Identification and characterisation of diabetes in Uganda: protocol for the nested, population-based 'Diabetes in low-resource Populations' (DOP) Study.

INTRODUCTION: Sub-Saharan Africa is experiencing an increasing burden of diabetes, but there are little reliable data, particularly at the community level, on the true prevalence or why this condition affects young and relatively lean individuals. Moreover, the detection of diabetes in Africa remains poor, not only due to a lack of resources but because the performance of available diagnostic tests is unclear. METHODS: This research aims to (1) determine the prevalence and risk factors of diabetes in a rural Ugandan population, (2) use clinical and biochemical markers to define different diabetes phenotypes and (3) study the progression of diabetes in this population. We will also assess the utility of the widely used tests (glycated haemoglobin (HbA1c), oral glucose tolerance test (OGTT) and fasting glucose) in diagnosing diabetes. DESIGN: This is a population-based study nested within the longstanding general population cohort in southwestern Uganda. We will undertake a population survey to identify individuals with diabetes based on fasting glucose, HbA1c, OGTT results or history of pre-existing diabetes. PARTICIPANTS: The study intends to enrol up to 11 700 individuals aged 18 years and above, residing within the study area and not pregnant or within 6 months post-delivery date. All participants will have detailed biophysical and biochemical/metabolic measurements. Individuals identified to have diabetes and a random selection of controls will have repeat tests to test reproducibility before referral and enrolment into a diabetic clinic. Participants will then be followed up for 1 year to assess the course of the disease, including response to therapy and diabetes-related complications. CONCLUSIONS: These data will improve our understanding of the burden of diabetes in Uganda, the risk factors that drive it and underlying pathophysiological mechanisms, as well as better ways to detect this condition. This will inform new approaches to improve the prevention and management of diabetes. ETHICS AND DISSEMINATION: This study protocol was approved by the Uganda Virus Research Institute Research Ethics Committee (REC) (number: G.C./127/21/09/858), the London School of Hygiene and Tropical Medicine REC (number: 26638) and the Uganda National Council for Science and Technology (protocol number: HS1791ES). Written informed consent will be obtained from all participants before being enrolled on to the study and conducting study-related procedures. Research findings will be disseminated in policy briefs, seminars, local and international conferences and publications in peer-reviewed open-access journals. As part of the dissemination plans, findings will also be disseminated to patient care groups and to clinicians. TRIAL REGISTRATION NUMBER: NCT05487079.

Waist circumference and glycaemia are strong predictors of progression to diabetes in individuals with prediabetes in sub-Saharan Africa: 4-year prospective cohort study in Malawi.

Sub-Saharan Africa is projected to have the highest increase in the number of people with diabetes worldwide. However, the drivers of diabetes in this region have not been clearly elucidated. The aim of this study was to evaluate the incidence of diabetes and the predictors of progression in a population-based cohort with impaired fasting glucose (IFG) in Malawi. We used data from an extensive rural and urban non-communicable disease survey. One hundred seventy-five, of 389 individuals with impaired fasting glucose (IFG) at baseline, age 48 ±15 years and body mass index 27.5 ±5.9 kg/m2 were followed up for a median of 4.2 years (714 person-years). Incidence rates were calculated, and predictors of progression to diabetes were analysed using multivariable logistic regression models, with overall performance determined using receiver operator characteristics (ROC) curves. The median follow-up was 4.2 (IQR 3.4-4.7) years. Forty-five out of 175 (26%) progressed to diabetes. Incidence rates of diabetes were 62.9 per 1000 person-years 95% CI, 47.0-84.3. The predictors of progression were higher; age (odds ratio [OR] 1.48, P = 0.046), BMI (OR 1.98, P = 0.001), waist circumference (OR 2.50,P<0.001), waist-hip ratio (OR 1.40, P = 0.03), systolic blood pressure (OR 1.56, P = 0.01), fasting plasma glucose (OR 1.53, P = 0.01), cholesterol (OR 1.44, P = 0.05) and low-density lipoprotein cholesterol (OR 1.80, P = 0.002). A simple model combining fasting plasma glucose and waist circumference was predictive of progression to diabetes (ROC area under the curve = 0.79). The incidence of diabetes in people with IFG is high in Malawi and predictors of progression are like those seen in other populations. Our data also suggests that a simple chart with probabilities of progression to diabetes based on waist circumference and fasting plasma glucose could be used to identify those at risk of progression in clinical settings in sub-Saharan Africa.

The influence of fasting and post-load glucose levels on maternal and neonatal outcomes in women with hyperglycaemia in pregnancy in Uganda: A prospective observational cohort study.

AIMS: The study aims to evaluate the strength of fasting versus post-load glucose levels in predicting adverse outcomes in women with hyperglycaemia in pregnancy (HIP). METHODS: Women attending antenatal clinics in urban and peri-urban Uganda had oral glucose tolerance test between 24 and 28 weeks of gestation to screen for HIP, and were followed up to collect data on maternal and neonatal outcomes. Univariable and multivariable Poisson regression models were used to estimate the relative risk adverse outcome associated with fasting hyperglycaemia alone post-load hyperglycaemia alone, or elevation of both fasting and post-load glucose levels. RESULTS: We included 3206 participants in the final analysis. HIP was associated with increased risk of Caesarean section, large for gestaional age babies, and neonatal intensive care admission. The risk was highest (2.54-fold compared to normal glycaemic women) when both FBG and post-load glucose levels were elevated. After adjustment for potential confounders, having elevated post-load glucose alone was not associated with increased risk of any of the outcomes, but elevated FBG alone increased the risk of Caesarian section by 1.36-fold. CONCLUSION: Fasting hyperglycemia appears to be more strongly associated with adverse pregnancy outcomes than post-load hyperglycaemia, but the risk is even higher in women with elevation of both fasting and post-load glucose levels.

Measurement of kidney function in Malawi, South Africa, and Uganda: a multicentre cohort study.

BACKGROUND: The burden of kidney disease in many African countries is unknown. Equations used to estimate kidney function from serum creatinine have limited regional validation. We sought to determine the most accurate way to measure kidney function and thus estimate the prevalence of impaired kidney function in African populations. METHODS: We measured serum creatinine, cystatin C, and glomerular filtration rate (GFR) using the slope-intercept method for iohexol plasma clearance (mGFR) in population cohorts from Malawi, Uganda, and South Africa. We compared performance of creatinine and cystatin C-based estimating equations to mGFR, modelled and validated a new creatinine-based equation, and developed a multiple imputation model trained on the mGFR sample using age, sex, and creatinine as the variables to predict the population prevalence of impaired kidney function in west, east, and southern Africa. FINDINGS: Of 3025 people who underwent measured GFR testing (Malawi n=1020, South Africa n=986, and Uganda n=1019), we analysed data for 2578 participants who had complete data and adequate quality measurements. Among 2578 included participants, creatinine-based equations overestimated kidney function compared with mGFR, worsened by use of ethnicity coefficients. The greatest bias occurred at low kidney function, such that the proportion with GFR of less than 60 mL/min per 1·73 m2 either directly measured or estimated by cystatin C was more than double that estimated from creatinine. A new creatinine-based equation did not outperform existing equations, and no equation, including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 race-neutral equation, estimated GFR within plus or minus 30% of mGFR for 75% or more of the participants. Using a model to impute kidney function based on mGFR, the estimated prevalence of impaired kidney function was more than two-times higher than creatinine-based estimates in populations across six countries in Africa. INTERPRETATION: Estimating GFR using serum creatinine substantially underestimates the individual and population-level burden of impaired kidney function in Africa with implications for understanding disease progression and complications, clinical care, and service provision. Scalable and affordable ways to accurately identify impaired kidney function in Africa are urgently needed. FUNDING: The GSK Africa Non-Communicable Disease Open Lab. TRANSLATIONS: For the Luganda, Chichewa and Xitsonga translations of the abstract see Supplementary Materials section.

Alternative pre-analytic sample handling techniques for glucose measurement in the absence of fluoride tubes in low resource settings.

INTRODUCTION: Sodium fluoride (NaF) tubes are the recommended tubes for glucose measurements, but these are expensive, have limited number of uses, and are not always available in low resource settings. Alternative sample handling techniques are thus needed. We compared glucose stability in samples collected in various tubes exposed to different pre-analytical conditions in Uganda. METHODS: Random (non-fasted) blood samples were drawn from nine healthy participants into NaF, Ethylenediaminetetraacetic acid (EDTA), and plain serum tubes. The samples were kept un-centrifuged or centrifuged with plasma or serum pipetted into aliquots, placed in cool box with ice or at room temperature and were stored in a permanent freezer after 0, 2, 6, 12 and 24 hours post blood draw before glucose analysis. RESULTS: Rapid decline in glucose concentrations was observed when compared to baseline in serum (declined to 64%) and EDTA-plasma (declined to 77%) after 6 hours when samples were un-centrifuged at room temperature whilst NaF-plasma was stable after 24 hours in the same condition. Un-centrifuged EDTA-plasma kept on ice was stable for up to 6 hours but serum was not stable (degraded to 92%) in the same conditions. Early centrifugation prevented glucose decline even at room temperature regardless of the primary tube used with serum, EDTA-plasma and NaF-plasma after 24 hours. CONCLUSION: In low resource settings we recommend use of EDTA tubes placed in cool box with ice and analysed within 6 hours as an alternative to NaF tubes. Alternatively, immediate separation of blood with manual hand centrifuges will allow any tube to be used even in remote settings with no electricity.

Handgrip strength as a simple measure for screening prediabetes and type 2 diabetes mellitus risk among adults in Malawi: A cross-sectional study.

OBJECTIVE: Handgrip strength, a simple measure of muscle strength, has been reported as a predictor of both prediabetes and type 2 diabetes mellitus (T2DM) and has been suggested for screening prediabetes and T2DM risk. This study examined the relationship of handgrip strength with prediabetes and T2DM among rural- and urban-dwelling adults in Malawi. METHODS: This was a cross-sectional study nested in a follow-up study of prediabetic and prehypertensive individuals identified during an extensive noncommunicable disease survey in Malawi. A total of 261 participants (women: 64%) were recruited. Univariate and multivariate binary logistic regression analyses were performed to examine the association of prediabetes and T2DM with relative handgrip strength. RESULTS: The mean (SD) age of the participants was 49.7 (13.6) years, and 54.0% were between the ages of 40 and 59 years. The mean (SD) absolute handgrip strength and relative handgrip strength were 28.8 (7.3) kg and 1.16 (0.40) kg/BMI, respectively, and the mean relative handgrip strength differed significantly (p < 0.001) by T2DM status. In unadjusted model, the odds ratio (OR) of prediabetes and T2DM per unit increase in relative handgrip strength was 0.12 [95% CI; 0.04-0.33]. The result remained significant after adjusting for age (continuous), sex, place of study, hypertension, dyslipidaemia and level of education (aOR [95% CI]; 0.19 [0.03-0.95]). CONCLUSIONS: The findings suggest that handgrip strength could be a relatively inexpensive, noninvasive measure for contributing to risk scores to identify high-risk individuals for screening diabetes in SSA.

Prevalence and risk factors for chronic kidney disease of unknown cause in Malawi: a cross-sectional analysis in a rural and urban population.

BACKGROUND: An epidemic of chronic kidney disease of unknown cause (CKDu) is occurring in rural communities in tropical regions of low-and middle-income countries in South America and India. Little information is available from Southern African countries which have similar climatic and occupational characteristics to CKDu-endemic countries. We investigated whether CKDu is prevalent in Malawi and identified its potential risk factors in this setting. METHODS: We conducted a cross-sectional study from January-August 2018 collecting bio samples and anthropometric data in two Malawian populations. The sample comprised adults > 18 years (n = 821) without diabetes, hypertension, and proteinuria. Estimates of glomerular filtration rate (eGFR) were calculated using the CKD-EPI equation. Linear and logistic regression models were applied with potential risk factors, to estimate risk of reduced eGFR. RESULTS: The mean eGFR was 117.1 ± 16.0 ml/min per 1.73m2 and the mean participant age was 33.5 ± 12.7 years. The prevalence of eGFR< 60 was 0.2% (95% confidence interval (95% CI) 0.1, 0.9); the prevalence of eGFR< 90 was 5% (95% CI =3.2, 6.3). We observed a higher prevalence in the rural population (5% (3.6, 7.8)), versus urban (3% (1.4, 6.7)). Age and BMI were associated with reduced eGFR< 90 [Odds ratio (OR) (95%CI) =3.59 (2.58, 5.21) per ten-year increment]; [OR (95%CI) =2.01 (1.27, 3.43) per 5 kg/m2 increment] respectively. No increased risk of eGFR < 90 was observed for rural participants [OR (95%CI) =1.75 (0.50, 6.30)]. CONCLUSIONS: Reduced kidney function consistent with the definition of CKDu is not common in the areas of Malawi sampled, compared to that observed in other tropical or sub-tropical countries in Central America and South Asia. Reduced eGFR< 90 was related to age, BMI, and was more common in rural areas. These findings are important as they contradict some current hypothesis that CKDu is endemic across tropical and sub-tropical countries. This study has enabled standardized comparisons of impaired kidney function between and within tropical/subtropical regions of the world and will help form the basis for further etiological research, surveillance strategies, and the implementation and evaluation of interventions.

How to estimate glomerular filtration rate in sub-Saharan Africa: design and methods of the African Research into Kidney Diseases (ARK) study.

BACKGROUND: Chronic kidney disease (CKD) is a substantial cause of morbidity and mortality worldwide with disproportionate effects in sub-Saharan Africa (SSA). The optimal methods to estimate glomerular filtration rate (GFR) and therefore to determine the presence of CKD in SSA are uncertain. We plan to measure iohexol excretion to accurately determine GFR in Malawi, South Africa and Uganda. We will then assess the performance of existing equations to estimate GFR and determine whether a modified equation can better improve estimation of GFR in sub-Saharan Africa. METHODS: The African Research on Kidney Disease (ARK) study is a three-country study embedded within existing cohorts. We seek to enrol 3000 adults > 18 years based on baseline serum creatinine. Study procedures include questionnaires on socio-demographics and established risk factors for kidney disease along with anthropometry, body composition, blood pressure, blood chemistry and urine microscopy and albuminuria. We will measure GFR (mGFR) by plasma clearance of iohexol at 120, 180 and 240 min. We will compare eGFR determined by established equations with mGFR using Bland-Altman plots. We will use regression methods to estimate GFR and compare the newly derived model with existing equations. DISCUSSION: Through the ARK study, we aim to establish the optimal approach to estimate GFR in SSA. The study has the advantage of drawing participants from three countries, which will increase the applicability of the findings across the region. It is also embedded within established cohorts that have longitudinal information and serial measures that can be used to characterize kidney disease over a period of time. This will help to overcome the limitations of previous research, including small numbers, selected population sub-groups, and lack of data on proteinuria. The ARK collaboration provides an opportunity for close working partnerships across different centres, using standardized protocols and measurements, and shared bio-repositories. We plan to build on the collaboration for this study for future work on kidney disease in sub-Saharan Africa, and welcome additional partners from across the continent.

Outcomes of in-hospital paediatric cardiac arrest from a tertiary hospital in a low-income African country.

Background: There are scarce data on outcomes of in-hospital paediatric cardiac arrest (CA) in resource-poor settings and none for World Bank-defined low-income countries.Aim: To report the outcomes of in-hospital paediatric CA from a university-affiliated referral hospital in Malawi.Methods: Data were collected prospectively on patients aged 30 days to 13 years who experienced CA and underwent cardiopulmonary resuscitation (CPR) at Kamuzu Central Hospital in Lilongwe, Malawi from January through June 2017. Utstein-style reporting guidelines for CAs were used to define outcomes; the primary outcome was survival to hospital discharge. A data collection form was used to record patient, arrest and resuscitation characteristics.Results: A total of 135 patients fulfilled the criteria for inclusion in the study. Resuscitation outcomes are presented in Figure 1 using a modified Utstein template. In-hospital CA was associated with 100% mortality. Return of spontaneous circulation (ROSC) was obtained in 6% of patients and sustained ROSC in 4%; 24-h survival was zero. The most common admission diagnosis was malaria (51%). Most arrests occurred on the paediatric ward (90%) rather than critical care units. Most resuscitations were led by trainees and mid-level providers (58%) rather than paediatricians (23%).Conclusion: Survival following in-hospital paediatric CA was zero, suggesting that CPR may have no benefit in this tertiary hospital. Future efforts to improve outcomes should focus on advocating better pre-arrest care and research interventions aimed to identify and treat children at risk of CA within the resource constraints of this setting.

Prevalence of impaired renal function among rural and urban populations: findings of a cross-sectional study in Malawi.

Background: Sub-Saharan Africa faces region-specific risk factors for chronic kidney disease (CKD), such as nephrotoxic herbal medicines, antiretroviral therapy and infections, in addition to hypertension and diabetes. However, large epidemiological studies from this area are scarce. Methods: In a cross-sectional survey of non-communicable diseases, we conducted a prevalence sub-study of CKD in two Malawian populations. Study participants (N=5264) of 18 years of age and above were recruited and data on demographics and CKD risk factors were collected. Glomerular filtration rate was estimated (eGFR) using the CKD-EPI equation. Results: The prevalence of eGFR<60ml/min/1.73m 2 was 1.4% (95% CI 1.1 - 1.7%) and eGFR<90ml/min/1.73m 2 was 20.6% (95% CI 19.5 - 21.7%). The rural area had higher age-standardized prevalence of both eGFR<60ml/min/1.73m 2, at 1.8% (95% CI 1.4 - 2.3) and eGFR <90 ml/min/1.73m², at 21.1% (95% CI 19.9 - 22.3), than urban location, which had a prevalence of 1.5%, (95% CI 1.0 - 2.2) and 19.4% (95% CI 18.0 - 20.8), respectively, with overlapping confidence intervals. The prevalence of CKD was lower in females than in males in both rural and urban areas. Older age (p < 0.001), a higher level of education (p = 0.03) and hypertension (p < 0.001) were associated with a higher adjusted odds ratio (aOR) of low eGFR. Diabetes was associated with a reduced aOR of eGFR<90ml/min/1.73m 2 of 0.69 (95% CI 0.49-0.96; p=0.03). Of participants with eGFR<60ml/min/1.73m 2, 14 (19.4%) had no history of hypertension, diabetes or HIV, while 36 (50%) had a single risk factor of being hypertensive. Conclusion s: Impaired renal function is prevalent, but lower than expected, in rural and urban Malawi. Further research is needed to increase understanding of CKD incidence, survival and validation of eGFR calculations in this population.