Ferozkhan Jadhakhan, Tom Marshall, Paramjit Gill
Primary Care Clinical Sciences, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
Address for correspondence: Mr Ferozkhan Jadhakhan
Primary Care Clinical Sciences, Institute of Applied Health Research,
University of Birmingham, Birmingham B15 2TT, UK
Tel: +44 (0)121 414 3758
E-mail: fxj733@bham.ac.uk
http://dx.doi.org/10.15277/bjd.2016.105
Objective: The risk of chronic kidney disease (CKD) is elevated in patients with diabetes mellitus but the effect of impaired glucose tolerance (IGT) is not known. This systematic review investigates the risk of CKD associated with IGT in young adults aged 18–40 years.
Methods: CINAHL, EMBASE, MEDLINE, PubMed, Cochrane libraries and grey literature were searched from inception to January 2015 without language restriction for case-control and cohort studies comparing the frequency of CKD in cases aged 18–40 years with IGT/IFG (impaired fasting glucose) with controls without glycaemic abnormality or with type 2 diabetes (T2DM). CKD outcomes were determined by: estimated glomerular filtration rate, albumin creatinine ratio, proteinuria ≥1, serum creatinine, protein creatinine ratio and creatinine clearance levels.
Results: Initial searches identified 90 citations potentially meeting the inclusion criteria. After full text review, 19 cohort studies and no case-control studies met the inclusion criteria, but only one cohort study reported separate data for persons aged 18–40 years. This study only compared the incidence of CKD in individuals with IGT with those with T2DM. The annual incidence of CKD was 0.13% per person-year compared with 2.4% in patients with T2DM.
Conclusion: The results of this systematic review demonstrate that the risk of CKD in young adults with IGT/IFG is lacking. Further research is needed to estimate the incidence of CKD in this cohort of individuals. To bridge this gap in evidence, large epidemiological databases may be examined to quantify the risk of CKD in young adults aged 18–40 years with IGT/IFG compared with those with normoglycaemia. Data from these databases may potentially inform a prognostic study which may be useful in understanding the course and factors associated with CKD development. Finally, the results may emphasise the importance of identifying individuals with IGT/IFG earlier and implementing interventions to prevent or delay the development of CKD.
Br J Diabetes 2016;16:162-167
Key words: impaired glucose tolerance, chronic kidney disease, estimated glomerular filtration rate, albumin creatinine ratio, type 2 diabetes
Chronic kidney disease (CKD) is a long-term condition characterised by the presence of kidney damage and/or a gradual loss of kidney function.1 Diabetes is a leading cause of CKD due to either diabetic nephropathy or vascular damage. A prospective cohort study conducted in England and Wales found the hazard of developing CKD in patients aged 35–74 years was five times higher in women and six times higher in men with diabetes than in those with normal glucose tolerance.2
Pre-diabetes indicates both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), collectively known as impaired glucose regulation (IGR). Individuals with IGR have a blood glucose raised beyond the normal level but not high enough for a diabetes diagnosis.3 Furthermore, the risk of young adults aged 18–40 years with IGT developing CKD is not well characterised. Despite the heavy burden of cardiovascular disease (CVD) including CKD, very few studies have evaluated the CVD risk profile in young adults using a prediction algorithm such as the Framingham risk score or QRISK. There is some evidence that the incidence of CKD is elevated in individuals with IGT; however, this is often confined to a specific population.4 It is not clear whether the risk of CKD is elevated in patients with IGT or whether any increased risk only occurs after patients develop diabetes. Cross-sectional studies show that albuminuria – an early marker of CKD – was approximately three times more common in patients with IGT than in those with normoglycaemia.5 These data are subject to some limitations, as it is unclear whether CKD precedes impaired glucose metabolism or vice versa. The purpose of this systematic review is to find out whether the presence of IGT in young adults aged 18–40 years is associated with an increased risk of CKD by comparing the risk of CKD in individuals with IGT and those without IGT, and also to evaluate whether any increased risk occurs only after they develop type 2 diabetes (T2DM).
Established guidelines for reviews were used to inform the search strategy, selection of studies, assessment of risks of bias and reporting of results.6,7 The comparison groups were either participants with normoglycaemia or those with confirmed diabetes. The review protocol has been published elsewhere.8
Types of participants and comparison group
This review includes studies where some participants are aged 18–40 years and results reported separately in this age group without a diagnosis of type 1 and type 2 diabetes but with IGT, ‘pre- diabetes’ or ‘pre-diabetic state’. IGT/IFG can be referred to as pre-diabetes,9 or metabolic syndrome where IGT is part of the metabolic syndrome. The comparison group was either participants with normoglycaemia or patients with diabetes. For the purpose of this review, IGT was classified as a fasting plasma glucose (FPG) <7 mmol/L (<126 mg/dL) or an oral glucose tolerance test (OGTT) ≥7.8 mmol/L and <11.1 mmol/L (140–200 mg/dL) or glycated haemoglobin (HbA1c) of 5.7–6.4% (42–47 mmol/mol), and IFG was defined as FPG 5.6–6.9 mmol/L (100–125 mg/dL) and HbA1c 5.7–6.4%.10
Participants and outcomes – cohort studies
This review includes any cohort studies where some participants are aged 18–40 years and results are reported separately in this age group with (1) IGT/IFG (exposed group) compared with participants without glycaemic abnormality (comparator); or (2) IGT/IFG but without a diagnosis of type 1 diabetes compared with participants with T2DM. Participants were free from CKD at baseline. A broad range of measures was used to ascertain CKD (outcome). This included estimated glomerular filtration rate (eGFR) stages 3A, 3B, 4 and 5; albuminuria; albumin creatinine ratio (ACR; ≥2.5 mg/mmol or ≥30 mg/g); protein creatinine ratio (PCR ≥45 mg/mmol or ≥300 mg/g); serum creatinine (SCr; 1.0 mg/dL or ≥50 μmol/L), proteinuria (≥1+) and creatinine clearance (CrCl; ≥60 ml/min). Studies reporting mean changes in continuous variables (e.g. eGFR) were also included. Studies reporting a single measure instead of two measures of eGFR or only by any of the above measures were included. Measures of association (HR, OR, IRR and RR) were extracted and reported or sufficient information to calculate these figures.
Participants and outcomes – case-control studies
This review also includes any case-control studies in which some cases were aged 18–40 years with an incident diagnosis of CKD (the outcome of interest) by any of the above definitions and controls without a diagnosis of CKD. The frequency of previous IGT/IFG (exposure to IGT/IFG) was compared with either the frequency of normoglycaemia (unexposed) or the frequency of diabetes (an alternative exposure). There was no restriction on the length of participant follow-up.
Search strategy and data extraction
The following electronic databases were systematically searched without language restriction from inception to January 2015: MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, PubMed, Database of Abstracts of Reviews of Effects (DARE), Cochrane Database of Systematic Reviews (CDSR), Trip Database and Google Scholar. Ongoing studies, scientific literature and abstract proceedings were identified by searching the following databases: ClinicalTrials.gov, Cochrane Renal Group specialised register, Renal Registry Database, British Renal Society, Renal Association, American Society of Nephrology, World Congress of Nephrology, Diabetes UK Conference, Primary Care Diabetes Society Conference and Zetoc. A comprehensive search of the Conference Proceedings Citation Index (CPCI) was also carried out. Search of these databases spanned from January 2011 to January 2014 as it is likely that studies would have been completed and published. Grey literature databases such as Grey Literature Report, OpenGrey, PubliCat and ScienceDaily.com were examined. Open access theses and dissertations were retrieved from the ProQuest Dissertation Thesis Database and thesis.com. The Science Citation Index (SCI) was used to scan and track study titles. The search strategy is shown in Appendix 1 (available online at bjd-abcd.com).
Two reviewers independently reviewed all titles and abstracts in two phases. First the retrieved titles and abstracts were reviewed to identify relevant studies. The full texts of retrieved studies were then read to determine eligibility. Any discrepancies or differences in opinion were resolved by consensus. An inclusion criteria checklist (Appendix 2 available online at bjd-abcd.com) was developed based on study eligibility criteria piloted on five papers.
Quality assessment
Study quality was assessed according to a modified tool based on the Ottawa-Newcastle scale (NOS).11 Risk of bias was assessed on the following domains: (1) sampling; (2) outcome measurement; (3) attrition; (4) analytical method; and (5) confounders (Appendix 3 available online at bjd-abcd.com). A composite score was not provided; instead, a risk of bias of ‘yes’ indicating adequate data were provided, ‘no’ if data were provided but did not meet the criteria for that domain and ‘unclear’ potentially at high risk of bias.12
Publication bias
If sufficient studies are identified for future updates, the Begg’s13 and Egger’s14 regression test will be carried out to detect publication bias. At least 10 studies will be needed to sufficiently detect publication bias.15 Studies will be grouped according to effects measures and reporting risk of CKD determined by any of the measures listed above.
Search results
Initial database searches identified 5,568 studies. After scanning the titles, 90 citations potentially met the inclusion criteria. These were reviewed in detail (full text) and 19 cohort studies were selected for further review (no case-control studies were selected). A summary of the overall quality of the 19 studies is provided in Table 1 and 2. Only one of the 19 cohort studies reported separate data for persons aged 18–40 years. This study compared the incidence of CKD in patients with IGT and those with T2DM. A PRISMA study flow diagram of included and excluded studies is provided along with reasons for exclusion in Figure 1. Data from this study were reported narratively.
Study characteristics
The characteristics of the 19 cohort studies are summarised in Appendix 4 and 5 (available online at bjd-abcd.com). Briefly, no case-control studies meeting the inclusion criteria were identified. Nineteen cohort studies were identified. One reported separate data in persons aged 18–40 years with IGT compared with T2DM.
Incidence of CKD in persons aged 18–40 years with IGT compared with T2DM
Kim et al reported the risk of CKD in young adults aged 18–40 years with IGT compared with T2DM.16 This cohort study followed 2,666 Pima Indian young adults aged ≤20 years with IGT and T2DM during a follow-up period of 25.2 years for the development of macroalbuminuria, defined as an ACR of ≥300 mg/g. The incidence of macroalbuminuria was 1.3 new cases of macroalbuminuria per 1,000 person-years, with a total of 28 cases in 21,830 person-years of follow-up in subjects with IGT, or 0.13% developing macroalbuminuria each year compared with 2.4% in patients with T2DM.
This systematic review showed that existing evidence does not allow quantification of CKD risk in young adults aged 18–40 years with IGT/IFG compared with normoglycaemia or T2DM. Pooled estimates of CKD and a meta-analysis were not possible because most studies did not report separate results in this age group. Only one study reported the risk of CKD in young adults aged 18–40 years. The annual incidence of CKD was 0.13% per person-year compared with 2.4% in those with T2DM.
Strengths of the study
This review was not limited to the English language or geographical area and a broad range of markers was used to ascertain CKD. Furthermore, to the best of our knowledge, no systematic review has evaluated the risk of CKD in young adults aged 18–40 years with IGT/IFG compared with normoglycaemia or T2DM.
Limitations of the study
Only one study provided risk estimates of CKD in persons aged 18–40 years with IGT compared with those with T2DM. Sufficient studies were not available to conduct a meta-analysis, therefore a more generalisable and precise estimate of CKD could not be presented. Furthermore, the results of this one study should be interpreted with caution because of the small sample size and study population (Pima Indians).
The results of this systematic review demonstrate that the risk of CKD in young adults aged 18–40 years with IGT/IFG is lacking. Further research is needed to estimate the incidence of CKD in this cohort of individuals. To bridge this gap in evidence, large epidemiological databases may be examined to quantify the risk of CKD in young adults aged 18–40 years with IGT/IFG compared with those with normoglycaemia.
Conflict of interest None.
Funding and Acknowledgments This review forms part of FJ’s PhD and is funded by the National Institute for Health Research School for Primary Care Research (NIHR SPCR) studentship grant. We thank the Librarian at Barnes library, Medical School, University of Birmingham for providing assistance with the search strategy.
Authors’ contributions FJ was responsible for developing the search strategy and conducting the literature search. TM and PG were involved in the design of the review. FJ performed data extraction and interpretation of the data. TM and PG provided important intellectual input and revised the manuscript critically. TM and PG read and approved the final manuscript. FJ was first reviewer, TM and PG acted as second reviewers for this systematic review. All authors read and approved the final manuscript.
PROSPERO registration: CRD42014007081
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