Our aim was to validate its use to identify births to a cohort of women, being drawn from a large cohort of people born in Scotland in the early 1950s.
The Children of the 1950s cohort includes 5868 females born in Aberdeen 1950–56 who were in primary schools in the city in 1962. In 2001 a postal questionnaire was sent to the cohort members resident in the UK requesting information on offspring. Probabilistic record linkage (based on surname, maiden name, initials, date of birth and postcode) was used to link the females in the cohort to birth records held by the Scottish Maternity Record System (SMR 2).
We attempted to mail a total of 5540 women; 3752 (68%) returned a completed questionnaire. Of these 86% reported having had at least one birth. Linkage to SMR 2 was attempted for 5634 women, one or more maternity records were found for 3743. There were 2604 women who reported at least one birth in the questionnaire and who were linked to one or more SMR 2 records. When judged against the questionnaire information, the linkage correctly identified 4930 births and missed 601 others. These mostly occurred outside of Scotland (147) or prior to full coverage by SMR 2 (454). There were 134 births incorrectly linked to SMR 2.
Probabilistic record linkage to routine maternity records applied to population-based cohort, using name, date of birth and place of residence, can have high specificity, and as such may be reliably used in epidemiological research.
PMCID: PMC1473197  PMID: 16553951
24.  Renal outcome in adults with renal insufficiency and irregular asymmetric kidneys 
BMC Nephrology  2004;5:12.
The commonest cause of end-stage renal failure (ESRF) in children and young adults is congenital malformation of the kidney and urinary tract. In this retrospective review, we examine whether progression to ESRF can be predicted and whether treatment with angiotensin converting enzyme inhibitors (ACEI) can delay or prevent this.
We reviewed 78 patients with asymmetric irregular kidneys as a consequence of either primary vesico-ureteric reflux or renal dysplasia (Group 1, n = 44), or abnormal bladder function (Group 2, n = 34). Patients (median age 24 years) had an estimated GFR (eGFR) < 60 ml/min/1.73 m2 with at least 5 years of follow up (median 143 months). 48 patients received ACEI. We explored potential prognostic factors that affect the time to ESRF using Cox-regression analyses.
At start, mean (SE) creatinine was 189 (8) μmol/l, mean eGFR 41 (1) ml/min 1.73 m2, mean proteinuria 144 (14) mg/mmol creatinine (1.7 g/24 hrs). Of 78 patients, 36 (46%) developed ESRF, but none of 19 with proteinuria less than 50 mg/mmol and only two of 18 patients with eGFR above 50 ml/min did so. Renal outcome between Groups 1 and 2 appeared similar with no evidence for a difference. A benefit in favour of treatment with ACEI was observed above an eGFR of 40 ml/min (p = 0.024).
The similar outcome of the two groups supports the nephrological nature of progressive renal failure in young men born with abnormal bladders. There is a watershed GFR of 40–50 ml/min at which ACEI treatment can be successful at improving renal outcome.
PMCID: PMC526254  PMID: 15462683
25.  Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis 
Objective To assess for the presence of a sex interaction in the associations of estimated glomerular filtration rate and albuminuria with all-cause mortality, cardiovascular mortality, and end stage renal disease.
Design Random effects meta-analysis using pooled individual participant data.
Setting 46 cohorts from Europe, North and South America, Asia, and Australasia.
Participants 2 051 158 participants (54% women) from general population cohorts (n=1 861 052), high risk cohorts (n=151 494), and chronic kidney disease cohorts (n=38 612). Eligible cohorts (except chronic kidney disease cohorts) had at least 1000 participants, outcomes of either mortality or end stage renal disease of ≥50 events, and baseline measurements of estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (mL/min/1.73 m2) and urinary albumin-creatinine ratio (mg/g).
Results Risks of all-cause mortality and cardiovascular mortality were higher in men at all levels of estimated glomerular filtration rate and albumin-creatinine ratio. While higher risk was associated with lower estimated glomerular filtration rate and higher albumin-creatinine ratio in both sexes, the slope of the risk relationship for all-cause mortality and for cardiovascular mortality were steeper in women than in men. Compared with an estimated glomerular filtration rate of 95, the adjusted hazard ratio for all-cause mortality at estimated glomerular filtration rate 45 was 1.32 (95% CI 1.08 to 1.61) in women and 1.22 (1.00 to 1.48) in men (Pinteraction<0.01). Compared with a urinary albumin-creatinine ratio of 5, the adjusted hazard ratio for all-cause mortality at urinary albumin-creatinine ratio 30 was 1.69 (1.54 to 1.84) in women and 1.43 (1.31 to 1.57) in men (Pinteraction<0.01). Conversely, there was no evidence of a sex difference in associations of estimated glomerular filtration rate and urinary albumin-creatinine ratio with end stage renal disease risk.
Conclusions Both sexes face increased risk of all-cause mortality, cardiovascular mortality, and end stage renal disease with lower estimated glomerular filtration rates and higher albuminuria. These findings were robust across a large global consortium.
PMCID: PMC3558410  PMID: 23360717

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